Intermediate-risk Rhabdomyosarcoma Research Articles

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.

Playing Bad Cards Properly: Challenges to Improving Cure Rates in Rhabdomyosarcoma

“Success . . . comes not from having the right cards, but from playing bad ones properly.” —Joshua Dool. At least two thirds of children and adolescents with intermediateand higher-risk nonmetastatic rhabdomyosarcoma can be cured with multidisciplinary therapy. Although a reasonably good outcome, it clearly is not good enough. The total burden of therapy is high, with substantial acute and chronic toxicity. The best established therapy is a three-drug chemotherapy combination using vincristine, dactinomycin, and an alkylator (either cyclophosphamide or ifosfamide) and local control measures that cause substantial morbidity, particularly in our youngest patients. The therapy approach and anticipated outcome have not substantially changed in the last two decades. Oberlin et al report in Journal of Clinical Oncology the results of the MMT95 trial, a well-designed prospective, randomized study comparing intensified six-drug therapy versus standard three-drug chemotherapy in nonmetastatic rhabdomyosarcoma and other chemosensitive childhood soft tissue sarcomas. Intensification of chemotherapy provided no survival advantage, no reduction in the intensity of local therapy, and added toxicity—certainly not the answer for which these investigators had hoped. Why have we been unable to make any recent progress in treating rhabdomyosarcoma? Successful clinical trials must be well designed. Most advances in pediatric oncology have used prospective, randomized comparative study designs. However, good trial design certainly does not guarantee success. The two most recently completed intermediate-risk rhabdomyosarcoma studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group (IRS-IV comparing vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide; and vincristine, ifosfamide, and etoposide) and the Children’s Oncology Group (COG; D9803 comparing VAC v VAC plus topotecan and cyclophosphamide) were well designed and appropriately powered and evaluated agents with substantial clinical activity, yet they failed to show any improvement in the experimental arms. The MMT95 (Malignant Mesenchymal Tumor 1995) study prospectively randomly assigned patients to receive threeor six-drug therapy, with a switch to the six-drug combination in patients who had disease progression, less than 50% imaging response, or poor histologic response. This design decreased the number of patients who received either only threeor only six-drug therapy. In addition, a relatively high number of eligible patients were not randomly assigned (149 of 606; 25%). However, these flaws, while decreasing the statistical power of this study, are relatively minor and do not seem to have affected the final negative results. Selection of the right patient population is a key component of sound clinical trial design. The MMT95 study enrolled higher-risk patients with rhabdomyosarcoma with both embryonal and alveolar histologies. These two histologies are biologically distinct, yet all cooperative group trials in higher-risk rhabdomyosarcoma have included both histologies, with few data to suggest substantial differences in treatment response for the different histologic entities. In addition, the MMT95 study enrolled 72 patients with chemotherapy-sensitive nonrhabdomyosarcoma soft tissue sarcomas. Soft tissue primitive neuroectodermal tumors (27 patients enrolled onto MMT95) share morphologic, immunohistochemical, and genetic features with Ewing tumors arising in bone, are classified by WHO inclusively as Ewing sarcoma/primitive neuroectodermal tumor, and are currently treated in studies of the Ewing family of tumors. COG trials previously enrolled patients with undifferentiated sarcomas together with rhabdomyosarcomas, but these patients were recently treated on a study for other nonrhabdomyosarcoma soft tissue sarcomas (COG ARST0332: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas in patients under30yearsofage).Ratesofmetastasis inMMT95werehigher inthese patient subsets (P .03); the number of patients enrolled with these histologies was insufficient to provide insights into the impact of more intensive therapy. Cure rates have improved in some childhood cancers with the optimization of chemotherapy schedules and doses. Decades of empiric adjustments using a modest number of active chemotherapy

Relationship of fusion protein status and outcome for children with intermediate-risk rhabdomyosarcoma: A Children's Oncology Group report.

