Abstract
Background:
The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites.
Methods:
A total of 113 patients aged 0–18 years were identified who were enrolled from January 1995 to December 2016 in Children’s Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin-D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols.
Results:
The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow-up of 97.5 months, the 5-year progression-free and overall survival was 80.0% (71.2%–86.4%) and 92.5% (85.6%–96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size (≤ or >5 cm) significantly influenced overall survival: 96.2% (88.6%–98.8%) vs. 80.6% (59.5%–91.4%), respectively (p = .01).
Conclusions:
Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low-intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors ≤5 cm.
Keywords: chemotherapy, embryonal rhabdomyosarcoma, extremity rhabdomyosarcoma, head and neck rhabdomyosarcoma, tumor resection
INTRODUCTION
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and adolescents. At presentation, RMS can vary in tumor size, extent of regional nodal and/or metastatic spread, and histological subtypes, which affect clinical behaviors.
With modern multidisciplinary treatment, the outcome of patients with RMS varies and ranges from a survival greater than 90% for patients with localized embryonal RMS occurring in favorable sites to less than 40% in those with metastasis at diagnosis.1
Studies in North America and Europe have identified a series of prognostic factors that are currently used to stratify patients into different risk groups and tailor treatment intensity. They include histology (alveolar vs. nonalveolar), FOXO1-fusion status, postsurgical stage (according to the Intergroup Rhabdomyosarcoma Study [IRS] Grouping system), TNM stage, tumor site, tumor size (> or <5 cm), lymph node involvement, and patient age (≥ or <10 years).2
Patients with tumors completely resected at diagnosis and having favorable histology (embryonal and spindle cell RMS) are included in the low-risk category.3,4 The majority of these present with RMS localized to the genitourinary tract, most commonly paratesticular or vaginal tumors. Patients with genitourinary (excluding bladder-prostate) RMS represented 51% of those enrolled in the low-risk category in the Children’s Oncology Group (COG) ARST0331 study and 89% of those enrolled in the low-/standard-risk group of the European pediatric Soft tissue sarcoma Study Group RMS 2005 protocol.4,5 The overall survival of these children with paratesticular/uterine/vaginal tumors is greater than 90%.6–9 Because of the limited number of patients, no specific analyses have been reported focusing on patients with tumors completely resected but arising in nongenitourinary regions.
To overcome this limitation, we performed an international analysis of patients with localized completely resected embryonal or spindle cell RMS, excluding those arising in the genitourinary favorable sites.
PATIENTS AND METHODS
Patients aged 0–18 years at diagnosis with histologically confirmed nonalveolar, localized RMS, microscopically completely resected at diagnosis (IRS Group I) diagnosed from January 1995 to December 2016 were included. Overall, 64 patients were enrolled in COG low-risk protocols (D9602, NCT00002995; ARST0331, NCT00075582) from 1997 to 2013, five in the Italian RMS96 protocol (1996–2005), 18 in the European pediatric Soft tissue sarcoma Study Group study (2005–2016, EUDRACT 2005–000217-35), and 26 in the Cooperative Weichteilsarkom Studiengruppe (CWS) studies (CWS96, CWS2002p, and the more recent Soft Tissue Sarcoma Registry) from 1995 to 2016. We excluded all patients with tumors arising in a nonbladder-prostate genitourinary sites (including paratesticular, vaginal/vulvar, and uterine RMS).
We assessed six demographic characteristics, including cooperative group, the era of enrollment, patients’ age, primary site, tumor size, and invasiveness (T stage). FOXO1-fusion status was not available for most patients; therefore, it was not included in our analysis. The site of recurrence was defined as locoregional if the tumor recurred at the primary site and/or in regional lymph nodes and considered distant if metastatic disease was present at the time of recurrence or combined when local and distant recurrence was evident at the same time.
