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Purpose Treatment recommendations for localized paratesticular rhabdomyosarcoma (PT RMS) differ in North America and Europe. We conducted a pooled analysis to identify demographic features and treatment choices that affect outcome. Patients and Methods We retrospectively analyzed the effect of nine demographic variables and four treatment choices on event-free survival (EFS) and overall survival (OS) from 12 studies conducted by five cooperative groups. Results Eight hundred forty-two patients with localized PT RMS who enrolled from 1988 to 2013 were included. Patients age ≥ 10 years were more likely than younger patients to have tumors that were > 5 cm, enlarged nodes (N1), or pathologically involved nodes ( P ≤ .05 each). With a median follow-up of 7.5 years, Kaplan-Meier estimates for 5-year EFS and OS were 87.7% and 94.8%, respectively. Of demographic variables, cooperative group, era of enrollment, age category, tumor size, Intergroup Rhabdomyosarcoma Study group, and T stage affected EFS ( P ≤ .05 each). Surgical assessment of regional nodes, which was performed in 23.5% of patients—usually in those age ≥ 10 years or with suspicious or N1 nodes—was the only treatment variable associated with EFS by univariable and multivariable analyses ( P ≤ .05 each) in patients age ≥ 1 year. A variable selection procedure on a proportional hazards regression model selected era of enrollment, age, tumor size, and surgical assessment of regional nodes as significant ( P ≤ .05 each) in the EFS model, and era of enrollment, age, tumor size, and histology ( P ≤ .05 each) in the OS model. Conclusion Localized PT RMS has a favorable prognosis. Age ≥ 10 years at diagnosis and tumor size larger than 5 cm are unfavorable prognostic features. Surgical assessment of regional nodes is important in patients age ≥ 10 years and in those with N1 nodes as it affects EFS.

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Purpose Intergroup Rhabdomyosarcoma Study Group (IRSG) studies III and IV showed improved failure-free survival (FFS) rates with vincristine, dactinomycin, and cyclophosphamide (VAC; total cumulative cyclophosphamide dose, 26.4 g/m2) compared with vincristine and dactinomycin (VA) for patients with subset-one low-risk embryonal rhabdomyosarcoma (ERMS; stage 1/2 group I/II ERMS or stage 1 group III orbit ERMS). The objective of Children's Oncology Group ARST0331 was to reduce the length of therapy without compromising FFS for this subset of low-risk patients by using VA in combination with lower-dose cyclophosphamide (total cumulative dose, 4.8 g/m2) plus radiotherapy (RT). Patients and Methods This noninferiority prospective clinical trial enrolled newly diagnosed patients with subset-one clinical features. Therapy included four cycles of VAC followed by four cycles of VA over 22 weeks. Patients with microscopic or gross residual disease at study entry received RT. Results With a median follow-up of 4.3 years, we observed 35 failures among 271 eligible patients versus 48.4 expected failures, calculated using a fixed outcome based on the FFS expected for similar patients treated on the IRSG D9602 protocol. The estimated 3-year FFS rate was 89% (95% CI, 85% to 92%), and the overall survival rate was 98% (95% CI, 95% to 99%). Patients with paratesticular tumors had the most favorable outcome. Three-year cumulative incidence rates for any local, regional, or distant failures were 7.6%, 1.5%, and 3.4%, respectively. Conclusion Shorter-duration therapy that included lower-dose cyclophosphamide and RT did not compromise FFS for patients with subset-one low-risk ERMS.

