Intermediate-risk Rhabdomyosarcoma Research Articles

Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group

The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete. Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified. Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population. The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).

RMS13: A phase II trial using risk adapted focal proton beam radiation and/or surgery with the addition of maintenance chemotherapy in intermediate risk rhabdomyosarcoma.

10008 Background: European trials have demonstrated improved outcomes in SIOP high-risk/COG intermediate risk (IR) rhabdomyosarcoma (RMS) when 6 months of maintenance therapy (MTC) was added to ifosfamide, vincristine (VCR), dactinomycin (DAC) +/-doxorubicin chemotherapy. The effectiveness of MTC integrated with VCR, DAC and cyclophosphamide (CYC), standard North American chemotherapy, remains unclear. Methods: RMS13 is a phase II multicenter trial evaluating the safety and efficacy of risk adapted proton radiation therapy (RT) and the addition of MTC in patients with IR RMS (embryonal stage 1, Group III non-orbit, and stage 3 Group I, II were not eligible for MTC). Patients received 12 cycles of VCR (1.5mg/m2 weekly), DAC (0.045mg/kg q3weeks), and CYC (1200mg/m2 q3weeks) (VAC) followed by MTC with 4 cycles of oral CYC (50mg/m2 daily), bevacizumab (15mg/kg) q3wks, and sorafenib (90mg/m2 bid) (CBvSor). RT was prescribed based on local tumor status at the time of RT (Table 1). Five-year disease-free survival (DFS) using the Kaplan-Meier method and the cumulative incidence (CI) of primary site local failure (LF) was described. Results: 46 patients were enrolled (Table 1). One patient refused further therapy and was removed from the analysis. 5-year DFS for the entire cohort was 67.5% with a median follow up of 54 mo. The trial was halted since < 75% of enrolled patients received all prescribed CBvSor MTC. Of the 35 who were eligible for MTC, 24 initiated MTC and 18 completed protocol-directed MTC. Three pts received vinorelbine/CYC MTC after enrollment was stopped. Reasons for not completing CBvSor MTC included: progression prior (6), toxicity (5), refusal (3). The 5-year DFS for the 24 patients that started cycle 3 was 70.3%. When limited to patients classified as high-risk in RMS2005 trial, the 5-year DFS was 81.4%. No patients experienced LF after margin negative surgery. The CI of LF was: 0% following 36GyRBE RT for microscopic residual disease, 8% for patients with unresected tumors < 5cm receiving standard dose RT (50.4GyRBE), and 10% for patients with unresected tumors > = 5cm receiving dose escalated RT (59.4GyRBE). 5/6 patients with alveolar N1 disease recurred. Conclusions: Local control with risk adapted dose-escalated RT was excellent in IR patients. Those with nodal involvement fared poorly. While 4-cycles of MTC with CBvSor was not feasible, those who underwent at least 3 cycles experienced enhanced DFS outcomes, aligning with the positive results seen in other trials incorporating MTC. Clinical trial information: NCT01871766 . [Table: see text]

Radiation dose escalation and local control for intermediate-risk rhabdomyosarcoma on ARST1431: A report from the Children’s Oncology Group

