Childhood Rhabdomyosarcoma, part 2

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]

Sources: 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]

Sources: 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]

Sources: 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]

Sources: 178 · 179 · 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]

Sources: 181 · 182 · 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]

Sources: COG-D9803 · 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]

Sources: 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]

Sources: SIOP-MMT-95 · 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.

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.

Sources: 188 · Level of evidence A1

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.

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.

Sources: ARST0531 (NCT00354835) · D9803 (NCT00003958)

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

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

Sources: ARST1431 (NCT02567435)

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).

Sources: 189

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;

Embryonal rhabdomyosarcoma with nodal involvement; or

Alveolar rhabdomyosarcoma without nodal involvement.

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

Sources: 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).

Sources: 191

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.

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.

Sources: ARST1431 · 192

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]).

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]

Sources: 197 · Level of evidence C1 · 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.

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

Bone and/or bone marrow involvement.

Three or more different metastatic sites or tissues.

The EFS rate 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 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.

Sources: 198 · 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.

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]

Sources: 199

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]

Sources: 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.

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

Sources: 182

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

Sources: 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.

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]

Sources: 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]

Sources: 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:

Sources: 197

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.

The addition of VI, including during RT.

A period of VDC therapy.

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]

Sources: 203 · Level of evidence C2

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]

Sources: 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:

Sources: 204 · Level of evidence C2

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.

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

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.

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

Sources: ARST0431 (NCT00354744)

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]

Sources: 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%).

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.

High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[206-208] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[208]

Sources: 206 · 208 · 208

The National Cancer Institute's (NCI) intramural Pediatric Oncology Branch conducted a pilot study of cytoreductive treatment followed by consolidative immunotherapy incorporating T-cell reconstitution, plus a dendritic-cell and tumor-peptide vaccine that was given with minimal toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma (n = 37) and alveolar rhabdomyosarcoma (n = 15). Ten patients with alveolar rhabdomyosarcoma had improved survival, compared with five patients who did not receive immunotherapy.[209][Level of evidence C1]

Sources: 209 · Level of evidence C1

ARST2032 (NCT05304585) (Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low-Risk, Fusion-Negative Rhabdomyosarcoma): The COG redefined low-risk rhabdomyosarcoma using both clinical and molecular criteria. The new criteria will be used in this study. Patients are required to enroll in the COG APEC14B1 trial and the Molecular Characterization Initiative. Low-risk patients have both fusion-negative and wild-type MYOD1 and TP53. In this trial, very low-risk patients will receive 24 weeks of VA therapy, and low-risk patients will receive four cycles of VAC followed by VA for a total of 24 weeks.

Sources: ARST2032 (NCT05304585) · APEC14B1

In a 1999 study of 605 children, the prognosis was most favorable (5-year survival rates, 50%–70%) for children who initially presented with Stage 1 or Group I disease and embryonal/botryoid histology with small tumors and for those with local or regional nodal recurrence. Patients with Group I alveolar rhabdomyosarcoma or undifferentiated sarcoma had 5-year overall survival (OS) rates of 40% to 50%. This population of patients with improved outcomes encompasses only 20% of all patients with a relapse.[1][Level of evidence C1]

Sources: 1 · Level of evidence C1

In a 2014 study of 24 children, 22 (82%) children with initially localized orbital sarcoma survived at least 5 years after relapse following re-treatment with curative intent.[4][Level of evidence C1]

Sources: 4 · Level of evidence C1

A 2005 study of 125 patients with nonmetastatic rhabdomyosarcoma whose disease recurred after previous complete remission observed that favorable factors at initial diagnosis included: nonalveolar histology; primary site in the orbit, genitourinary/nonbladder-prostate, or head/neck nonparameningeal regions; tumor size of 5 cm or smaller; local relapse; relapse after 18 months from the primary diagnosis; and lack of initial radiation therapy (RT).[2]