11570 Background: Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols included treatment modifications, which may have ameliorated late health outcomes for rhabdomyosarcoma (RMS) survivors treated in more recent era. Methods: We evaluated chronic health conditions (CHCs) and late mortality ( > 5 years from diagnosis) among survivors treated 1970-1990 (IRSG I-III) and 1991-1999 (IRSG IV), and associations with specific treatments to identify treatment-related factors for adverse outcomes. Associations between treatments and CHCs and mortality were evaluated using Fine and Gray’s proportional hazards method accounting for competing risks. Results: 856 survivors treated 1970-90 (median diagnosis age 5.4 years [0- 20]) and 306 treated 1991-99 (median diagnosis age 5.5 years [0-20]) were included. Significant exposure differences between eras included higher percentage (53% vs. 17%, p < 0.01) receiving ≥ 20gm/m2 cumulative alkylators in 1991-99, but more receiving platinums (13% vs 5%, p < 0.01) and abdomen/ pelvis radiation (29% vs. 23%, p = 0.04) in 1970-90. 20-year cumulative incidence for any (40% vs. 28%, p < 0.01), ≥2 (16% vs. 7%, p < 0.01), and endocrine (8% vs. 2.5%, p < 0.01) grade 3-5 CHCs was higher in 1970-90 compared to 1991-99. The hazard ratio (HR) for any (HR 0.7, 95% Confidence Interval [CI] 0.55-0.9), ≥2 (HR 0.38, 95% CI 0.22-0.66) and endocrine (HR 0.25, 95% CI 0.09-0.67) grade 3-5 CHC was lower for 1991-99 survivors than 1970-90. The effect of era (1991-99 vs 1970-90, HR 0.73; 95% CI 0.59-0.91) on CHC was not attenuated when treatment variables were added to multivariable model. Exposures with increased risk of grade 3-5 CHC included platinums (hearing, HR 2, 95% CI 1.07-3.8), anthracycline ≥250mg/m2 (cardiovascular, HR 2.7, 95% CI 1.2-6) and abdomen/ pelvis radiation (second malignant neoplasms, HR 2.1, 95% CI 1.1-4, gastrointestinal, HR 7.4, 95% CI 3.5-16 and endocrine, HR 2.5, 95% CI 1.4-4.4). Gonadal dysfunction was the most common endocrine CHC. There was no difference in all cause or cause-specific mortality between the two cohorts. Conclusions: RMS survivors from the IRSG IV era are at reduced risk for late onset chronic health conditions compared to previous era.

This Special Series issue of Journal of Clinical Oncology highlights collaborative efforts that have contributed to the remarkable progress achieved in advancing survival for pediatric cancers. These efforts have involved collaborations across a variety of medical subspecialties, institutions, and national and international cooperative study groups and, most importantly, collaborations among clinicians, scientists, and patients and their families. Unique to the pediatric cancer experience is a high level of participation in clinical trials that has been instrumental in establishing effective therapies for virtually all types of pediatric cancers; characterizing acute, long-term, and late-onset toxicities of therapy; refining treatment approaches adapted to the biologic characteristics of the disease; and, in recent decades, modifying therapy to prevent treatment-related adverse effects. Particularly featured within this series are innovative and genomic discoveries that have guided risk-adapted stratification of therapy and use of targeted therapy providing real prospects for precision medicine.

Purpose To compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression. Patients and Methods Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m2/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m2 administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m2/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen. Results Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%). Conclusion There was no difference in the response rates between the two irinotecan-vincristine schedules. We recommend the shorter, more convenient regimen (1B) for further investigation.

11525Background: Response to neoadjuvant chemotherapy correlates with a positive outcome in localized osteosarcoma patients. However, there are no reliable predictors of chemotherapy response. We i...

PurposeWe investigated whether tumors from diagnostic biopsies of primary rhabdomyosarcoma (RMS) contain relevant prognostic information in the form of gene expression signatures that can be used to model and predict outcome of patients.Patients and MethodsA 22,000-probe set microarray was used to evaluate 120 RMS specimens and correlate gene expression patterns to survival. Multivariate gene expression models or metagenes were developed using cross-validated Cox regression proportional hazards modeling and were evaluated using Kaplan-Meier analysis.ResultsA 34-metagene, based on expression patterns of 34 genes, was highly predictive of outcome. It was not highly correlated with individual clinical risk factors such as patient age, stage, tumor size, or histology. However, it was correlated with a risk classification used by the Children's Oncology Group and the biologic subsets of alveolar histology tumors.ConclusionThese data support further evaluation of RMS metagenes to discriminate patients with good prognosis from those with poor prognosis, with the potential to direct risk-adapted therapy.