9535 Background: Rhabdomyosarcoma (RMS) includes both alveolar (ARMS) and embryonal (ERMS) subtypes, with ARMS generally having a worse prognosis. Most ARMS express one of two fusion genes generated by balanced translocations fusing DNA binding domains of PAX3 or PAX7 with FOXO1 (P3F and P7F, respectively). The prognostic value of fusion gene versus histological subtype is not clear. We carried out a multi-institutional clinical trial through the Children’s Oncology Group (COG) to evaluate this molecular feature. Methods: All participants were enrolled on COG D9803 from 1999-2005 for children and young adults with intermediate risk ARMS or ERMS, and were treated with vincristine, dactinomycin, and cyclophosphamide (+/- topotecan), radiotherapy, and surgery. Diagnostic specimens were reviewed centrally and fusion gene was assessed by fluorescence in situ hybridization (FISH), RT-PCR, or both. Event-free (EFS) and overall survival (OAS) at 5 years (yr) was correlated with histology and fusion gene status. Results: Of 327 cases included in a re-review of the pathology, 295 could be classified biologically. Cases with ARMS but unknown trans status (N=23) and those with mixed or RMS-NOS histology without trans (N=17) and 12 with inadequate clinical data were excluded. ARMS cases with detectable fusion gene were defined as ARMS P3F+, ARMS P7F+, while ARMSn was reserved for those without detectable fusion. P3F and P7F were not observed in ERMS. An additional 189 pts with ERMS tumors not re-reviewed were also included in the survival analysis. There was a trend toward better EFS for those with ARMSn than for ERMS (p=0.15); EFS for ARMS P3F+ and P7F+ were worse than that for ERMS (p<0.001). Only ALV P3F+ cases had poorer OAS (p=0.004). Conclusions: ARMSn has an outcome similar to ERMS and a superior EFS compared to ARMS with P3F or P7F, when given therapy designed for intermediate risk RMS. This analysis, from a single, prospective trial restricted to those with non-metastatic disease and with near universal molecular evaluation, supports incorporating fusion status into treatment allocation. [Table: see text]

Abstract 5581: A non-coding RNA panel is prognostically superior to standard pathologic criteria and coding transcripts in rhabdomyosarcoma

Abstract INTRODUCTION: Rhabdomyosarcoma (RMS), the most common pediatric soft-tissue sarcoma, is stratified by the Children's Oncology Group (COG) into low/intermediate/high risk based on clinical outcomes. Most RMS patients, however, are categorized as intermediate-risk where survival is highly heterogeneous, suggesting an inherent inability to accurately stratify a large proportion of patients. This study profiled intermediate-risk RMSs for expressions of coding and non-coding transcripts with the aim of constructing prognostic signatures. The goal was to identify RNA panels that reflect underlying tumor biology and provide better risk stratification than routine clinicopathologic parameters. METHODS: RNAs extracted from 79 prospectively-obtained primary tumors from intermediate-risk RMS patients under COG clinical trial protocols were profiled on Affymetrix Human Exon 1.0 ST microarrays. Expressions of 1,400,033 probe set regions (PSRs) representing annotated and unannotated transcripts were analyzed using the Genetrix suite of microarray analysis tools. Cox regression and leave-n-out cross validation were used to derive and finalize the expression signatures. Individual prognostic potentials of the coding and non-coding signatures, and that of a signature that combined both features were compared against each other. RESULTS: Standard pathologic prognosticators such as histologic subtype classification (alveolar versus embryonal) and PAX-FKHR fusion gene status were unable to predict outcome in this cohort (p=0.40 and 0.45, respectively). Cox regression analysis on 17,049 coding transcripts created a 42-gene meta-feature that was able to predict survival (p=0.00024). Leave-n-out cross validation of this meta-feature upheld its prognostic ability (p=0.00030). Analysis of PSRs corresponding to unannotated transcripts identified a 32-PSR meta-feature that also predicted survival with greater significance than PSRs corresponding to coding transcripts (p<0.00001). To eliminate feature redundancy, multiple PSRs interrogating the same unannotated genomic locus were replaced by a representative PSR that reduced the meta-feature size to 24 PSRs, which was still able to predict survival better than the coding gene meta-feature (p<0.00001). A meta-feature that combined coding and non-coding RNA features retained its ability to predict outcome (p=0.00002), with non-coding RNA features contributing towards the bulk of its prognostic potential. CONCLUSIONS: A more concise non-coding RNA meta-feature was able to better predict outcome in intermediate-risk RMS than a larger coding gene meta-feature, where standard pathologic prognosticators failed. These observations point to the possible role of non-coding transcripts in regulating and determining RMS biology and aggressiveness, and their potential to serve as novel prognostic indicators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5581. doi:1538-7445.AM2012-5581