10007 Background: The objective of this study was to evaluate local failure (LF) rates for patients with intermediate-risk rhabdomyosarcoma (IR-RMS) treated on the Children’s Oncology Group (COG) ARST1431 clinical trial. To improve local control, the radiation therapy (RT) dose was increased to 59.4 Gy for patients with tumors > 5cm at diagnosis and residual gross disease at the time of RT. Methods: The297 patients randomized on ARST1431 were included. LF was defined as progression or relapse at the primary tumor site. Gray’s test was used to compare the cumulative incidence of LF across variables. Results: There was a trend for lower 3-year LF in group III patients with fusion-positive disease (11.1%, 95% confidence interval (CI) 4.5%-21.1%) compared to patients with fusion-negative disease (21.8%, 95% CI 15.8%-28.4%), p = 0.09.There was no difference in the 3-year LF rate for patients who underwent proton RT (16.3%, 95% CI 9.6%-24.7%) compared to photon RT (16.2%, 95% CI 10.2%-23.6%;), p = 0.8. The 3-year LF rate for all patients with tumors > 5cm at diagnosis (24.9%, 95% CI 18.6%-31.7%) was significantly higher than that of patients with tumors ≤5cm at diagnosis (9.9%, 95% CI 5.2%-16.4%), p < 0.01. Of 81 patients with tumors > 5cm and residual gross disease after induction chemotherapy who went on to receive RT, 62 (76.5%) received the protocol-specified boost to 59.4 Gy. Patients who received the boost had a 3-year LF rate of 32.1% (95% CI 20.1%-44%), while patients who did not undergo an RT boost had a 3-year LF rate of 16.1% (95% CI 3.8%-36.2%), p = 0.3. For patients with group III, non-parameningeal disease, those who underwent delayed primary excision (DPE) had a significantly lower LF rate compared to those who did not undergo DPE (3-year rate of 5.6% (95% CI 1.4%-14.0%) vs. 22.0% (95% CI 14.5-30.7%), p < 0.01). Conclusions: On ARST1431, larger tumors ( > 5cm at diagnosis) were associated with increased risk of LF. Dose escalation to 59.4 Gy did not improve local control for patients with tumors > 5cm at diagnosis with residual gross disease at the time of RT. For a select group of non-parameningeal, group III patients who underwent DPE followed by RT, local control was improved. Clinical trial information: NCT02567435 .

Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group.

Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard Children's Oncology Group (COG) chemotherapy backbone of vincristine, actinomycin-D, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (VI) in children with intermediate-risk (IR) RMS. The feasibility phase of the COG IR-RMS trial, ARST1431 (NCT02567435), assigned 10 patients to receive 15mg/m2 /dose (dose level 1) of temsirolimus on days 1, 8, and 15 of each of three weekly VAC and VI cycles for the first 12weeks of induction chemotherapy. The primary endpoint of the feasibility phase was to establish the safe dose and safety of combining temsirolimus with VAC/VI. The combination regimen was deemed feasible if less than 40% of patients developed a priori defined nonhematological dose-limiting toxicities (DLTs). Ten patients (seven males and three females; median age=4.5 years [range: 0.2-14.4years]) with IR-RMS were enrolled and received dose level 1 of temsirolimus. Eight patients had FOXO1-negative disease, while two had FOXO1-positive disease. Two patients had metastatic disease. Of 10 patients, two developed DLTs: grade 3 oral mucositis and pneumonitis. Four patients (40%) had grade 4 neutropenia. No treatment-related mortality occurred. The median duration of the completion of the feasibility phase was 12.1weeks (range: 11.7-15weeks). Weekly temsirolimus at 15mg/m2 /dose during VAC/VI chemotherapy was feasible and well tolerated. The efficacy of this regimen is currently being tested in a phase III randomized trial against VAC/VI chemotherapy alone in the ARST1431 trial.

Circulating Tumor DNA Is Prognostic in Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor DNA (ctDNA) in IR RMS and to determine whether ctDNA detection before therapy is associated with outcome. Pretreatment serum and tumor samples were available from 124 patients with newly diagnosed IR RMS from the Children's Oncology Group biorepository, including 75 patients with fusion-negative rhabdomyosarcoma (FN-RMS) and 49 with fusion-positive rhabdomyosarcoma (FP-RMS) disease. We used ultralow passage whole-genome sequencing to detect copy number alterations and a new custom sequencing assay, Rhabdo-Seq, to detect rearrangements and single-nucleotide variants. We found that ultralow passage whole-genome sequencing was a method applicable to ctDNA detection in all patients with FN-RMS and that ctDNA was detectable in 13 of 75 serum samples (17%). However, the use of Rhabdo-Seq in FN-RMS samples also identified single-nucleotide variants, such as MYOD1L122R, previously associated with prognosis. Identification of pathognomonic translocations between PAX3 or PAX7 and FOXO1 by Rhabdo-Seq was the best method for measuring ctDNA in FP-RMS and detected ctDNA in 27 of 49 cases (55%). Patients with FN-RMS with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (event-free survival, 33.3% v 68.9%; P = .0028; overall survival, 33.3% v 83.2%; P < .0001) as did patients with FP-RMS (event-free survival, 37% v 70%; P = .045; overall survival, 39.2% v 75%; P = .023). In multivariable analysis, ctDNA was independently associated with worse prognosis in FN-RMS but not in the smaller FP-RMS cohort. Our study demonstrates that baseline ctDNA detection is feasible and is prognostic in IR RMS.