Sources: 2

A report of 337 patients with nonmetastatic rhabdomyosarcoma in 2008 observed that favorable factors at initial diagnosis were age 10 years or younger, embryonal histology, tumor size of 5 cm or smaller, favorable site, and lack of initial RT.[5]

Sources: 5

In a 2009 study of 234 patients who had a relapse after achieving complete remission and completing primary treatment, the favorable prognostic factors for 3-year OS were reported. These factors were favorable primary site, local relapse, time to relapse of more than 12 months, tumor size of 5 cm or smaller, and no previous RT.[6][Level of evidence C1]

Sources: 6 · Level of evidence C1

A 2011 study of 474 patients with nonmetastatic rhabdomyosarcoma who had complete local control at the primary site noted the unfavorable factors for survival 3 years after first relapse. These unfavorable factors included relapse with metastatic disease, previous (initial) RT, tumor size more than 5 cm, time to relapse of less than 18 months, regional lymph node involvement, alveolar histology, and unfavorable disease at primary diagnosis.[7]

Sources: 7

In 2013, 90 patients with nonmetastatic alveolar rhabdomyosarcoma were re-treated with additional chemotherapy, with or without local re-excision of the primary site (if indicated) and with or without RT. The four most important factors for survival after relapse were no lymph node involvement, no metastases, adequate local therapy, and a second complete remission. The OS rate at 5 years was 21%.[8][Level of evidence C1]

Sources: 8 · Level of evidence C1

A single-institution, retrospective review identified 23 patients with central nervous system (CNS) relapse after initial treatment for rhabdomyosarcoma.[9][Level of evidence C1] High-risk features at initial presentation included 16 alveolar patients, 13 Stage 4 patients, and 13 patients with primary tumor in parameningeal locations. All of the patients died. Twenty-one patients died of CNS disease, and two died of metastatic disease at other sites. Median survival post-CNS relapse was 5 months (range, 0.1–49 months).

Sources: 9 · Level of evidence C1

Surgery. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases.[10,11] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[10] A review examined 108 Italian children with bladder or prostate tumors who did not achieve tumor eradication after chemotherapy, with or without RT. The study found that only two factors correlated with inability to achieve progression-free survival (PFS) at 5 or more years: initial histology showing undifferentiated sarcoma (P = .008) and diameter of the surgically removed tumor exceeding 5 cm. Positive tumor margins at the salvage operation did not predict ultimate failure.[12][Level of evidence C2]

Sources: 10 · 11 · 10 · 12 · Level of evidence C2

RT. RT should be considered for patients with rhabdomyosarcoma who have not already received RT in the area of recurrence, or selectively for those who have received previous RT, particularly for those in whom surgical excision is not possible. RT techniques may include external beam in fractionated or hypofractionated courses (e.g., stereotactic body radiation therapy, CyberKnife, or brachytherapy). The rationale is primarily to improve local control that can translate into a better quality of life. An impact on OS is unlikely because of the metastatic disease that often occurs. Even a benefit on local control is difficult to unequivocally demonstrate because of small patient numbers in available reports. For example, in a multi-institutional study of 23 patients with local relapse only (n = 19) or local relapse with distant failure (n = 4) who were managed with (n = 12) or without (n = 11) re-irradiation, the local failure-free survival and OS in re-irradiated versus unirradiated patients was 19.6 months versus 12.4 months (P = .1) and 26.1 months versus 18.8 months (P = .46). In this report, patients with favorable site and Group 3 disease local (only) failure, and/or embryonal histology had improved 3-year local relapse-free survival rates with re-irradiation (62.3% vs. 40%; P = .11).[13]

Sources: 13

Chemotherapy. A German study found that treatment with multiagent chemotherapy incorporating carboplatin and etoposide, plus RT, was efficacious for patients with embryonal rhabdomyosarcoma (5-year event-free survival [EFS] rate, 41%), but it was less effective for patients with alveolar rhabdomyosarcoma (5-year EFS rate, 25%).[14] Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.