Abstract A23: A non-coding RNA panel predicts intermediate-risk childhood rhabdomyosarcoma prognosis better than standard pathologic criteria and coding genes

Abstract Introduction: Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma, stratified by the Children's Oncology Group (COG) into low/intermediate/high risk based on clinical outcomes. However, most patients are categorized as intermediate-risk where survival is highly heterogeneous, thus suggesting an inability to accurately stratify a majority of patients. We profiled intermediate-risk RMS's for levels of coding and non-coding transcripts to construct prognostic signatures. The goal was to identify panels of RNAs that reflect underlying tumor biology and provide better risk stratification than routine clinicopathologic parameters. Methods: Transcriptomes from 79 prospectively-obtained primary tumors from intermediate-risk RMS patients under COG clinical trial protocols were profiled on Affymetrix Human Exon 1.0 ST microarrays. Expressions of 1,400,033 probe sets representing annotated and unannotated transcripts were analyzed using Genetrix suite of microarray analysis tools. Cox regression and leave-n-out cross validation were used to derive and finalize the expression signatures. An effort was made compare individual prognostic potentials of the coding and non-coding signatures, and that of a signature that combined both features. Results: Standard pathologic prognosticators such as histologic subtype classification (alveolar versus embryonal) and PAX-FKHR fusion gene status were unable to predict outcome in this cohort (p=0.40 and 0.45, respectively). Cox regression analysis on 17,049 coding transcripts created a 42-gene meta-feature that was able to predict survival (p=0.00024). Leave-n-out cross validation of this meta-feature upheld its prognostic ability (p=0.00030). Analysis of probe set regions (PSRs) corresponding to unannotated “dark matter” transcripts identified a 32-PSR meta-feature that also predicted survival with greater significance than PSRs corresponding to coding transcripts (p<0.00001). To reduce feature redundancy, multiple PSRs interrogating the same genomic locus were replaced by a representative PSR that shrunk the meta-feature size to 24 PSRs, which was still able to predict survival better than the coding gene meta-feature (p<0.00001). A meta-feature that combined coding and non-coding RNA features retained its ability to predict outcome (p=0.00002), with non-coding RNA features contributing towards the bulk of its prognostic potential. Conclusions: A more concise non-coding RNA meta-feature was able to better predict outcome than a larger coding gene meta-feature in intermediate-risk RMS, where standard pathologic prognosticators failed. This suggests the role of non-coding transcripts in regulating and determining RMS biology and aggressiveness, and their potential to serve as novel prognostic indicators. Citation Format: Anirban P. Mitra, Jonathan D. Buckley, Sheetal A. Mitra, Elai Davicioni, James R. Anderson, Philipp Kapranov, Stephen X. Skapek, Douglas S. Hawkins, Timothy J. Triche. A non-coding RNA panel predicts intermediate-risk childhood rhabdomyosarcoma prognosis better than standard pathologic criteria and coding genes [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A23.