Purpose 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 and Methods 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 α level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC. Results 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. Conclusion For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

Purpose Some patients with rhabdomyosarcoma (RMS) achieve less than a complete response (CR) despite receiving all planned therapy. We assessed the impact of best response at the completion of all therapy on patient outcome. Patients and Methods We studied 419 clinical group III participants who completed all protocol therapy without developing progressive disease for Intergroup Rhabdomyosarcoma Study (IRS) IV. Response (complete resolution [CR], partial response [PR; ≥ 50% decrease], or no response [NR; < 50% decrease and < 25% increase]) was determined by radiographic measurement and categorized by the best response. Results At the end of therapy, 341 participants (81%) achieved a best response of CR and 78 (19%) had a best response of PR/NR. Five-year failure-free survival was similar for participants achieving CR (80%) and PR/NR (78%). After adjustment for age, nodal status, primary site, and histology, there was no significant indication of lower risk of failure (hazard ratio [HR], 0.77; 95% CI, 0.46 to 1.27; P = .3) nor death (HR, 0.63; 95% CI, 0.36 to 1.09; P = .1) for CR versus PR/NR participants. Seventeen participants with a best response of PR/NR had surgical procedures; eight (50%) of 16 with available pathology reports had residual viable tumor and only three achieved a complete resection. Resection of residual masses was not associated with improved outcome. Conclusion CR status at the end of protocol therapy in clinical group III participants was not associated with a reduction of disease recurrence and death. Aggressive alternative therapy may not be warranted for RMS patients with a residual mass at the end of planned therapy.

Purpose To estimate the antitumor activity and toxicity of irinotecan alone and in combination with vincristine when administered as window therapy and in combination with standard chemotherapy in pediatric patients with newly diagnosed metastatic rhabdomyosarcoma. Patients and Methods Nineteen patients younger than age 21 years with newly diagnosed metastatic rhabdomyosarcoma or undifferentiated sarcoma received window therapy with two cycles of irinotecan (20 mg/m2 daily for 5 days, repeated for 2 weeks) and 50 patients received window therapy with vincristine 1.5 mg/m2 (weeks 0, 1, 3, and 4) and two cycles of irinotecan (20 mg/m2 daily for 5 days, repeated for 2 weeks). Patients who achieved a partial response (PR) or complete response (CR) received these agents alternating with vincristine (V; 1.5/mg/m2), dactinomycin (A; 1.5 mg/m2), and cyclophosphamide (C; 2.2 g/m2) during weeks 6 through 41. Nonresponders were treated with VAC alone. Radiotherapy was administered to sites of disease at weeks 15 to 21. Results The window response rate (PR/CR) for patients who received irinotecan was 42% (95% CI, 38% to 80%) but the high progressive disease (PD) rate of 32% (95% CI, 11% to 52%) prompted closure of the trial. The window CR/PR rate for patients who received vincristine and irinotecan was 70% (95% CI, 57% to 83%), and the PD rate was only 8%. GI toxicities (abdominal pain, diarrhea, dehydration) were the most common adverse effects associated with the administration of irinotecan. Conclusion The combination of vincristine and irinotecan is highly active in metastatic rhabdomyosarcoma. The different mechanism of action and nonoverlapping toxicity profile with VAC makes this combination an attractive candidate for further testing in intermediate risk patients with rhabdomyosarcoma.

Purpose The outcome for localized rhabdomyosarcoma (RMS) or undifferentiated sarcoma (UDS) is affected by age, histology, primary anatomic site, extent of disease, and therapy. Patients and Methods We evaluated patient and disease characteristics for their ability to predict outcome for patients with nonmetastatic RMS or UDS treated on Intergroup Rhabdomyosarcoma Study (IRS) -III (1984 to 1991) or IRS-IV (1991 to 1997). Results The estimated 5-year failure-free survival (FFS) rate was 90% for patients with embryonal RMS (ERMS) stage 1, group I or IIa; stage 2, group I; or group III orbit. The estimated 5-year FFS rate was 87% for patients with ERMS stage 1, group IIb or IIc; stage 1, group III nonorbit; stage 2, group II; and stage 3, group I or II; and 73% for patients with ERMS stage 2 or 3, group III. The estimated 5-year FFS rate was poor for patients with stage 2 or 3, group III ERMS with invasive (T2) tumors who were age younger than 1 year or 10 years or older (56%) and patients with stage 2 or 3, group III extremity primary tumors (43%). Overall, outcomes for patients with alveolar RMS (ARMS) or UDS were worse than for patients with ERMS. However, the 5-year FFS rate was good for patients with ARMS/UDS at favorable sites with group I or II (80%) or group III (76%) disease. The FFS rate was poorer for patients with ARMS/UDS at unfavorable sites with group I or II (66%) or group III (45%) disease. The estimated 5-year FFS rate was 31% for patients with group III ARMS/UDS at unfavorable sites with regional lymph node disease, which is similar to metastatic RMS. Conclusion Patient and disease characteristics identify distinct subsets with different outcomes, allowing the Soft Tissue Sarcoma Committee of the Children's Oncology Group to refine risk-adapted therapy assignment.