Treatment
In European trials, these patients were included in the low-risk group (subgroup A) or in the standard-risk group (subgroup B). In COG, they were included in low-risk group subgroup A or B in the D9602 protocol and subset 1 or 2 in the ARST0331 protocol. Group definition and treatment are described in Table 1. The vincristine 1.5 mg/m2 (maximum single dose, 2 mg) and actinomycin D 1.5 mg/m2 (maximum single dose, 2 mg) (VA) chemotherapy regimen was used in the European and COG protocols, but the duration of therapy differed by study and alkylating agents were given to defined groups of patients. In the RMS2005 protocol and in the CWS studies, ifosfamide 3 g/m2/d for 2 consecutive days was given in subgroup B for four cycles (cumulative dose 24 g/m2). In COG ARST0331, patients received 1.2 g/m2/cycle cyclophosphamide dose (cumulative dose 4.8 g/m2) except for patients with tumors >5 cm at unfavorable sites treated on the D9602 protocol. Those patients received 2.2 g/m2/cycle for four cycles (cumulative dose 28.6 g/m2) followed by VA for four cycles or 12 cycles if the tumor was >5 cm and/or had regional lymph node involvement and arose in an unfavorable site (all sites except nonbladder-prostate genitourinary, nonparameningeal head and neck, or orbit). Patients with tumors >5 cm and/or regional lymph node involvement arising in unfavorable sites treated on the D9602 protocol received 2.2 g/m2/cycle cyclophosphamide for 13 cycles (cumulative dose 28.6 g/m2). The use of radiotherapy was not recommended.
TABLE 1.
Treatment regimen used for IRS group I nonalveolar patients by different Cooperative Groups
| Study | Risk group definition | No. of patients | Recommended chemotherapy regimen | Cumulative drug doses | Duration of chemotherapy (wk) |
|---|---|---|---|---|---|
|
| |||||
| D9602 | Subgroup A: ERMS stage 1 or 2, IRS group I | 27 | VA | V: 54 mg/m2 A: 0.72 mg/kg |
48 |
| D9602 | Subgroup B: ERMS stage 3, IRS group I | 9 | VACa | V: 54 mg/m2 A: 0.72 mg/kg C: 28.6 g/m2 |
44 |
| ARST0331 | Subset 1: ERMS stage 1 or 2, IRS group I | 20 | VACx4 + VAx4 | V: 27 mg/m2 A: 0.36 mg/kg C: 4.8 g/m2 |
24 |
| ARST0331 | Subset 2: ERMS stage 3, IRS group I | 8 | VACx4 + VAx12 | V: 54 mg/m2 A: 0.72 mg/kg C: 4.8 g/m2 |
48 |
| RMS96 and CWS96 | ERMS, IRS group I, N0, T1 | 20 | VA | V: 24 mg/m2 A: 12 mg/m2 |
24 |
| RMS2005 and CWS 2002p | Subgroup A: ERMS, IRS group I, tumor ≤5 cm, and patient age <10 y | 18 | VA | V: 24 mg/m2 A: 12 mg/m2 |
24 |
| RMS2005 and CWS2002p | Subgroup B: ERMS, IRS group I, tumor >5 cm or patient age ≥10 y | 11 | IVAx4 + VAx5 | I: 24 g/m2 V: 24 mg/m2 A: 12 mg/m2 |
27 |
Note: Stage 1: favorable site, any T, any size, and N, M0. Stage 2: unfavorable site, any T, size ≤5 cm, N0 or Nx, M0. Stage 3: unfavorable site, any T, size >5 cm, N0 or Nx, M0.
Abbreviations: ERMS, embryonal rhabdomyosarcoma; IRS, Intergroup Rhabdomyosarcoma Study; VA, vincristine and actinomycin-D; VAC, vincristine and actinomycin-D plus cyclophosphamide.
Higher cyclophosphamide doses (2.2 g/m2 per cycle) than in the other VAC regimen.