Abstract B6: Human genome contains a large number of very long intergenic transcribed regions, some of which are associated with cancer outcome

Abstract Introduction: Transcriptional output of human genome is far more complex than predicted by the current set of protein-coding annotations. However, the fraction of the genome that is utilized to produce cellular RNA whose function is hitherto not completely defined, the so called “dark matter RNA”, and its role in regulating cancer progression remains an open issue. Furthermore, our understanding of the repertoire of human RNAs is far from complete, and almost all RNA-Seq studies have missed this complexity due to the limited view obtained when only interrogating the polyA+ RNA fraction confounded by biases due to PCR amplifications. This study aimed to assess the complexity of RNAs produced by cancerous and normal human tissues in an unbiased fashion, and examine any potential roles of such transcripts in modulating cancer outcome using pediatric rhabdomyosarcoma as a model malignancy. Methods: Total RNA was profiled from a number of tissues using single-molecule sequencing (SMS) to examine the complexity of transcriptome in the human genome in an unbiased fashion. To minimize methodological biases, no PCR amplification, ligation, or size selection were used. In parallel, to examine the relevance of different RNAs in predicting cancer outcome, expression profiles on 79 intermediate-risk childhood rhabdomyosarcoma primary tumors were generated on Affymetrix Human Exon 1.0 ST microarrays and compared to prospectively-obtained outcome information. Results: SMS analysis revealed that “dark matter RNAs” comprised up to two-thirds of total non-ribosomal, non-mitochondrial RNA in human cells. PolyA+ RNA fraction had a significantly lower complexity then the total RNA, especially in non-exonic regions. Strikingly, several hundreds of very long (100′s of kbs) abundant intergenic transcribed regions (vlinc's) were identified in areas of the genome that were devoid of protein-coding annotations. Most (~80%) of the genomic sequences covered by vlincs did not overlap with previously documented long intergenic non-coding (linc) RNAs, suggesting large number of RNAs in intergenic space are yet to be uncovered. To address the question whether vlincs may be associated with prognosis in cancer, specifically childhood rhabdomyosarcoma, array-based whole-genome expression profiles were analyzed. Interestingly, probe sets that were the best predictors of cancer outcome were found to be outside boundaries of exons of protein-coding transcripts. Strikingly, most of the top-ranked probe sets were found to cluster together and defined a >230 kb vlinc region on chromosome 2, previously found by the SMS analysis. This vlinc region was singularly able to predict survival for the entire cohort (p=0.007). Conclusions: Our data suggest that many genomic regions currently defined as intergenic give rise to very long transcribed regions that can modulate ultimate cancer behavior. This indicates that a great number of the “dark matter” RNAs uncharacterized thus far may be involved in tumorigenesis, and can be used as diagnostic, prognostic and therapeutic-response indicators. In turn, this argues for functional importance of the genome's “dark matter”. Citation Format: Anirban P. Mitra, Timothy J. Triche, Sheetal A. Mitra, Jonathan D. Buckley, Poul H. B. Sorensen, C Patrick Reynolds, Robert J. Arceci, Patrice Milos, Georges St. Laurent, Philipp Kapranov. Human genome contains a large number of very long intergenic transcribed regions, some of which are associated with cancer outcome [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B6.

Effect of Radiotherapy Techniques (IMRT vs. 3D-CRT) on Outcome in Patients With Intermediate-Risk Rhabdomyosarcoma Enrolled in COG D9803—A Report From the Children’s Oncology Group

To compare the dosimetric parameters of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in patients with intermediate-risk rhabdomyosarcoma and to analyze their effect on locoregional control and failure-free survival (FFS). The study population consisted of 375 patients enrolled in the Children's Oncology Group protocol D9803 study, receiving IMRT or 3D-CRT. Dosimetric data were collected from 179 patients with an available composite plan. The chi-square test or Fisher's exact test was used to compare the patient characteristics and radiotherapy parameters between the two groups. The interval-to-event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards regression analysis was used to examine the effect of the treatment technique on FFS after adjusting for primary site and risk group. The median follow-up time was 5.7 and 4.2 years for patients receiving 3D-CRT and IMRT, respectively. No differences in the 5-year failure of locoregional control (18% vs. 15%) or FFS (72% vs. 76%) rates were noted between the two groups. Multivariate analysis revealed no association between the two techniques and FFS. Patients with primary tumors in parameningeal sites were more likely to receive IMRT than 3D-CRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50 Gy, photon energy of ≤6 MV, and >5 radiation fields than those who received 3D-CRT. The coverage of the IMRT planning target volume by the prescription dose was improved compared with the coverage using 3D-CRT with similar target dose heterogeneity. IMRT improved the target dose coverage compared with 3D-CRT, although an improvement in locoregional control or FFS could not be demonstrated in this population. Future studies comparing the integral dose to nontarget tissue and late radiation toxicity between the two groups are warranted.