Purpose The Soft Tissue Sarcoma Committee of the Children's Oncology Group has conducted five upfront window trials in patients with newly diagnosed metastatic rhabdomyosarcoma to identify promising new treatment agents. Patients and Methods This pooled analysis identified a total of 420 patients (115 from Intergroup Rhabdomyosarcoma Study III [IRS-III] and 305 from the five window trials). We assessed window therapy response rate, failure-free survival (FFS), and overall survival (OS). Results Response rates (complete + partial response) assessed at week 6 of window therapy ranged from 41% to 55% and did not predict FFS (P = .073) or OS (P = .31). FFS was influenced by trial (P = .048); patients enrolled onto IRS-III and the ifosfamide/etoposide and ifosfamide/doxorubicin trials fared best. When grouped and compared with topoisomerase I poison trials, ifosfamide/topoisomerase II inhibitor trials had superior FFS (P = .013). However, there was no difference in survival. Conclusion Upfront phase II window trials can efficiently provide robust estimates of activity for new agents and combinations in newly diagnosed patients with high-risk rhabdomyosarcoma. Our data indicate that, for some phase II window trials, the risk of treatment failure may be increased but that the trend towards lower survival for some of the window trials compared with IRS-III is not statistically significant. Window nonresponders did not suffer worse FFS or OS than patients who responded to window therapy. Finally, these results provide a rationale for incorporating ifosfamide, etoposide, doxorubicin, and topoisomerase I poisons in future trials of high-risk metastatic rhabdomyosarcoma.

Purpose To analyze patterns of failure and factors predictive of local treatment failure in children enrolled on the third Intergroup Rhabdomyosarcoma Study who had either biopsy only or subtotal resection of their primary tumor, had no distant metastases, and received radiation therapy for local control. Patients and Methods Treatment failure was categorized as local, regional nodal, or distant metastatic. The 5-year cumulative risk of failure was estimated for each category and factors predictive of local failure risk were determined using the Cox model and binary recursive partitioning. Results The estimated 5-year cumulative incidence rates by failure category were: total local (with or without concurrent regional or distant failure), 19%; total regional nodal, 2%; total distant, 11%; and death from toxicity or unknown recurrence type, 4%. Lymph node involvement at diagnosis was the single factor most predictive of increased total local failure risk (5-year cumulative incidence 32%) compared with children with negative nodes or unknown node status (16%). No significant effect on local failure risk was observed by total radiotherapy dose over the prescribed range of 41.4 Gy to 50.4 Gy. For all patients (N = 405), the estimated 5-year failure-free survival and overall survival were, respectively, 70% and 78%. Conclusion Local failure after radiotherapy for group III rhabdomyosarcoma patients is the predominant type of relapse. Involved lymph nodes at diagnosis predict a higher risk of local and distant treatment failure compared with patients whose lymph nodes are negative.

Purpose To determine the antitumor activity and toxicity of topotecan given immediately after cyclophosphamide as window therapy, then in combination with conventional agents in pediatric patients with newly diagnosed metastatic rhabdomyosarcoma (RMS). Patients and Methods Sixty-one patients younger than 21 years with newly diagnosed metastatic RMS or undifferentiated sarcoma were assigned window therapy (weeks 0 to 6) with topotecan (0.75 mg/m2 daily × 5 every 21 days) immediately after cyclophosphamide (250 mg/m2 daily × 5 every 21 days; TC). We continued to give these agents in combination with vincristine (VTC) to patients who showed objective improvement, partial response (PR), or complete response (CR) to TC and alternated courses of VTC with vincristine, dactinomycin and cyclophosphamide (VAC) during weeks 6 to 41 (VTC/VAC). Those who showed no response or progressive disease after TC received only VAC. All patients received radiotherapy to sites of unresected disease (weeks 15 to 21). Results The overall response rate (CR + PR) to TC was 47% (95% CI, 35% to 60%). Tumor size ≤ 5 cm was associated with early response. Myelosuppression was the primary toxicity to TC. Overall 3-year disease-free survival and survival were estimated to be 10% (95% CI, 2% to 19%) and 20% (95% CI, 8% to 32%), respectively. Toxicity profiles for patients who received VTC/VAC or VAC alone were comparable. Conclusion Topotecan after cyclophosphamide is a combination that is active against newly diagnosed RMS, with an acceptable toxicity profile. Disease-free survival and overall survival, however, remain disappointing for children with metastatic RMS at diagnosis.