Data were prospectively collected. All participating centers were required to obtain written approval from their local authorities and ethics committees and written informed consent from patients and/or their parents or legal guardians.
Statistical analysis
Patients’ characteristics were compared by cooperative groups using the χ2 test or Fisher exact test according to the frequency distribution.
The primary end point was progression-free survival (PFS), defined as the time from diagnosis or study enrollment to tumor relapse or progression, death due to any cause or time of the latest follow-up. The secondary outcome was overall survival (OS), measured as the time from diagnosis to death from any cause or time to the latest follow-up.
Survival probabilities were calculated using the Kaplan–Meier method and reported with 95% CI. Cox regression models for PFS and OS, including all variables with p < .25 at univariate analysis, were provided to estimate hazard ratios. They were reported together with 95% CI, calculated according to the Wald method. The proportional hazards assumption was assessed for all the variables including time-dependent covariates in the model and interaction among variables was tested. A backward selection procedure was applied to detect significant prognostic factors (p < .05). All data analyses were performed using SAS statistical package (SAS, Version 9.4; SAS Institute, Cary, North Carolina, USA).
RESULTS
Clinical characteristics for the 113 patients (64 from COG and 49 from European Groups) analyzed in this study are presented in Table 2.
TABLE 2.
Patients’ clinical characteristics
| COG | Europe | |||
|---|---|---|---|---|
| N (%) | N (%) | N total (%) | ||
| 64 (56.6) | 49 (43.4) | 113 (100) | p | |
|
| ||||
| Age at diagnosis, y | ||||
| ≤1 | 6 (9.4) | 7 (14.3) | 13 (11.5) | .1904b |
| 1–9 | 40 (62.5) | 35 (71.4) | 75 (66.4) | |
| 10–17 | 18 (28.1) | 7 (14.3) | 25 (22.1) | |
| Median age | 4.9 | 2.3 | 3.3 | |
| Range | 34 d-17.9 y | 10 d-16.6 y | 10 d-17.9 y | |
| Sex | ||||
| Female | 34 (53.1) | 25 (51.0) | 59 (52.2) | .8243b |
| Male | 30 (46.9) | 24 (49.0) | 54 (47.8) | |
| Histology | ||||
| Embryonal RMS | 35 (54.7) | 40 (81.6) | 75 (66.4) | .0080a |
| Botryoid RMS | 12 (18.8) | 5 (10.2) | 17 (15.0) | |
| Spindle cell RMS | 17 (26.6) | 4 (8.2) | 21 (18.6) | |
| Tumor primary site | ||||
| Orbit | 5 (7.8) | 2 (4.1) | 7 (6.2) | .4337a |
| HNnoPM | 29 (45.3) | 17 (34.7) | 46 (40.7) | |
| HNPM | 1 (1.6) | - | 1 (0.9) | |
| GUBP | 3 (4.7) | 6 (12.2) | 9 (8.0) | |
| Extremities | 13 (20.3) | 10 (20.4) | 23 (20.4) | |
| Other sites | 13 (20.3) | 14 (28.6) | 27 (23.9) | |
| Primary tumor site | ||||
| Favorable site | 34 (53.1) | 19 (38.8) | 53 (46.9) | .1298b |
| Unfavorable site | 30 (46.9) | 30 (61.2) | 60 (53.1) | |
| T-invasiveness | ||||
| T1 | 58 (90.6) | 41 (83.7) | 99 (87.6) | .3944c |
| T2 | 6 (9.4) | 7 (14.3) | 13 (11.5) | |
| Tx | - | 1 (2.0) | 1 (0.9) | |
| Tumor size | ||||
| ≤5 cm | 49 (76.5) | 35 (71.4) | 84 (74.3) | .4414d |
| >5 cm | 14 (21.9) | 14 (28.6) | 28 (24.8) | |
| x: not evaluable | 1 (1.6) | 1 (0.9) | ||
| Locoregional N | ||||
| N0 | 64 (100.0) | 49 (100.0) | 113 (100.0) | |
| Radiotherapy given | ||||
| Yes | 3 (4.7) | 5 (10.2) | 8 (7.1) | .2901a |
| No | 61 (95.3) | 44 (89.8) | 105 (92.9) | |
Abbreviations: GUBP, genitourinary bladder-prostate; HNnoPM, head and neck nonparameningeal; HNPM, head and neck parameningeal; RMS, rhabdomyosarcoma.