Tumor volume and patient weight as predictors of outcome in children with intermediate risk rhabdomyosarcoma

AbstractBACKGROUND:The objectives of this study were to compare tumor volume and patient weight versus traditional factors of tumor size (greatest dimension) and patient age and to determine which parameters best discriminated outcome among pediatric patients with intermediate‐risk rhabdomyosarcoma (RMS).METHODS:Complete information was available for 370 patients with nonmetastatic RMS who were enrolled in the Children's Oncology Group (COG) intermediate‐risk study D9803 (1999‐2005). The Kaplan‐Meier method was used to estimate survival distributions. A recursive partitioning model was used to identify prognostic factors that were associated with event‐free survival (EFS). Cox proportional hazards regression models were used to estimate the association between patient characteristics and the risk of failure or death.RESULTS:For all patients with intermediate‐risk RMS, a recursive partitioning algorithm for EFS suggested that prognostic groups should be defined optimally by tumor volume (with a transition point at 20 cm3), patient weight (with a transition point at 50 kg), and embryonal histology. Tumor volume and patient weight added significant outcome information to the standard prognostic factors, including greatest tumor dimension and patient age (P = .02). The ability to resect the tumor completely was not associated significantly with the size of the patient, and patient weight did not significantly modify the association between tumor volume and EFS after adjustment for standard risk factors (P = .2).CONCLUSIONS:The factors that had the strongest association with EFS were tumor volume, patient weight, and histology. On the basis of regression modeling, tumor volume and patient weight were superior predictors of outcome compared with greatest tumor dimension and patient age in children with intermediate‐risk RMS. The current results indicated that the prognostic performance of tumor volume and patient weight should be assessed in an independent prospective study. Cancer 2011. © 2010 American Cancer Society.

The Effect of Radiation Therapy Techniques (IMRT vs. 3DCRT) on Outcome in Patients with Intermediate Risk Rhabdomyosarcoma Enrolled in COG D9803: A Report from COG

The Effect of Radiation Therapy Techniques (IMRT vs. 3DCRT) on Outcome in Patients with Intermediate Risk Rhabdomyosarcoma Enrolled in COG D9803: A Report from COG

Early Treatment Failure in Intermediate-Risk Rhabdomyosarcoma: Results From IRS-IV and D9803—A Report From the Children's Oncology Group

The goal of this study was to determine the frequency and clinical features of early treatment failure during induction chemotherapy before protocol radiation therapy for children with intermediate-risk rhabdomyosarcoma (RMS). Patients with intermediate-risk RMS enrolled onto the Intergroup Rhabdomyosarcoma Study-IV and the Children's Oncology Group D9803 study were reviewed for an early treatment failure. Early failure was defined as failure caused by progressive disease, death as a result of progressive disease, or death as a result of other causes occurring fewer than 120 days from study entry. Patients with parameningeal site RMS with high-risk features who received radiation therapy at week 1 were excluded from analysis. Overall survival (OS) was estimated using the Kaplan-Meier method. Fisher's exact test was used to compare differences between groups. Cumulative incidence of progression was estimated. Of 916 patients, 20 (2.2%) were found to have an early disease progression and did not receive planned protocol radiotherapy. Three additional early failures resulted from treatment-related death without progression. Median time to failure was 48 days (range, 7 to 106 days). Nineteen (95%) of the 20 patients experienced progression at their primary site. Five-year OS was 32% (95% CI, 12% to 54%) for patients experiencing an early progression. A small proportion of patients with intermediate-risk RMS suffer an early failure as a result of early progression (2.2%) or treatment-related mortality (0.3%). The majority of patients with early progression had a local failure. Earlier radiotherapy could potentially improve outcome by preventing early local progression.