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...

PURPOSE The tolerance of escalating targeted doses of carboplatin combined with ifosfamide (IFOS)/etoposide (VP-16) (ICE) was assessed in children with recurrent solid tumors. PATIENTS AND METHODS To reduce interpatient variability in carboplatin systemic exposure, 45 children were treated with doses individualized to a target area under the serum concentration versus time curve (AUC) based on renal function, using technetium 99-diethyl-enetriamine pentaacetic acid (99mTc-DTPA) clearance to estimate glomerular filtration rate (GFR). Cohorts of at least three patients received carboplatin at an initial target AUC of 2 mg/mL x min, with escalations of 1 mg/mL x min in subsequent cohorts. Courses consisted of carboplatin on day 1 followed by IFOS 2 g/m2 plus VP-16 100 mg/m2 on days 2 and 3. Patients received at least two courses, with a maximum of eight courses possible in the absence of progressive disease. When only moderate toxicity occurred after escalation to 5 mg/mL x min, a third dose of IFOS plus VP-16 was added. After three patients were treated at this level, carboplatin escalation proceeded. RESULTS Neutropenia and thrombocytopenia were the dominant toxicities in the 43 assessable patients. At the target AUC of 8 mg/mL x min, 13 of 20 cycles were associated with febrile neutropenia. For phase II trials, we recommend a carboplatin target AUC of 6 mg/mL x min with three doses of IFOS and VP-16 for patients with prior craniospinal irradiation or high-dose cisplatin (CDDP)/VP-16, or 7 mg/mL x min for patients without such histories. There were two complete responses (CRs), 13 partial responses (PRs), and 17 objective responses (ORs). CONCLUSION The ICE regimen shows promising activity in pediatric solid tumors. The clear relationship between hematologic toxicity and carboplatin systemic exposure supports the use of targeted dosing in further trials of ICE chemotherapy.

Altering the study design considerably lengthened the accrual duration; however, the investigators made a difficult but appropriate decision that maintained the decision rule hazard ratio (HR) of 1.43. Of the potentially eligible 1,103 patients (representing 43.6% of all patients with Ewing sarcoma assessed for eligibility), 247 patients (22.4%) were not randomly assigned; this was the rate of screen failure. This rate included 130 potential accruals for which either the family or physician declined participation and more than 100 potential accruals who did not participate for miscellaneous or unknown reasons. Although not unusual for multisite, international cooperative group studies, the loss of these potential accruals increased the time period to reach the accrual goal. The primary planned analysis of 3-year event-free survival (EFS) was based on the intention-to-treat population. The study showed EFS rates of 75.4% (VAC) and 78.2% (VAI), with the HR for events

Three of 218 children treated with ifosfamide plus the uroprotectant mesna, in single- or combination-agent protocols, have developed Fanconi's renal syndrome, all of whom were in a subgroup of 86 children who had also received cisplatin or carboplatin therapy. Patients receiving ifosfamide who have received prior cisplatin (or carboplatin) are at significantly higher risk of developing Fanconi's syndrome than are those who have received no prior nephrotoxic therapy (P = .04). The role of prior nephrotoxic therapy, including cisplatin and its derivatives, and the total dose of ifosfamide should be considered in the assessment of this rare but serious and apparently irreversible side effect.

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...

10003 Background: Patients with RMS have a poor prognosis at first relapse/disease progression. VC has activity in RMS and preclinical data supports the use of bevacizumab and temsirolimus in RMS. Methods: Patients with biopsy proven RMS, 8 weeks, performance status < 2, adequate organ function and written informed consent. Patients were randomized between two regimens administered every 3 weeks for a maximum of 12 cycles: Regimen A- V 25 mg/m2 intravenously (IV) days 1 & 8, C 1.2 gms/m2 IV day 1, bevacizumab 15 mg/Kg IV day 1; b) Regimen B- VC identical to regimen A, temsirolimus 15 mg/m2 IV days 1, 8 & 15. Primary endpoint was event free survival (EFS) at 6 months. Disease response at week 6 was assessed using RECIST. The study had a phase 2 screening design and was powered to detect a 15% difference in EFS between the two regimens (α=0.2, 1-β=0.8, 2-sided test). Interim analysi...

