Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, and can be subcategorized histologically and/or based on PAX-FOXO1 fusion gene status. Over the last four decades, there ...have been no significant improvements in clinical outcomes for advanced and metastatic RMS patients, underscoring a need for new treatment options for these groups. Despite significant advancements in our understanding of the genomic landscape and underlying biological mechanisms governing RMS that have informed the identification of novel therapeutic targets, development of these therapies in clinical trials has lagged far behind. In this review, we summarize the current frontline multi-modality therapy for RMS according to pediatric protocols, highlight emerging targeted therapies and immunotherapies identified by preclinical studies, and discuss early clinical trial data and the implications they hold for future clinical development.
Background
We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma ...(STS) studies: CWS‐91, CWS‐96, and CWS‐2002P.
Methods
Patients were treated in CWS‐91 with four‐ (vincristine, dactinomycin, doxorubicin, and ifosfamide VAIA or cyclophosphamide VACA II) or five‐drug (+etoposide EVAIA) cycles, in CWS‐96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS‐2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT).
Results
Two hundred forty‐three patients fulfilled the eligibility criteria. The 5‐year event‐free survival (EFS) and overall survival (OS) were 63% (95% confidence interval CI 57–69) and 73% (95% CI 67–79), respectively. The 5‐year EFS by study was 64% (95% CI 54–74) in CWS‐91, 57% (95% CI 48–66) in CWS‐96, and 79% (95% CI 67–91) in CWS‐2002P (n.s.). The 5‐year OS was 72% (95% CI 62–82) in CWS‐91, 70% (95% CI 61–79) in CWS‐96, and 86% (95% CI 76–96) in CWS‐2002P (n.s.). In CWS‐96, 5‐year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52–81) versus 55% (95% CI 39–76) log‐rank p = .13, and 85% (95% CI 75–96) versus 61% (95% CI 45–82), log‐rank p = .09.
Conclusion
Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET–ETS fusion positive tumors.
Background
Prognostic factors for localized synovial sarcoma are well defined. However, few data exist regarding patients with metastases at diagnosis. Poor outcome is described but the optimal ...therapeutic regimen remains unclear. Our aim was to assess the outcome, identify prognostic factors, and analyze treatment strategies.
Methods
Patients <21 years with synovial sarcoma and primary distant metastases treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe trials 1980–2010 were analyzed.
Results
Twenty‐nine of 296 patients had primary metastases. Twenty‐seven could be included. Median age was 16.7 years. Primaries were mainly located in the limbs (78%) and 74% were ≥10 cm. Metastases involved the lungs in all patients. Two patients presented with synchronous bone metastases. Sixty‐three percent of patients achieved a first remission, whereas only 26% maintained it. Relapses were metastatic with pulmonary metastases in nearly all patients. Five‐year event‐free survival and overall survival (OS) rates were 26% and 30%, respectively. Prognosis was best for patients with oligometastatic lung metastases (5‐year OS probability 85%). Prognosis was worse for patients with multiple bilateral lung metastases (5‐year OS 13%) and even poorer for those with concurrent bone metastases. Treatment elements associated with superior survival were adequate local therapy of the primary tumor and, if feasible, for metastases, chemotherapy with an ifosfamide/doxorubicin‐based regimen. The use of whole lung irradiation was not correlated with better outcomes.
Conclusions
The overall prognosis of primary metastatic synovial sarcoma is poor. However, individuals with oligometastatic lung metastases had very good chance for long‐term survival when treated with adequate multimodal therapy.
We report here the results of the prospective, non-randomized, historically controlled CWS-2002P study in patients ≤ 21 years with localized RMS developed with the aim to improve the long-term ...outcome by adapting the burden of therapy to risk profile and to investigate the feasibility and relation to the outcome of maintenance therapy (MT) in the high-risk groups. Patients were allocated into low-risk (LR), standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. Chemotherapy consisted of vincristine (VCR) and dactinomycin (ACTO-D) for all patients with the addition of ifosfamide (IFO) in the SR, HR, and VHR and doxorubicin (DOX) in the HR and VHR groups. Low-dose cyclophosphamide and vinblastine maintenance therapy (MT) over 6 months was recommended in the HR and VHR groups. A total of 444 patients have been included in this analysis. With a median follow-up of 9·6 years (IQR 7·6-10·9) for patients alive, the 5-year EFS and OS for the whole group was 73% (95% CI 69-77) and 80% (95% CI 76-84), respectively. The 5-year EFS by risk group was 100% in the LR, 79% (95% CI 72-84) in the SR, 69% (95% CI 63-75) in the HR, and 42% (95% CI 23-61) in the VHR (log-rank
= 0.000). The 5-year EFS was 77% (95% CI 70-84) for 155 patients in the HR group who received MT as compared to 63% (95% CI 50-76) for 49 patients who did not (log-rank
= 0.015). Neither the reduction in the IFO dose in the SR nor the increased dose intensity of DOX in HR groups influenced the outcome when compared to the previous CWS and other European studies. MT was feasible, seemed to have an impact on prognosis, and should be studied in a well-controlled prospective trial in this patient population. The weighting of risk factors used for therapy stratification needs to be reevaluated.