Second-look operation with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma (RMS): A report from the Children's Oncology Group (COG).

9504 Background: The majority of intermediate risk RMS patients have gross residual disease (Group III) after their first operative procedure. In these patients local control is usually obtained wi...

Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803

The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC). Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided alpha level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC. A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups. For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS‐IV in intermediate risk rhabdomyosarcoma: A report from the Children's Oncology Group

Over 50% of patients with rhabdomyosarcoma (RMS) have intermediate risk disease, with a 3-year failure-free survival (FFS) of 50%-70% depending on histology. Doxorubicin is active against RMS, but its role in improving outcome remains controversial. Ifosfamide is as active as cyclophosphamide in RMS, with the Fourth Intergroup RMS Study (IRS-IV) showing equivalent outcomes for patients treated with ifosfamide for the first 28 weeks compared to cyclophosphamide. Treatment with alternating cycles of non-cross-resistant chemotherapy has been used in a number of diseases with good results. The results of a pilot study utilizing alternating courses of vincristine, doxorubicin, cyclophosphamide, and etoposide/ifosfamide (VDC/IE) were compared for outcome and patient characteristics to a group of similar matched patients treated on IRS-IV. The 5-year FFS for patients with parameningeal (PM) primaries on IRS-IV and the VDC/IE study were 72% and 82%, respectively (P = 0.26); for patients with non-PM primaries, the estimated risk of failure for VDC/IE study versus IRS-IV was 0.54. Combining all disease sites and performing analysis for relative risk of failure for 46 VDC/IE patients and 342 IRS-IV patients, the relative risk of failure for the VDC/IE study compared to the IRS-IV study is 0.5 (P = 0.06). VDC/IE is as effective therapy for intermediate risk RMS as IRS-IV therapy. It is being explored along with irinotecan in relapsed patients and newly diagnosed high-risk patients.

Nasal ala rhabdomyosarcoma misdiagnosed as a facial infection

Summary We present the case of an 18-month-old female with nasal ala swelling thought to be of infectious etiology. There was no response to multiple courses of oral and topical antibiotics. Biopsy of the lesion revealed alveolar rhabdomyosarcoma. The patient received the D9803 closed trial chemotherapy protocol for intermediate risk rhabdomyosarcoma standard arm and high-dose-rate brachytherapy. Treatment with a combination of chemotherapy and brachytherapy is becoming increasingly accepted for this type of tumor and is associated with limited morbidity. Although facial rhabdomyosarcoma is relatively uncommon, it should be part of the differential diagnosis in the presence of a rapidly growing facial swelling unresponsive to antibiotics.

Randomized phase III trial comparing vincristine, actinomycin, cyclophosphamide (VAC) with VAC/V topotecan/cyclophosphamide (TC) for intermediate risk rhabdomyosarcoma (IRRMS). D9803, COG study