Fisher exact test.
χ2 test.
χ2 test excluding patients with Tx.
χ2 test excluding patients with size x.
Median age at initial diagnosis was 3.3 years (range, 10 days –17.9 years). The most common site was the nonparameningeal head and neck region, followed by the extremities and other sites. Only one patient had a tumor arising in a parameningeal site. The two populations had comparable characteristics apart from a higher rate of spindle cell RMS in the COG series.
In the COG protocols, 27 (42%) patients were treated with VA only and 37 (58%) received VA plus cyclophosphamide. This compared with 26 receiving VA only (53%) and 23 (47%) receiving VA plus ifosfamide in Europe. Alkylating agents were administered significantly more often to children with invasive (T2) and large (>5 cm) tumors (Table 3). Radiotherapy was administered to one patient with an initial diagnosis of alveolar RMS (that was changed to embryonal after the diagnosis was reviewed by the protocol pathology panel), and in seven at the discretion of the treating center (four had orbital RMS and three had tumors in unfavorable sites, with tumor diameter >5 cm in two of three).
TABLE 3.
Patients’ clinical characteristics by chemotherapy regimen received
| Chemotherapy without alkylating | Chemotherapy with alkylating | |||
|---|---|---|---|---|
| N (%) | N (%) | N total (%) | ||
| 53 (46.9) | 60 (53.1) | 113 (100) | p | |
|
| ||||
| Age at diagnosis, y | ||||
| ≤ 1 | 6 (11.3) | 7 (11.7) | 13 (11.5) | .2215b |
| 1–9 | 39 (73.6) | 36 (60.0) | 75 (66.4) | |
| 10–17 | 8 (15.1) | 17 (28.3) | 25 (22.1) | |
| Sex | ||||
| Female | 30 (56.6) | 29 (48.3) | 59 (52.2) | .3798b |
| Male | 23 (43.4) | 31 (51.7) | 54 (47.8) | |
| Histology | ||||
| Embryonal RMS | 32 (60.4) | 46 (76.6) | 75 (66.4) | .2955b |
| Botryoid RMS | 8 (15.1) | 9 (15.0) | 17 (15.0) | |
| Spindle cell RMS | 13 (24.5) | 8 (13.4) | 21 (18.6) | |
| Tumor primary site | ||||
| Orbit | 3 (5.7) | 4 (6.7) | 7 (6.2) | .9467a |
| HNnoPM | 23 (43.4) | 23 (38.3) | 46 (40.7) | |
| HNPM | 1 (1.7) | 1 (0.9) | ||
| GUBP | 3 (5.7) | 6 (10.0) | 9 (8.0) | |
| Extremities | 11 (20.8) | 12 (26.7) | 23 (20.4) | |
| Other sites | 13 (24.5) | 14 (23.3) | 27 (23.9) | |
| Tumor primary site | ||||
| Favorable site | 26 (49.1) | 27 (45.0) | 53 (46.9) | .6663b |
| Unfavorable site | 27 (50.9) | 33 (55.0) | 60 (53.1) | |
| T-stage | ||||
| T1 | 51 (96.2) | 48 (80.0) | 99 (87.6) | .0175c |
| T2 | 2 (3.8) | 11 (18.3) | 13 (11.5) | |
| Tx | 1 (1.7) | 1 (0.9) | ||
| Tumor size | ||||
| ≤5 cm | 48 (90.6) | 36 (60.0) | 84 (74.3) | .0004d |
| >5 cm | 5 (9.4) | 23 (38.3) | 28 (24.8) | |
| x: not evaluable | 1 (1.7) | 1 (0.9) | ||
| Radiotherapy given | ||||
| Yes | 3 (5.7) | 5 (8.3) | 8 (7.1) | .7210a |
| No | 50 (94.3) | 55 (91.7) | 105 (92.9) | |
Abbreviations: GUBP, genitourinary bladder-prostate; HNnoPM, head and neck nonparameningeal; HNPM, head and neck parameningeal; RMS, rhabdomyosarcoma.