Chemotherapy-induced thrombocytopenia in pediatric oncology: Scope of the problem and opportunities for intervention.

Chemotherapy-induced thrombocytopenia (CIT) is a known hematologic complication of oncology treatment. This single-institution study examines the degree with which CIT impacts specific pediatric solid tumor cohorts reflected by platelet transfusion burden and treatment modifications. Data regarding clinically relevant CIT were obtained via a retrospective chart review of pediatric solid tumor patients treated at Memorial Sloan Kettering Cancer Center from 2013 to 2020. Patients were stratified based on histologic diagnoses as well as chemotherapy regimen. CIT impact was assessed through platelet transfusion means, chemotherapy dose reductions, and treatment delays. A total of 150 patients were included with mean age 10.3 [0.2-21.0]. Patients receiving therapy for high-risk neuroblastoma and localized Ewing sarcoma, both of which included high-dose cyclophosphamide and doxorubicin, required the most platelet transfusions over the treatment course, with a mean of 13 and 9, respectively. Reduced relative dose intensity (RDI), due in part to CIT, was greatest for the patients receiving therapy for high-risk and intermediate-risk rhabdomyosarcoma. Fifty-six percent of high-risk patients experienced a reduced RDI during the final two cycles of treatment and 69% of intermediate-risk patients experienced one during the final four cycles of treatment. The impact of CIT varied by the administered chemotherapy regimens and dose intensity of chemotherapy agents. This study demonstrated that CIT causes both marked platelet transfusion burden as well as treatment reduction and delay within certain solid tumor cohorts. This can lend to future studies aimed at reducing the burden of CIT and targeting the most at-risk populations.

Rising drug cost impacts on cost-effectiveness of 2 chemotherapy regimens for intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group.

The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective. A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs. Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices. Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions. Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.

Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group.

In vitro data suggest that the growth of rhabdomyosarcoma (RMS) cells is suppressed in a concentration-dependent manner by 4-hydroxycyclophosphamide (4HCY), the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY). Various retrospective studies on the relationship between genes encoding proteins involved in the formation and elimination of 4HCY (i.e., 4HCY pharmacokinetics) and cyclophosphamide (CY) efficacy and toxicity have been conflicting. We evaluated germline pharmacogenetics in 262 patients with newly diagnosed intermediate-risk RMS who participated in one prospective Children's Oncology Group clinical trial, ARST0531. Patients were treated with either vincristine/actinomycin/cyclophosphamide (VAC) or VAC alternating with vincristine/irinotecan (VAC/VI). We analyzed the associations between event-free survival and 394 single-nucleotide polymorphisms (SNP) in 14 drug metabolizing enzymes or transporters involved in 4HCY pharmacokinetics. Eight SNPs were associated (p-value <.05 by univariate analysis) with 3-year event-free survival; no SNPs survived a false discovery rate <0.05. Our data suggest that a pharmacogenomic approach to therapy personalization of cyclophosphamide in intermediate-risk rhabdomyosarcoma is not viable. Other methods to personalize therapy should be explored.

Advances in the management of pediatric genitourinary rhabdomyosarcoma.