This issueof JournalofClinicalOncologypresents twocontemporary manuscripts describing the absence of prognostic importance of gene fusion subtype in Ewing sarcoma (ES). Van Doorninck et al, reporting for the Children’s Oncology Group (COG), claim that this loss is a result of modern, more effective therapy that has eliminated the prognostic advantageof type1fusions inES.Similarly,LeDeleyetal foundthatgene fusion subtype has no prognostic significance in the Euro-E.W.I.N.G. 99 trial. However, they suggest that prior reports may have been premature and based on retrospective analyses—underscoring the need for large prospectivestudies.Regardlessofreasons, thesetwoarticlesare important additions to our understanding of the importance of gene fusion subtype in ES, stress that therapy is always an important prognostic factor, and remind us that the ability of clinicians to better tailor therapy must be based on robust prognostic factors. Although both studies claim to prospectively evaluate gene fusion subtype in ES, the actual sample set in both studies appears to be a convenience sample of the available tumor tissue from these clinical trials, withfusiondataonlyavailable forasubsetof theentirepatientpopulation enrolled. This is both a testament to the patients and families to enroll in these critically important biology studies and to local treating institutions for faithfully submitting tumor samples, but also a caveat that in neither study were the majority of enrollments available for fusion analysis. The Euro-E.W.I.N.G. 99 study had the larger data set (703 v 132). The COG study only used fresh-frozen tissue, while the Euro-E.W.I.N.G. 99 trial used both fresh and formalin-fixed paraffin-embedded tumors, although thevastmajorityoftumorsstudiedwerefresh-frozentumors(82%).Both studiesusedsimilarreverse-transcriptionpolymerasechainreaction(RTPCR) methodology and sequencing to detect fusion subtypes in these samples. Patient demographics were quite similar. From an enrollment perspective, the Euro-E.W.I.N.G. trial evaluated patients with both localized and metastatic disease, while the COG study only enrolled patients with localized disease. Both reports address the statistical power of their research. Assuming a progression-free survival difference of 20% in different fusion types, the Euro-E.W.I.N.G. analysis required a minimal sample size (localized tumors only) of 111 type 1 EWS-FLI1 fusions, 38 type 2 EWS-FLI1 fusions, 19 other EWS-FLI1 fusions, and 18 EWS-ERG fusionstotesttheirhypothesis.TheCOGreportstatesthattheyhada95% power to detect a relative failure rate of 4.5, with an 80% power to detect a relative failure rate of 3.0, using a 5% type 1 error. The treatment eras encompassing the two ES studies were quite similar. Although therapy in the two studies shared similarities, treatments were also clearly quite distinct. Patients in both studies received doxorubicin, etoposide, vincristine, and classic alkylators, although the COG study used both cyclophosphamide and ifosfamide, and some Euro-E.W.I.N.G. patients only received ifosfamide. There are substantial differences in dose, schedule, and timing of therapy; this issue may be important in that the recently completed AEWS0031 study clearly showed that dose-compressed therapy resulted in better outcomes. Some patients enrolled on Euro-E.W.I.N.G. were randomly assigned to either cyclophosphamide or ifosfamide, and many patients also received other agents including dactinomycin or high-dose therapy with stem cell reconstitution; some patients received whole-lung irradiation. Although the comparison of demographics and therapy approaches identified substantial differences, these two studies report remarkably similar results. There was a quite similar distribution of fusion subtypes, with the Euro-E.W.I.N.G. study having a slightly higher proportion of type 2 fusions (Table 1). More importantly, both studies report quite similar outcomes for each of the fusion subtypes, although details of analysis and presentation of data make a head-to-head comparison difficult (Table 2). Both studies therefore come to the same conclusion that fusion subtype is of no prognostic significance with the current therapy. Thesefindingsraiseadditionalconsiderationsconcerningutilization of molecular pathology testing for the fusion products in ES. The major technologies to detect these molecular changes are in situ hybridization (ISH)for thegenefusions,RT-PCRfor the fusiontranscripts, andimmunohistochemistry (IHC) for the fusion proteins. Though several comparisons can be made concerning the relative utility of these assays, an important issuegermanetothisdiscussionis the inabilityofbothISHand IHC assays to provide fusion subtype information. In contrast, as shown in the two articles in this issue, RT-PCR assays provide fusion subtype information by size fractionation after gel electrophoresis and direct sequencing of RT-PCR products. Previous studies established that ES diagnosis does not vary with fusion subtype. Furthermore, the two studies in this issue now conclude that fusion subtype does not impact on ES prognosis. Therefore, the need for collecting fusion subtype information