9509 Background: IRRMS was defined as nonmetastatic alveolar (A) RMS or undifferentiated sarcoma (UDS); stage (stg) 2 and 3, group (gr) III embryonal (E) RMS; stg 4 ERMS <10y. IRRMS had a 5 yr failure free survival (FFS) of 64% on IRS IV. Since T alone and with C has significant activity in RMS, we tested whether alternating VAC/VTC improved FFS for IRRMS compared with VAC alone. Methods: Patients (pts) < 50 y with IRRMS with adequate organ function were randomized to 39 wks of VAC (V=1.5 mg/m2, A=0.045 mg/kg, C=2.2 g/m2 q 3 wk) vs VAC alternating with VTC (T=0.75 mg/m2/d ×5, C=250 mg/m2/d ×5 q 3 wk), with additional wkly V; doses adjusted for age <3y; local therapy was after wk 12. Pts with parameningeal RMS/meningeal extension (PME) were nonrandomly treated with VAC and immediate XRT. Primary study endpoint was FFS. The study was designed with 80% power (5% 2-sided alpha level) to detect an increase in 5 yr FFS from 64% to 75%, a relative risk (RR) of 0.64, with VAC/VTC, requiring 518 randomized pts. Results reflect the 3rd of 4 planned analyses (75% information); O'Brien Fleming adjusted alpha level is 0.0166; and Cox PH model was used. Results: 620 eligible pts were entered from 9/99 to 8/05: 266 randomized to VAC, 253 to VAC/VTC, 101 PME patients were nonrandomly treated with VAC. Treatment strata were ERMS stg 2/3, gr III 37%; ERMS grp IV <10 y 6%; ARMS/UDS stg 1 or gr I 16%; ARMS/UDS other 25%; PME 16%. 3% of pts were <1 y, 69% 1–9 y, 28% ≥10 y; 13% of pts were stg 1; 26% stg 2; 54% stg 3; 7% stg 4. 77% pts had gr III tumors. Primary tumor sites were PM in 35% pts, extremity 15%, bladder/prostate 16%, retroperitoneal/perineal 15%, other 19%. Median follow up is 2.4 yrs. FFS at 2 yrs is 77% with VAC and 72% with VAC/VTC. Observed data are inconsistent with hypothesized improvement under VAC/VTC (RR=1.20, 98.34% CI: 0.78–1.85, p=0.3). Similar patients on IRS IV had 2 yr FFS of 77%. 2 yr survival (OS) with VAC: 91%; VAC/VTC: 87% (RR=0.94, CI: 0.55–1.59, p=0.8). There were 12 2nd malignancies and 10 deaths as first events. 4 of 10 deaths were from hepatopathy, which decreased in incidence following dose changes for A and C. Conclusions: In IRRMS, VAC/VTC does not significantly improve FFS nor OS versus VAC, and outcome is similar to IRS IV. No significant financial relationships to disclose.

Cyclophosphamide Dose Intensification During Induction Therapy for Intermediate-Risk Pediatric Rhabdomyosarcoma Is Feasible but Does Not Improve Outcome: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group

Cyclophosphamide Dose Intensification During Induction Therapy for Intermediate-Risk Pediatric Rhabdomyosarcoma Is Feasible but Does Not Improve Outcome: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group

Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide

Over 50% of patients with newly diagnosed rhabdomyosarcoma (RMS) are in the ‘intermediate risk’ group with a 3-year progression-free survival of approximately 65%. This group consists of stage 1, group III, non-orbit tumours; stage 2, group II and III; and all stage 3 patients utilising the Intergroup Rhabdomyosarcoma Study (IRS) staging system. The role of doxorubicin in the treatment of RMS has been controversial. Ifosfamide, both alone and in combination with etoposide, has significant activity in patients with RMS. The aim of this pilot study was to examine the efficacy and toxicity of a chemotherapy regimen of alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for intermediate risk RMS. 30 patients with intermediate risk RMS or undifferentiated sarcoma (US) were treated with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and etoposide/ifosfamide (EI) at planned intervals of 3 weeks. Local treatment of the tumour in most cases was performed after four cycles of chemotherapy, followed by an additional 10 cycles of chemotherapy. At a median follow-up of 37.5 months, the Kaplan–Meier estimate of 3-year event-free survival was 85% (95% confidence interval 72–99%). The overall survival at 3 years was 91% (95% confidence interval 80–100%). No patient died from toxicity. The most common toxicity was febrile neutropenia in 35% of VDC and 26% of El cycles. No nephrotoxicity or cardiac toxicity was seen. No patient progressed prior to week 12 local therapy. Alternating cycles of VDC and EI are an effective treatment for patients with intermediate risk RMS and US. Toxicity is tolerable. Delaying local treatment until week 12 does not compromise outcome.