Recent clinical trials have revealed several unanticipated complexities in the optimal management of genitourinary rhabdomyosarcoma (RMS). Improvement in outcomes for low- and intermediate-risk RMS over the past several decades led to the design of clinical trials aimed at reducing acute and late toxicity from extirpative surgeries, conventional radiotherapy, and cytotoxic chemotherapy. Results from these studies are mixed and have illuminated areas where historical risk stratification strategies need refining. Although radiotherapy has now become the standard for local control for most patients with genitourinary RMS, recent studies are demonstrating that there may be opportunities to minimize radiation toxicity while maintaining acceptable failure-free survival. A reduction in cyclophosphamide exposure may benefit select low-risk RMS patients but recent results illustrate that decreasing therapy intensity for most genitourinary RMS patients will require careful consideration in future prospective trials. Finally, recent studies highlight differences in perspective between European and North American investigators regarding the optimal balance of increased local failure rates but less toxicity versus improved event-free survival at a cost of higher toxicity. This review focuses on the results from the most recent RMS clinical trials and discusses their implications for the management of pediatric genitourinary RMS.

Abstract A55: Circulating tumor DNA in newly diagnosed intermediate-risk rhabdomyosarcoma

Abstract Background: Patients with intermediate-risk rhabdomyosarcoma (IR RMS) have approximately 60-70% chance of survival with current therapies. However, biomarkers of outcome and response to therapy are lacking for these patients. Circulating tumor DNA (ctDNA) has been shown to be prognostic in a wide range of cancer types, but it is unknown whether patients with IR RMS have detectable levels of ctDNA. Objective: To study ctDNA prevalence and prognostic impact in newly diagnosed IR RMS, we utilized two next-generation sequencing (NGS) approaches that detect the presence of somatic copy-number changes and oncogenic translocations. Methods: Cell-free DNA was extracted from serum samples obtained from patients with newly diagnosed IR RMS who enrolled on the COG studies ARST0531 and D9803, including patients with embryonal (ERMS) and alveolar (ARMS) histology subtypes. While both subtypes are characterized by frequent somatic copy-number variants (CNVs), ARMS is also defined by recurrent translocations. To detect CNVs, we performed ultra-low passage whole-genome sequencing (ULP-WGS). Translocations were detected with a validated custom hybrid capture assay (TranSS-Seq). Results: Serum samples were analyzed from 132 patients with IR RMS, including 75 with ERMS and 57 with ARMS. ctDNA was detected by CNVs in 70% (92/132) of IR RMS patients with similar detection rates in each histology: 65% (49/75) in ERMS and 75% (43/57) in ARMS. Among the ARMS samples sequenced, only 37% (18/49) were positive by TranSS-Seq. Furthermore, copy-number events resulting in amplifications of the somatic translocation frequently resulted in miscalculation of ctDNA content by the TranSS-Seq method. Estimates of event-free and overall survival were lower in patients with detectable ctDNA, though the differences were not statistically significant. Conclusion: Patients with IR RMS frequently have detectable levels of ctDNA that can be measured by NGS assays designed to detect somatic structural events. This study relied on previously banked serum samples and a relatively small retrospective analysis. These findings provide justification for our current efforts to utilize a large prospective study, COG ARST1431, to collect pretreatment and serial blood samples using procedures optimized for ctDNA assays. Sequencing of matched tumor samples is ongoing to understand the differences in sensitivity between ULP-WGS and TranSS-Seq for ctDNA detection in patients with ARMS. Citation Format: Samuel Abbou, David Hall, Donald A. Barkauskas, Kelly Klega, Anwesha Nag, Aaron R. Thorner, Mark Krailo, Steven Dubois, Douglas S. Hawkins, Brian D. Crompton. Circulating tumor DNA in newly diagnosed intermediate-risk rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A55.

Increased local failure for patients with intermediate-risk rhabdomyosarcoma on ARST0531: A report from the Children's Oncology Group.

The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531. This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803. For patients with group I/II alveolar RMS (n=55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n=141), it was 20.2%; and for group III embryonal RMS (n=228), it was 27.9% (P=.03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5cm (32.3% vs 16.7%; P=.001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P=.03). After the exclusion of patients 24months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P=.02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P=.004 and P=.05, respectively). Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.

Treatment Approach and Outcomes in Infants With Localized Rhabdomyosarcoma (RMS): Analysis of Children’s Oncology Group (COG) Protocols ARST 0331 and ARST0531

For children ≤ 2 years old enrolled on two recent COG studies for low-(ARST0331) and intermediate-risk RMS (ARST0531) clinical trials, recommended local control guidelines were provided but individualized treatment was permitted. Adherence to protocol guidelines by COG radiation oncologists and surgeons, variation in treatment from the protocol guidelines, and outcomes for this group were analyzed.

Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) has historically been of prognostic and therapeutic importance. However, classification has been complicated by shifting histologic criteria required for an ARMS diagnosis. Children's Oncology Group (COG) studies after IRS-IV, which included the height of this diagnostic shift, showed both an increased number of ARMS and an increase in the proportion of fusion-negative ARMS. Following diagnostic standardization and histologic re-review of ARMS cases enrolled during this era, analysis of low-risk (D9602) and intermediate-risk (D9803) rhabdomyosarcoma (RMS) studies showed that fusion status rather than histology best predicts prognosis for patients with RMS. This analysis remains to be completed for patients with high-risk RMS. We re-reviewed cases on high-risk COG studies D9802 and ARST0431 with an enrollment diagnosis of ARMS. We compared the event-free survival (EFS) and overall survival by histology, PAX-FOXO1 fusion, and clinical risk factors (Oberlin score) for patients with metastatic RMS using the log-rank test. Histology re-review resulted in reclassification as ERMS for 12% of D9802 cases and 5% of ARST0431 cases. Fusion-negative RMS had a superior EFS to fusion-positive RMS; however, poorer outcome for metastatic RMS was most related to clinical risk factors including age, primary site, and number of metastatic sites. In contrast to low- or intermediate-risk RMS, in metastatic RMS, clinical risk factors have the most impact on patient outcome. PAX-FOXO1 fusion is more common in patients with a high Oberlin score, but fusion status is not an independent biomarker of prognosis.

18F 2Fluoro-2deoxy-D-glucose positron emission tomography (FDG-PET) response to predict event-free survival (EFS) in intermediate risk (IR) or high risk (HR) rhabdomyosarcoma (RMS): A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG).

10549Background: Change in tumor size by anatomic imaging is not a reliable predictor of outcome in RMS. We reviewed metabolic response by FDG-PET for patients with IR and HR RMS enrolled on two CO...

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene-Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group.

Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion gene-negative RMS (FN-RMS) patients, but this has not been independently validated. The goal of this study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS. Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS, and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathologic characteristics as well as overall and event-free survival. MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N = 57; HR, 7.3; 95% CI, 1.9-27.0; P = 0.003) and failure-free survival (N = 57; HR, 6.1; 95% CI, 1.9-19.7; P = 0.002). This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk stratification in future prospective clinical trials.

Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

The majority of intermediate-risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999-2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy-three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5-year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS-IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.

Vincristine, dactinomycin, cyclophosphamide (VAC) versus VAC/V plus irinotecan (VI) for intermediate-risk rhabdomyosarcoma (IRRMS): A report from the Children’s Oncology Group Soft Tissue Sarcoma Committee.

10004 Background: The long-term event free survival (EFS) for IRRMS is 65%. Since VI had significant activity in metastatic and recurrent RMS, we tested whether adding VI to VAC would improve EFS for IRRMS. Methods: Patients (pts) with alveolar (A)RMS or incompletely resected (Group III) embryonal (E)RMS arising in an unfavorable primary site (Stage 2/3), both without distant metastases, < 50 years, and adequate organ function were eligible to be randomized to 42 weeks of VAC (V=1.5 mg/m2, A=0.045 mg/kg, C=1.2 g/m2 every 3 weeks) vs VAC/VI (I=50 mg/m2/day x 5 days) intravenously; doses were adjusted for children < 3 years; radiation therapy (36-50.4 Gy) was started at week 4, with individualized local control for children < 2 years allowed. The primary study endpoint was EFS. The study was designed with 80% power (5% 1-sided alpha level) to detect an increase in 5 yr EFS from 65% to 76%, a relative risk of 0.64. Results: 481 pts were entered between 12/2006-12/2012, with 461 confirmed eligible. Clinical f...