Sources: 14

Carboplatin and etoposide.[14]

Sources: 14

Ifosfamide, carboplatin, and etoposide.[15,16]

Sources: 15 · 16

Cyclophosphamide and topotecan.[17]

Sources: 17

Topotecan, carboplatin, cyclophosphamide, and etoposide.[18]

Sources: 18

Topotecan, carboplatin, cyclophosphamide, and etoposide.[18]

In a 2018 Italian study, 38 patients with recurrent or refractory rhabdomyosarcoma were treated with topotecan, carboplatin, cyclophosphamide, and etoposide.[18][Level of evidence C1]

Sources: 18 · Level of evidence C1

Topotecan, carboplatin, cyclophosphamide, and etoposide.[18] › In a 2018 Italian study, 38 patients with recurrent or refractory rhabdomyosarcoma were treated with topotecan, carboplatin, cyclophosphamide, and etoposide.[18][Level of evidence C1]

Nine of 32 patients had a complete or partial response. However, the 5-year OS rate was 17%, and the PFS rate was 14%.

Single-agent vinorelbine.[19,20]

Sources: 19 · 20

Single-agent vinorelbine.[19,20]

In one phase II trial, 4 of 11 patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[19]

Sources: 19

In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[20]

Sources: 20

In a meta-analysis of five studies, patients with relapsed alveolar rhabdomyosarcoma responded better to vinorelbine, either alone or in combination with other agents, than patients with relapsed embryonal and unclassified rhabdomyosarcoma.[21]

Sources: 21

Vinorelbine and cyclophosphamide.[22,23]

Sources: 22 · 23

Vinorelbine and cyclophosphamide.[22,23]

In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[22]

Sources: 22

In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide.[23][Level of evidence C3]

Sources: 23 · Level of evidence C3

Vinorelbine and cyclophosphamide.[22,23] › In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide.[23][Level of evidence C3]

Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.

Gemcitabine and docetaxel.[24]

Sources: 24

Gemcitabine and docetaxel.[24]

In a single-institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[24]

Sources: 24

Sirolimus.[25]

Sources: 25

Topotecan, vincristine, and doxorubicin.[26][Level of evidence C3]

Sources: 26 · Level of evidence C3

Vincristine, irinotecan, and temozolomide.[27-29]

Sources: 27 · 29

Vincristine, irinotecan, and temozolomide.[27-29]

One of four patients with recurrent alveolar rhabdomyosarcoma had a complete radiographic response sustained for 27 weeks with no grade 3 or 4 toxicities.[27]; [28][Level of evidence C2]

Sources: 27 · 28 · Level of evidence C2

A group of 15 patients with relapsed rhabdomyosarcoma were treated with vincristine, irinotecan, and temozolomide. Many of the patients had received previous relapse therapy.[29][Level of evidence C1]

Sources: 29 · Level of evidence C1

Vincristine, irinotecan, and temozolomide.[27-29] › A group of 15 patients with relapsed rhabdomyosarcoma were treated with vincristine, irinotecan, and temozolomide. Many of the patients had received previous relapse therapy.[29][Level of evidence C1]

There were no complete or partial remissions; four patients had stable disease, and 11 patients had progressive disease.

Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30]

Sources: 30

Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30]

In 2019, the Children's Oncology Group (COG) reported three trials of patients with recurrent or refractory rhabdomyosarcoma with specific criteria for eligibility. Unfavorable-risk patients with measurable disease could undergo a 6-week phase II window study of vincristine and irinotecan (VI). Patients with at least a partial response then received 44 weeks of assigned chemotherapy. Unfavorable-risk patients without measurable disease, no radiographic response, or refusal to go on window therapy received 31 weeks of multiagent chemotherapy plus tirapazamine.[30][Level of evidence C1]

Sources: 30 · Level of evidence C1

Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30] › In 2019, the Children's Oncology Group (COG) reported three trials of patients with recurrent or refractory rhabdomyosarcoma with specific criteria for eligibility. Unfavorable-risk patients with measurable disease could undergo a 6-week phase II window study of vincristine and irinotecan (VI). Patients with at least a partial response then received 44 weeks of assigned chemotherapy. Unfavorable-risk patients without measurable disease, no radiographic response, or refusal to go on window therapy received 31 weeks of multiagent chemotherapy plus tirapazamine.[30][Level of evidence C1]

Favorable-risk patients had a 3-year failure-free survival (FFS) rate of 79% and an OS rate of 84%.