9516 Background: Intergroup Rhabdomyosarcoma Study (IRS) trials showed excellent survival with VA or VAC for patients with Stage 1 or 2, Group I or II ERMS or with Stage 1, Group III orbit ERMS. In...

9503 Background: The outcome for patients with metastatic RMS has remained approximately 30% survival for several decades. The COG phase 3 trial, ARST0431 aimed to 1) improve early disease control using interval compressed therapy of known active agents: vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide, etoposide (IE) and 2) to determine the feasibility and toxicity of vincristine/irinotecan (VI) given concurrently with radiation therapy. Methods: We conducted a phase 3, single arm study. Previously untreated patients

9505 Background: We present pooled data from 643 patients (pts) treated in 14 studies conducted by European and American cooperative groups. Methods: Clinical factors, including age, histology, sit...

10035 Background: Patients with RMS in first relapse/disease progression have a poor prognosis. TPZ, a hypoxic cell toxin, has been shown to enhance activity of traditional cytotoxic chemotherapy. Methods: Eligible patients comprised those with biopsy proven RMS, 5days, and any ≥ Grade 3 vomiting, stomatitis, cardiotoxicity or other non-hematopoietic toxicity. Post-recurrence survival was t...

10013 Background: Patients with RMS have a poor prognosis at first relapse/disease progression. CPT-11 has significant and schedule-dependent preclinical activity in RMS, and prolonged exposure results in increased efficacy. Methods: Patients with biopsy proven RMS, < 21 years of age at original diagnosis and unfavorable prognosis at first relapse/progression were eligible. Entry criteria were: life expectancy ≥ 2 months, performance status ≤ 2, adequate organ function and written informed consent. Patients were randomized to one of two schedules of CPT-11/VCR: Regimen 1A: CPT-11, 20 mg/m2 intravenously (IV) daily × 5d × 2w on weeks 1 and 4, VCR 1.5 mg/m2 IV on day 1 of weeks 1, 2, 4 and 5; Regimen 1B: CPT-11, 50 mg/m2 IV daily × 5d on weeks 1 and 4, VCR identical to IA. Disease response at week 6 was assessed using RECIST. Secondary endpoints included toxicity, progression free survival (PFS) and survival (OS). The study was powered to detect a 25% improvement in response to IA when compared to IB (α=0.1...

9542 Background: Prognosis factors on outcome for metastatic RMS are still matter of discussion. The analysis of a large cohort of patients can give arguments for development of risk-based therapy. Methods: We studied data from SIOP 84, SIOP 98, European Intergroup MMT89–91, Italian RMS4.99, IRS-III, -IV Pilot, -IV, -V, -D9501 to look at the influence of age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease at the 3 year event-free survival. Results: 788 patients were included in the analyze and 776 in the multivariate analyse. The 3 year overall survival and EFS were 34% (se 1.7) and 27 % (se 1.6) respectively. By univariate analysis, 3-year EFS was significantly influenced by age 10 years or more (15% vs 36%), alveolar histology (28% vs 40%), location of primary tumor in unfavorable site -parameningeal, extremity and “other” sites- (31% vs 48%) the presence of three or more metastatic (17% vs 38%), the presence of bone or bone marrow involvement (24% vs 45%). By multivariate analysis, histology had no more impact on EFS. The EFS was strongly correlated to the number of the 4 other unfavorable prognostic factors: age, site of the primary, number of metastis sites, bone/bone marrow involvement relative risks were 1.6 for age (p No significant financial relationships to disclose.

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 2, 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 rd 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 nd 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.