Background
Treatment algorithms for patients with aggressive fibromatosis (AF) are challenging. There are limited data available about the use of systemic therapy (ST) in pediatric patients with AF.
...Methods
Patient‐, tumor‐, and treatment‐related factors of 90 children and adolescents with AF treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (1981–2015) were analyzed with focus on response and outcome of ST.
Results
Median age was 9.48 years (0.02–18.05). Primary resection was performed in 54 patients and ST was administered in 29 of 54 patients because of disease progression or relapse. In 35 patients, ST was the initial treatment modality. A secondary resection was performed in 21 of 35 patients after ST. A total of 64 patients received ST, mainly methotrexate and vinblastine (40%) with a median duration of 380 days. The most frequent radiological response to ST was stable disease at 3 months (39%) and partial response at 6 months (53%). Radiotherapy was administered to 15 of 90 patients. One patient remained on observation only. The 5‐year overall survival was 100% and the 5‐year event‐free survival (EFS) was 44%. Patients who had a primary resection showed a 5‐year EFS of 35% versus 59% in patients who had received primary ST (P = 0.08). Functional deficiencies as long‐term sequelae following resection occurred in 11 patients. At a median follow‐up of 5.05 years (0.25–14.88), complete remission was achieved in 51 patients and partial remission in 28 patients.
Conclusions
ST seems appropriate if a primary complete resection is not feasible and at relapse/progression after resection.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, ...with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (
= 21, EFS 19%,
= 0.02, OS 24%,
= 0.002). The outcome of LTML was slightly improved compared to HDCT (
= 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower.
Background
The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.
Methods
SS patients treated in the consecutive trials CWS-81, ...CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.
Results
Median age of 185 patients was 13.9 years (0.1–56)—with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3–5 cm in 59 (32%), 5–10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.
Discussion
Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.
Background
Older age is associated with worse outcome in synovial sarcoma (SS) patients. Differences in disease presentation among distinct age groups, however, are currently unknown.
Methods
SS ...patients < 21 years registered in consecutive CWS trials over the period of 1981–2018 were evaluated. Characteristics were analyzed according to age groups using the Fisher’s exact test.
Results
The study population included 432 SS patients. Disease characteristics differed according to age groups of children (0–12 years,
n
= 176), adolescents (13–16 years,
n
= 178), and young adults (17–21 years,
n
= 78). The proportion of invasive tumors (T2) was significantly higher in older patients: children 33%, adolescents 39% and young adults 54%,
p
= 0.009805. Similarly, the proportion of tumors > 10 cm was higher (13%, 21%, 31%;
p
= 0.005657) whereas conversely, the proportion of small tumors < 3 cm was lower in older patients (29%, 24%, 6%;
p
= 0.000104). The presence of metastases at first diagnosis was also highest in older patients (6%, 10%, 21%,
p
= 0.000963).
Notably, the proportion of thigh tumors was higher in older patients (
p
= 0.04173), whereas the proportion of head–neck tumors was lower in older patients (
p
= 0.08896).
Conclusions
The rates of large, invasive tumors and the presence of metastases are significantly associated with older patient age. Localization to the thigh is more frequent in older patients.
Discussion
The causes for these variations require further exploration.
Background
To evaluate optimal therapy and potential risk factors.
Methods
Data of DSRCT patients <40 years treated in prospective CWS trials 1997‐2015 were analyzed.
Results
Median age of 60 ...patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high‐dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three‐year event‐free (EFS) and overall survival (OS) were 11% (±8 confidence interval CI 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra‐abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse.
Conclusion
Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
To evaluate optimal therapy and potential risk factors, data of DSRCT patients <40 years treated in prospective CWS trials 1997‐2015 were analyzed. Pleural effusions, venous thrombosis, and CRP elevation were identified as novel potential risk factors. The VAIA scheme (ifosfamide, vincristine, adriamycin, actinomycin D) showed best outcome in a multivariable model. Maintenance therapy should be investigated further.
Background and Objectives
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that present as large, invasive tumors. Our aim was to assess outcomes, identify ...prognostic factors, and analyze treatment strategies in a prospectively collected pediatric cohort.
Methods
Patients less than 21 years with MPNST treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe (CWS)‐trials (1981‐2009) and the CWS‐SoTiSaR registry (2009‐2015) were analyzed.
Results
A total of 159 patients were analyzed. Neurofibromatosis type I (NF1) was reported in thirty‐eight patients (24%). Most were adolescents (67%) with large (>10 cm, 65%) tumors located at extremities (42%). Nodal involvement was documented in 15 (9%) and distant metastases in 15 (9%) upon diagnosis. Overall, event‐free survival (EFS) was 40.5% at 5 and 36.3% at 10 years, and overall survival (OS) was 54.6% at 5 and 47.1% at 10 years. Age, NF1 status, tumor site, tumor size, Intergroup Rhabdomyosarcoma Study (IRS) group, metastatic disease, and achieving first complete remission (CR1) were identified as prognostic factors for EFS and/or OS in the univariate analysis.
Conclusions
Prognostic factors were identified and research questions for future clinical trials were addressed.
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