Thirty patients with unfavorable-risk disease who were not treated with VI had a 3-year FFS rate of 21% and an OS rate of 39%.

Irinotecan with or without vincristine and with or without temozolomide.[31-36]

Sources: 31 · 36

Irinotecan with or without vincristine and with or without temozolomide.[31-36]

A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma.[35][Level of evidence A1]

Sources: COG-ARST0121 · 35 · Level of evidence A1

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma.[35][Level of evidence A1]

At 1 year after initiation of treatment for recurrence, the FFS rate was 37% and the OS rate was 55% for Regimen 1A.

At 1 year after initiation of treatment for recurrence, the FFS rate was 38% and OS rate was 60% for Regimen 1B.

The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.

Irinotecan with or without vincristine and with or without temozolomide.[31-36]

In a European Soft Tissue Sarcoma Study Group study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]

Sources: 37 · Level of evidence A1

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › In a European Soft Tissue Sarcoma Study Group study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]

The objective response rate was 44% (24 of 55 evaluable patients) for patients who received VIT, compared with 31% (18 of 58) for patients who received VI.

The patients in the VIT arm achieved significantly better OS (adjusted hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35–0.84; P = .006), than patients on the VI arm, with consistent PFS results (adjusted HR, 0.68; 95% CI, 0.46–1.01; P = .059).

Overall, patients experienced grade 3 or greater adverse events more frequently with VIT than VI (98% vs. 78%, respectively; P = .009), including a significant excess of hematological toxicity (81% vs. 61%; P = .025).

Temsirolimus, irinotecan, and temozolomide.[38]

Sources: 38

Temsirolimus, irinotecan, and temozolomide.[38]

In a phase I trial of these agents, four patients had rhabdomyosarcoma.[38]

Sources: 38

Temsirolimus, irinotecan, and temozolomide.[38] › In a phase I trial of these agents, four patients had rhabdomyosarcoma.[38]

The regimen was well tolerated.

One patient had a partial response, and another patient had stable disease.

Temsirolimus, cyclophosphamide, and vinorelbine.[39]

Sources: 39

Temsirolimus, cyclophosphamide, and vinorelbine.[39]

A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]

Sources: 40 · Level of evidence C2

Temsirolimus, cyclophosphamide, and vinorelbine.[39] › A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]

Patients on the temsirolimus arm had improved EFS (P = .003). The 6-month and 12-month EFS rates in the temsirolimus arm were 65% (95% CI, 44%–79%) and 40.5% (95% CI, 25.6%–55.3%), respectively, compared with 50% (95% CI, 32%–66%) and 18.2% (95% CI, 6.8%–29.6%) in the bevacizumab arm.

The complete response rate (complete remission plus partial remission) was higher on the temsirolimus arm (47%) than on the bevacizumab arm (28%). The difference was not statistically significant at the 0.05 level (P = .12).

These results are the basis for the subsequent COG trial randomizing the use of temsirolimus for newly diagnosed patients with nonmetastatic rhabdomyosarcoma (ARST1431 [NCT02567435]).

Sources: ARST1431 [NCT02567435]

Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC).

Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC).