Fisher exact test.
χ2 test.
χ2 test excluding patients with Tx.
χ2 test excluding patients with size x.
Outcome and prognostic factors
The median follow-up for alive patients was 97.5 months (range, 12.0–247.5): 97.7 months (range, 12.0–153.9) in the COG studies and 95.6 months (range, 33.8–247.5) in European studies. At the time of the analysis, 27 patients had an event (16 in the COG and 11 in the European studies), with 12 proving fatal. Tumor recurrence was locoregional in 17 patients, metastatic in five, and combined in two. Three children on European protocols who were treated without alkylating agents developed a secondary malignancy: medulloblastoma, a new RMS, and acute lymphoblastic leukemia. Li-Fraumeni syndrome was reported in two children (information not available for the third patient). The child with medulloblastoma died 4.7 years after the diagnosis of RMS.
Among the 24 patients with tumor recurrence, 12 were alive in complete remission, one was alive with disease, and 11 died (two of which died from unspecified causes not related to the RMS, 76 and 127 months from diagnosis). The cumulative incidence for disease recurrence was 19.0% (12.3%–26.8%) and for RMS-related death was 6.4% (2.8%–12.1%). Cumulative incidence curves including those for locoregional and metastatic events are shown in Figures S1–S4. According to site, 12/46 (26%) patients with head and neck RMS developed a tumor relapse (10 locoregional, one metastatic, and one combined). The recurrence rate was 13.2% in those treated with VA and 28.3% in those receiving VA plus alkylating agents (p = .1094). None of the irradiated patients had a relapse. The 5-year PFS and OS rates for the whole population was 80.0% (71.2%–86.4%) and 92.5% (85.6%–96.2%) (Figure 1), respectively, without significant differences comparing COG and European protocols. We did not find any difference in outcome based on alkylating agents used or duration of VA therapy with PFS rates of 87.4% (65.6%–95.8%) for the 24-week regimen vs. 88.7% (69.0%–96.2%) in the 48-week regimen (p = .9466), as shown in Table S1. In univariate (but not in multivariate) analysis, patient age was associated with PFS and, interestingly, no events in children aged younger than 1 year were recorded. Tumor size was the only factor significantly affecting survival (but not PFS) both in univariate and multivariate analysis, with 96.2% (88.6%–98.8%) OS in children with tumor ≤5 cm vs. 80.6% (59.5%–91.4%) in those with tumor >5 cm (p = .0139) as shown in Table S2. No interactions among variables were found (Table S3).
FIGURE 1.
Progression-free survival and overall survival for the whole population
DISCUSSION
Since the inception of cooperative trials, it has been recognized that children with nonalveolar RMS and microscopically completely resected tumors at diagnosis have superior outcomes. Other factors, including tumor size and site, have been included to better define the group of patients with low risk of relapse that can be cured with less intensive systemic treatment and without radiotherapy.10 Tumor site is a predominant factor that determines resectability. This is particularly evident in the European experience: among all patients enrolled onto the RMS2005 study, initial surgery resulted in microscopically complete resection in 219 patients (12.6% of the enrolled population) of whom 171 (78%) had paratesticular tumor. This is explained by the fact that tumors arising in the paratesticular site are more amenable to complete surgical resection than tumors arising in other body sites. COG protocols have a higher rate of upfront complete resection in nonparatesticular sites compared with European studies.5 Because RMS arising in the genitourinary sites, excluding bladder and prostate, had traditionally contributed to the majority of IRS group I patients, outcome data were largely influenced by them. By excluding them in this analysis, we had the opportunity to study if low-intensity treatment is appropriate for non-genitourinary group I embryonal RMS patients.