Histology and Fusion Status in Rhabdomyosarcoma

The International Classification of Rhabdomyosarcoma (ICR) has provided diagnostic criteria for rhabdomyosarcoma (RMS) and formed the basis of histologic risk stratification since its publication in 1995. However, the recognition of new variants of embryonal rhabdomyosarcoma (ERMS), shifts in the diagnostic criteria of alveolar rhabdomyosarcoma (ARMS), the increasing use of myogenin immunohistochemistry and recognition of the distinct biologic properties associated with fusion status all raised questions about the continued use of this classification system in the diagnosis and treatment of patients with RMS. Recent Children's Oncology Group Soft Tissue Sarcoma Committee analysis of histology and fusion status in the intermediate risk RMS study D9803 refined the histologic criteria of RMS. We validated the new diagnostic criteria against fusion status, allowing prospective examination of the prognostic value of histology compared with fusion status for risk-stratification of patients with RMS. This article summarizes the evolution of and current practices in the histologic and molecular classification of rhabdomyosarcoma.

PAX-FOXO1fusion status drives unfavorable outcome for children with rhabdomyosarcoma: A children's oncology group report

Rhabdomyosarcoma (RMS) is divided into two major histological subtypes: alveolar (ARMS) and embryonal (ERMS), with most ARMS expressing one of two oncogenic genes fusing PAX3 or PAX7 with FOXO1 (P3F and P7F, respectively). The Children's Oncology Group (COG) carried out a multi-institutional clinical trial to evaluate the prognostic value of PAX-FOXO1 fusion status. Study participants were treated on COG protocol D9803 for intermediate risk ARMS or ERMS using multi-agent chemotherapy, radiotherapy, and surgery. Central diagnostic pathology review and molecular testing for fusion genes were carried out on prospectively collected specimens. Event-free (EFS) and overall survival (OS) at 5 years were correlated with histological subtype and PAX-FOXO1 status. Of 616 eligible D9803 enrollees, 434 cases had adequate clinical, molecular, and pathology data for definitive classification as ERMS, ARMS P3F+ or P7F+, or ARMSn (without detectable fusion). EFS was worse for those with ARMS P3F+ (54%) and P7F+ (65%) than those with ERMS (77%; P < 0.001). EFS for ARMSn and ERMS were not statistically different (90% vs. 77%, P = 0.15). ARMS P3F+ had poorer OS (64%) than ARMS P7F+ (87%), ARMSn (89%), and ERMS (82%; P = 0.006). ARMSn has an outcome similar to ERMS and superior EFS compared to ARMS with either P3F or P7F, when given therapy designed for children with intermediate risk RMS. This prospective analysis supports incorporation of PAX-FOXO1 fusion status into risk stratification and treatment allocation.

Does body mass index at diagnosis or weight change during therapy predict toxicity or survival in intermediate risk rhabdomyosarcoma? A report from the Children's Oncology Group soft tissue sarcoma committee

Weight loss prevalence and its impact on toxicities and survival in intermediate risk rhabdomyosarcoma (IRMS) patients are unknown. We evaluated the association between weight change during therapy and number of toxicities, hospital days, infections, and overall survival and between baseline body mass index (BMI) and survival in patients treated on Children's Oncology Group trial D9803. Four hundred sixty-eight IRMS patients age ≥2 and <21 years treated on D9803 had required data. Regression models evaluated association between weight loss from baseline and toxicities, hospital days, infections, and survival. Kaplan-Meier curves and regression models evaluated baseline BMI percentile's association with survival. Thirty-five percent and 37% of patients had >5% weight loss at 12 and 24 weeks, respectively, with 16% and 19% losing >10% weight respectively. Greater than 10% weight loss at 24 weeks was associated with more toxicities and hospital days during subsequent therapy but not infection rate or survival. Baseline underweight patients (<5th percentile BMI) had borderline inferior survival compared with baseline average weight patients while there was no difference in survival seen between average weight and overweight or obese patients. Nearly one in five IRMS patients experienced >10% weight loss on therapy. This was associated with increased toxicity but not decreased survival compared with patients who had less weight loss. Baseline BMI percentile trended toward a significant association with survival. Future studies might investigate nutritional impact on quality of life and if weight loss is preventable by early nutritional intervention.