The Cooperative Weichteilsarkom Studiengruppe (CWS) examined second-line treatment for patients who had recurrence of rhabdomyosarcoma after initial treatment. Second-line chemotherapy based on anthracyclines (ACCTTIVE) was recommended for patients in initial low-risk, standard-risk, and high-risk groups after their original treatment did not include anthracyclines. TECC was recommended for patients in the very high-risk group after their initial treatment included anthracycline-based regimens. The risk groups included low risk, standard risk, high risk, and very high risk.[41]

Sources: 41

Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC). › The Cooperative Weichteilsarkom Studiengruppe (CWS) examined second-line treatment for patients who had recurrence of rhabdomyosarcoma after initial treatment. Second-line chemotherapy based on anthracyclines (ACCTTIVE) was recommended for patients in initial low-risk, standard-risk, and high-risk groups after their original treatment did not include anthracyclines. TECC was recommended for patients in the very high-risk group after their initial treatment included anthracycline-based regimens. The risk groups included low risk, standard risk, high risk, and very high risk.[41]

Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors for postrelapse survival.

The 5-year OS rates were 80% (± 21%) for patients with relapsed disease in the standard-risk group, 20% (± 16%) for patients in the high-risk group, and 13% (± 23%) for patients in the very high-risk group (P = .008).

ADVL1621 (NCT02332668) (A Study of Pembrolizumab [MK-3475] in Pediatric Participants With Advanced Melanoma or Advanced, Relapsed, or Refractory PD-L1-Positive Solid Tumors or Lymphoma [MK-3475-051/KEYNOTE-051]): This is a two-part study of pembrolizumab in pediatric participants who have either advanced melanoma or a programmed cell death ligand 1–positive advanced, relapsed, or refractory solid tumor or lymphoma. Part 1 will find the maximum tolerated dose/maximum administered dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 will further evaluate the safety and efficacy at the pediatric recommended phase II dose.

Sources: ADVL1621 (NCT02332668)

The patient's age.

Where in the body the tumor started.

Sources: tumor

The size of the tumor at the time of diagnosis.

Whether the tumor has been completely removed by surgery.

The type of rhabdomyosarcoma (embryonal, alveolar, spindle cell/sclerosing, or pleomorphic).

Sources: embryonal · alveolar · spindle cell · pleomorphic

Whether there are certain changes in the genes.

Whether the tumor had spread to other parts of the body at the time of diagnosis.

Whether the tumor was in the lymph nodes at the time of diagnosis.

Whether the tumor responds to chemotherapy and/or radiation therapy.

Sources: responds · chemotherapy · radiation therapy

Where in the body the tumor recurred (came back).

How much time passed between the end of cancer treatment and when the cancer recurred.

Sources: recurred

Whether the cancer was previously treated with radiation therapy.

There are different types of treatment for patients with childhood rhabdomyosarcoma.

Children with rhabdomyosarcoma should have their treatment planned by a team of health care providers who are experts in treating cancer in children.

Three types of standard treatment are used:

Three types of standard treatment are used:

Surgery

Radiation therapy

Chemotherapy

New types of treatment are being tested in clinical trials.

New types of treatment are being tested in clinical trials.

Immunotherapy

Targeted therapy

Treatment for childhood rhabdomyosarcoma may cause side effects.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up tests may be needed.

Pediatrician.

Sources: Pediatrician

Pediatric surgeon.

Sources: Pediatric surgeon

Radiation oncologist.

Sources: Radiation oncologist

Pediatric hematologist.

Sources: Pediatric hematologist

Pediatric radiologist.

Sources: Pediatric · radiologist

Pediatric nurse specialist.

Sources: Pediatric nurse specialist

Geneticist or cancer genetics risk counselor.

Sources: Geneticist · genetics risk counselor

Social worker.

Sources: Social worker

Rehabilitation specialist.

Sources: Rehabilitation specialist

Where in the body the tumor started.

The effect the surgery will have on the way the child will look.

The effect the surgery will have on the child's important body functions.

How the tumor responded to chemotherapy or radiation therapy that may have been given first.