In this multinational cooperative analysis, we demonstrated that patients with embryonal RMS completely resected at diagnosis have an excellent prognosis even after we eliminated the possible confounding effect of patients with tumor arising in the genitourinary nonbladder/prostate site. OS is greater than 90% and comparable to the 94.8% recently reported by two pooled analyses of North American and European groups on paratesticular and vaginal/uterine RMS.6–8 With the limitations of an indirect comparison, the PFS in the present group of patients is lower than that reported in the paratesticular group (87.7%). There was evidence of a salvage gap (i.e., the difference between PFS and OS).11 Approximately 50% of patients who relapsed were cured with second-line therapy and explain the difference between PFS and OS. This effect may be explained by the fact that more than 50% of patients in our series have been treated with only two drugs (vincristine and actinomycin D) and only eight patients received radiotherapy. These two factors were found to be associated with a much better prognosis in a nomogram developed to estimate the chance of cure after relapse for individual patients.12
Similar to paratesticular RMS, tumor size (>5 cm) influenced survival (but not PFS).6 Tumor size might be used to further refine the category of low-risk patients and identify those patients in whom chemotherapy may be even further reduced.
We did not find a significant difference in the relapse rate of patients treated with or without alkylating agents. Patients treated with VA plus cyclophosphamide or ifosfamide plus VA tended to have larger and more invasive tumors, making it difficult to determine if alkylating agents may be safely omitted. However, our data confirm that the VA regimen can be used in children with small tumors and, with the limitation of numbers, it seems that the treatment duration can be safely reduced to 24 weeks. Notably we reported three children with second malignancies after VA treatment, but this is explained by the presence of an inherited cancer predisposing syndrome in at least two of them.
One limitation of our study is the lack of information on molecular features. The presence of alterations such as MYOD1 or TP53 mutation may lead to worse outcomes in RMS.13 With the aim of selecting a population at very low risk of relapse, patients whose tumors harbor these molecular alterations should not be considered as low risk in future protocols. Similarly, a rare subgroup of intraosseous RMS with spindle and epithelioid morphology harboring TFCP2 fusions and ALK overexpression and dismal prognosis has recently been described. In contrast, infantile spindle cell RMS has been associated with recurring fusions involving VGLL2 or NCOA2.14 The majority of cases reported in the literature suggest that this group of RMS may be a biologically distinct entity with a favorable prognosis.15
In conclusion, survival of patients with embryonal RMS microscopically completely resected at diagnosis is excellent regardless of primary tumor site, and they may be treated with a low-intensity short-duration chemotherapy. Tumor size may be used to further refine the low-risk category.
Supplementary Material
ACKNOWLEDGMENTS
We thank Ilaria Zanetti for her help in data management and analysis and Julia Daragjati for her supporting activity. Data management and statistical processing have been funded by Alice’s Arc, a children’s cancer charity focusing on rhabdomyosarcoma, United Kingdom (alicesarc.org).
Footnotes
CONFLICT OF INTEREST
The authors made no disclosures.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.