Sources: responded · chemotherapy · radiation therapy

External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. These types of external radiation therapy include the following:

Sources: External radiation therapy

External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. These types of external radiation therapy include the following:

Conformal radiation therapy: Conformal radiation therapy is a type of external radiation therapy that uses a computer to make a 3-dimensional (3-D) picture of the tumor and shapes the radiation beams to fit the tumor. This allows a high dose of radiation to reach the tumor and causes less damage to nearby healthy tissue.

Sources: Conformal radiation therapy · 3-dimensional · dose

Intensity-modulated radiation therapy (IMRT): IMRT is a type of 3-dimensional (3-D) radiation therapy that uses a computer to make pictures of the size and shape of the tumor. Thin beams of radiation of different intensities (strengths) are aimed at the tumor from many angles.

Sources: Intensity-modulated radiation therapy · 3-dimensional (3-D) radiation therapy

Volumetrical modulated arc therapy (VMAT): VMAT is type of 3-D radiation therapy that uses a computer to make pictures of the size and shape of the tumor. The radiation machine moves in a circle around the patient once during treatment and sends thin beams of radiation of different intensities (strengths) at the tumor. Treatment with VMAT is delivered faster than treatment with IMRT.

Stereotactic body radiation therapy: Stereotactic body radiation therapy is a type of external radiation therapy. Special equipment is used to place the patient in the same position for each radiation treatment. Once a day for several days, a radiation machine aims a larger than usual dose of radiation directly at the tumor. By having the patient in the same position for each treatment, there is less damage to nearby healthy tissue. This procedure is also called stereotactic external-beam radiation therapy and stereotaxic radiation therapy.

Sources: Stereotactic body radiation therapy

Proton beam radiation therapy: Proton-beam therapy is a type of high-energy, external radiation therapy. A radiation therapy machine aims streams of protons (tiny, invisible, positively-charged particles) at the cancer cells to kill them. This type of treatment may cause less damage to nearby healthy tissue.

Sources: Proton beam radiation therapy · protons

Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. It is used to treat cancer in areas such as the vagina, vulva, uterus, bladder, prostate, head, or neck. Internal radiation therapy is also called brachytherapy, internal radiation, implant radiation, or interstitial radiation therapy. This approach involves special technical skills and is offered in only a few medical centers.

Sources: Internal radiation therapy · radioactive · seeds · catheters · vagina · vulva · uterus · bladder · prostate

Vaccine therapy is a cancer treatment that uses a substance or group of substances to stimulate the immune system to find the tumor and kill it. Vaccine therapy is being studied to treat metastatic rhabdomyosarcoma.

Sources: Vaccine therapy · metastatic

Immune checkpoint inhibitor therapy uses the body's immune system to kill cancer cells. Two types of immune checkpoint inhibitors are being studied in the treatment of childhood rhabdomyosarcoma that has come back after treatment:

Sources: Immune checkpoint inhibitor

Immune checkpoint inhibitor therapy uses the body's immune system to kill cancer cells. Two types of immune checkpoint inhibitors are being studied in the treatment of childhood rhabdomyosarcoma that has come back after treatment:

CTLA-4 is a protein on the surface of T cells that helps keep the body’s immune responses in check. When CTLA-4 attaches to another protein called B7 on a cancer cell, it stops the T cell from killing the cancer cell. CTLA-4 inhibitors attach to CTLA-4 and allow the T cells to kill cancer cells. Ipilimumab is being studied in the treatment of childhood rhabdomyosarcoma that has come back or progressed during treatment.

Sources: CTLA-4 · T cells · immune responses · protein · Ipilimumab · progressed

PD-1 and PD-L1 inhibitor therapy: PD-1 is a protein on the surface of T cells that helps keep the body’s immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells. Nivolumab and pembrolizumab are types of PD-1 inhibitors that are being studied in the treatment of childhood rhabdomyosarcoma that has come back or progressed during treatment.

Sources: PD-1 · PD-L1 · Nivolumab · pembrolizumab

mTOR inhibitors stop the protein that helps cells divide and survive. Sirolimus is a type of mTOR inhibitor therapy being studied in the treatment of recurrent rhabdomyosarcoma.

Sources: mTOR inhibitors · Sirolimus · recurrent

Tyrosine kinase inhibitors block signals that cancer cells need to grow and divide. MK-1775, cabozantinib-s-malate, and palbociclib are tyrosine kinase inhibitors being studied in the treatment of newly diagnosed or recurrent rhabdomyosarcoma.

Sources: Tyrosine kinase inhibitors · cabozantinib-s-malate · palbociclib · diagnosed

Physical problems that affect the following:

Physical problems that affect the following:

Teeth, eye, or gastrointestinal function.

Sources: gastrointestinal

Fertility (ability to have children).

Sources: Fertility

Changes in mood, feelings, thinking, learning, or memory.

Second cancers (new types of cancer).

Sources: Second cancers

For tumors of the brain: Treatment may include surgery to remove the tumor, radiation therapy, and chemotherapy.

Sources: tumors · brain · surgery · radiation therapy · chemotherapy

For tumors of the head and neck that are in or near the eye: Treatment may include chemotherapy and radiation therapy. If the tumor remains or comes back after treatment with chemotherapy and radiation therapy, surgery to remove the eye and some tissues around the eye may be needed.

Sources: tissues

For tumors of the head and neck that are near the ear, nose, sinuses, or base of the skull but not in or near the eye: Treatment may include radiation therapy and chemotherapy.

Sources: sinuses · skull

For tumors of the head and neck that are not in or near the eye and not near the ear, nose, sinuses, or base of the skull: Treatment may include chemotherapy, radiation therapy, and surgery to remove the tumor.

For tumors of the head and neck that cannot be removed by surgery: Treatment may include chemotherapy and radiation therapy including stereotactic body radiation therapy.

Sources: stereotactic body radiation therapy

For tumors of the larynx (voice box): Treatment may include chemotherapy and radiation therapy. Surgery to remove the larynx is usually not done, so that the voice is not harmed.

Sources: larynx

Chemotherapy followed by surgery to remove the tumor. If the tumor was not completely removed, a second surgery to remove the tumor may be done. Radiation therapy may also be given.

Sources: Chemotherapy · surgery · tumor · second surgery · Radiation therapy

For tumors of the hand or foot, radiation therapy and chemotherapy may be given. The tumor may not be removed because it would affect the function of the hand or foot.

Lymph node dissection (one or more lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer).

Sources: Lymph node dissection · lymph nodes · tissue · microscope · signs · cancer

Lymph node dissection (one or more lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer).

For tumors in the arms, lymph nodes near the tumor and in the armpit area are removed.

For tumors in the legs, lymph nodes near the tumor and in the groin area are removed.

Sources: groin

For tumors in the chest or abdomen (including the chest wall or abdominal wall): Surgery (wide local excision) may be done. If the tumor is large, chemotherapy and radiation therapy are given to shrink the tumor before surgery.

Sources: tumors · abdomen · chest wall · abdominal · Surgery · wide local excision · chemotherapy · radiation therapy

For tumors of the pelvis: Surgery (wide local excision) may be done. If the tumor is large, chemotherapy is given to shrink the tumor before surgery. Radiation therapy may be given after surgery.

Sources: pelvis

For tumors of the diaphragm: A biopsy of the tumor is followed by chemotherapy and radiation therapy to shrink the tumor. Surgery may be done later to remove any remaining cancer cells.

Sources: diaphragm · biopsy · cancer · cells

For tumors of the gallbladder or bile ducts: A biopsy of the tumor is followed by chemotherapy and radiation therapy. Surgery may be done later to remove any remaining cancer cells.

Sources: gallbladder · bile ducts

For tumors of the muscles or tissues around the anus or between the vulva and the anus or the scrotum and the anus: Surgery may be done to remove as much of the tumor as possible and some nearby lymph nodes, followed by chemotherapy and radiation therapy.