REFERENCES
- 1.Skapek SX, Ferrari A, Gupta AA, et al. Rhabdomyosarcoma. Nat Rev Dis Prim. 2019;5(1):1. 10.1038/s41572-018-0051-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Arndt CAS, Bisogno G, Koscielniak E. Fifty years of rhabdomyosarcoma studies on both sides of the pond and lessons learned. Cancer Treat Rev. 2018;68:94–101. 10.1016/j.ctrv.2018.06.013 [DOI] [PubMed] [Google Scholar]
- 3.Hibbitts E, Chi YY, Hawkins DS, et al. Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: a report from the Children’s Oncology Group. Cancer Med. 2019;8(14):6437–6448. 10.1002/cam4.2504 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bergeron C, Jenney M, De Corti F, et al. European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Embryonal rhabdomyosarcoma completely resected at diagnosis: the European Paediatric Soft Tissue Sarcoma study group RMS2005 experience. Eur J Cancer. 2021;146:21–29. 10.1016/j.ejca.2020.12.025 [DOI] [PubMed] [Google Scholar]
- 5.Walterhouse DO, Pappo AS, Meza JL, et al. Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol. 2014;32(31):3547–3552. Erratum in: J Clin Oncol. 2018;36(14):1459. 10.1200/jco.2014.55.6787 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Walterhouse DO, Barkauskas DA, Hall D, et al. Demographic and treatment variables influencing outcome for localized paratesticular rhabdomyosarcoma: results from a pooled analysis of North American and European cooperative groups. J Clin Oncol. 2018;36(35):JCO2018789388. 10.1200/jco.2018.78.9388 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Seitz G, Fuchs J, Martus P, et al. Cooperative Weichteilsarkom Studiengruppe (CWS). Outcome, treatment, and treatment failures in patients suffering localized embryonal paratesticular rhabdomyosarcoma: results from the “Cooperative Weichteilsarkom Studiengruppe” trials CWS-86, -91, -96, and -2002P. Ann Surg. 2016;264(6):1148–1155. 10.1097/sla.0000000000001550 [DOI] [PubMed] [Google Scholar]
- 8.Minard-Colin V, Walterhouse D, Bisogno G, et al. International Society of Pediatric Oncology Sarcoma Committee, the Children’s Oncology Group, the Italian Cooperative Soft Tissue Sarcoma Group, and the European pediatric Soft tissue sarcoma Study Group. Localized vaginal/uterine rhabdomyosarcoma - results of a pooled analysis from four international cooperative groups. Pediatr Blood Cancer. 2018;65(9):e27096. 10.1002/pbc.27096 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Sparber-Sauer M, Matle M, Vokuhl C, et al. Rhabdomyosarcoma of the female genitourinary tract: primary and relapsed disease in infants and older children. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. Pediatr Blood Cancer. 2021;68(4):e28889. 10.1002/pbc.28889 [DOI] [PubMed] [Google Scholar]
- 10.Raney RB, Maurer HM, Anderson JR, et al. The Intergroup Rhabdomyosarcoma Study Group (IRSG): major lessons from the IRS-I through IRS-IV studies as background for the current IRS-V treatment protocols. Sarcoma. 2001;5(1):9–15. 10.1080/13577140120048890 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Stevens MC. Treatment for childhood rhabdomyosarcoma: the cost of cure. Lancet Oncol. 2005;6(2):77–84. 10.1016/s1470-2045(05)01733-x [DOI] [PubMed] [Google Scholar]
- 12.Chisholm JC, Marandet J, Rey A, et al. Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol. 2011;29(10):1319–1325. 10.1200/jco.2010.32.1984 [DOI] [PubMed] [Google Scholar]
- 13.Shern JF, Selfe J, Izquierdo E, et al. Genomic classification and clinical outcome in rhabdomyosarcoma: a report from an International Consortium. J Clin Oncol. 2021;39(26):2859–2871. 10.1200/jco.20.03060 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Xu B, Suurmeijer AJH, Agaram NP, Zhang L, Antonescu CR. Head and neck rhabdomyosarcoma with TFCP2 fusions and ALK overexpression: a clinicopathological and molecular analysis of 11 cases. Histopathology. 2021;79(3):347–357. 10.1111/his.14323 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Whittle S, Venkatramani R, Schönstein A, et al. Congenital spindle cell rhabdomyosarcoma: an international cooperative analysis. Eur J Cancer. 2022;168:56–64. 10.1016/j.ejca.2022.03.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
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