Sources: anus · vulva · scrotum · lymph nodes

For tumors of the kidney: Surgery to remove as much of the tumor as possible. Chemotherapy and radiation therapy may also be given.

Sources: tumors · kidney · Surgery · tumor · Chemotherapy · radiation therapy

For tumors that are only at the top of the bladder: Surgery (wide local excision) is done.

Sources: tumors · bladder · Surgery · wide local excision

For tumors of the prostate or bladder (other than the top of the bladder):

Sources: prostate

For tumors of the prostate or bladder (other than the top of the bladder):

Chemotherapy and radiation therapy are given first to shrink the tumor. If cancer cells remain after chemotherapy and radiation therapy, the tumor is removed by surgery. Surgery may include removal of the prostate, part of the bladder, or pelvic exenteration without removal of the rectum. (This may include removal of the lower colon and bladder. In girls, the cervix, vagina, ovaries, and nearby lymph nodes may be removed).

Sources: Chemotherapy · radiation therapy · cancer · cells · pelvic exenteration · rectum · colon · cervix · vagina · ovaries · lymph nodes

Chemotherapy is given first to shrink the tumor. Surgery to remove the tumor, but not the bladder or prostate, is done. Internal or external radiation therapy may be given after surgery.

Sources: Internal · external radiation therapy

Surgery to remove the tumor, but not the bladder or prostate. Internal radiation therapy is given after surgery.

Surgery to remove the testicle and spermatic cord. The lymph nodes in the back of the abdomen may be checked for cancer, especially if the lymph nodes are large. Patients older than 10 years with no sign of enlarged lymph nodes in the back of the abdomen should have a nerve-sparing retroperitoneal lymph node dissection.

Sources: Surgery · testicle · spermatic cord · lymph nodes · abdomen · cancer · nerve-sparing · retroperitoneal · lymph node dissection

Radiation therapy may be given if the tumor cannot be completely removed by surgery.

Sources: Radiation therapy

For tumors of the vulva and vagina: Treatment may include chemotherapy followed by surgery to remove the tumor. Internal or external radiation therapy may be given after surgery.

Sources: tumors · vulva · vagina · chemotherapy · surgery · Internal · external radiation therapy

For tumors of the uterus: Treatment may include chemotherapy with or without radiation therapy. Sometimes surgery may be needed to remove any remaining cancer cells.

Sources: uterus · radiation therapy · cancer · cells

For tumors of the ovary: Treatment may include chemotherapy followed by surgery to remove any remaining tumor.

Sources: ovary

A clinical trial of combination chemotherapy with or without temsirolimus.

Sources: clinical trial · combination chemotherapy · temsirolimus

A clinical trial of targeted therapy with cabozantinib-s-malate.

Sources: targeted therapy · cabozantinib-s-malate

A clinical trial of immunotherapy (vaccine therapy).

Sources: clinical trial · immunotherapy · vaccine therapy

Surgery.

Sources: Surgery

Radiation therapy.

Sources: Radiation therapy

Chemotherapy.

Sources: Chemotherapy

A clinical trial of combination chemotherapy with or without temsirolimus.

Sources: clinical trial · combination chemotherapy · temsirolimus

A clinical trial of targeted therapy or immunotherapy (sirolimus, ipilimumab, nivolumab, or pembrolizumab).

Sources: targeted therapy · immunotherapy · sirolimus · ipilimumab · nivolumab · pembrolizumab

A clinical trial of targeted therapy with a tyrosine kinase inhibitor (MK-1775, cabozantinib-s-malate, or palbociclib) and chemotherapy.

Sources: tyrosine kinase inhibitor · cabozantinib-s-malate · palbociclib

A clinical trial that checks a sample of the patient's tumor for certain gene changes. The type of targeted therapy that will be given to the patient depends on the type of gene change.

Sources: tumor · gene

New therapies being studied in early stage clinical trials should be considered for patients with recurrent rhabdomyosarcoma.