8509 Background: Children with metastatic RMS continue to fare poorly and new agents are needed. CPT is active in pediatric RMS xenografts when given in protracted schedules (JCO 17:1815, 1999). A ...

8501 Background: At the end of therapy, some patients with RMS have residual masses despite receiving all planned chemotherapy and radiotherapy. For IRS IV subjects with Group III (non-metastatic, ...

9502 Background: RMS is the most common soft-tissue sarcoma in childhood and is generally sensitive to currently available chemotherapeutic regimens. At present, there is no way to prospectively identify the 30–40% of patients destined to fail initial therapy. We sought to develop a proteomic signature comprised of signal pathway endpoints to predict outcome in a group of uniformly treated children with Stage III RMS and identify new targets for therapy. Methods: Thirty-four pre-treatment patient samples selected on the basis of tissue availability representing both embryonal and alveolar histologies were analyzed employing laser capture microdissection with multiplexed proteomic analysis using reverse phase protein microarray technology. All patients had been entered onto IRS studies and treated with combined chemotherapy and XRT. A panel of 13 specific antibodies was employed based on ongoing work pointing toward specific cell signaling pathways playing a role in the biological behavior of RMS. Validate...

8513 Background: Initial response to induction chemotherapy (CT) predicts FFS in osteosarcoma and Ewing sarcoma. Current European studies in RMS tailor therapy based on induction response. For IRS IV subjects with Group III RMS, we assessed whether reported response to induction therapy predicted FFS. Methods: We studied 453 Group III subjects who received induction CT, had response assessed at week 8 and continued with protocol therapy. Induction CT was followed by radiation therapy (RT) starting after week 9. Response to induction therapy was determined by radiographic measurement of tumor at weeks 0 and 8. Complete response (CR: complete resolution of disease), partial response (PR: ≥ 50% decrease in the sum of the products of the maximum perpendicular diameters of measurable lesions), no response (NR: 25% increase) was coded by local institutions. Results: Response rate at week 8 was 77% (CR=21%, PR=56%) but response had no influence on FFS ...

PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd × 5] × 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m2 (qd × 5) × 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m2, despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m2/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd × 5) × 2 schedule, beginning at a dose of 20 mg/m2. These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.

One hundred seventy-seven children and young adults with various malignant neoplasms were prospectively tested for hearing loss after they had received cisplatin (n = 146), cranial irradiation (n = 18), or both (n = 13). Adequate renal function, no history of treatment with ototoxic drugs other than cisplatin, and availability for repeated audiometric testing were requirements for enrollment. Substantial hearing loss, defined as a hearing threshold of 50 dB or greater, was noted in only 11% of the cohort on tests conducted at the common speech frequencies (500 to 3,000 Hz). About half the patients had substantial deficits at higher frequencies (4,000 to 8,000 Hz). The probability of substantial hearing loss was directly related to the cumulative dose of cisplatin. In nonirradiated patients tested at the speech frequencies, there was a negligible risk of substantial deficits over the dose range of 90 to 360 mg/m2. As the dose increased to 720 mg/m2, the risk increased to 22%. In irradiated patients who later received cisplatin, cumulative drug doses as low as 270 mg/m2 were associated with a high probability of substantial hearing loss, suggesting potentiation of ototoxicity when these therapies are used together. Hearing acuity was either not affected or only minimally decreased in the irradiation-only group. Younger age, prior irradiation, and the presence of a CNS tumor each contributed significantly to the severity of hearing deficits at given cisplatin dose levels. We conclude that early increases in hearing threshold at a stimulus frequency of 4,000 Hz indicate probable subsequent deficits at lower frequencies, especially in young children with CNS tumors who have received cranial irradiation. The probability charts derived from this analysis should provide a useful tool for predicting hearing loss in the speech frequencies.

We determined the risk of impaired excretion of methotrexate (MTX) in children with osteosarcoma, who also were receiving cisplatin, by analyzing urinary markers of renal tubular damage, as well as serum creatinine measured before each dose of MTX. MTX clearance was impaired in seven of the ten patients studied after cisplatin therapy. Patients with a urinary N-acetyl-beta-D-glucosaminidase (NAG) concentration of greater than 1.5 U/mmol creatinine or a greater than 50% increase in serum creatinine relative to the pretherapy level were approximately 30 times more likely to have MTX half-lives greater than 3.5 hours than were patients with lower values for these markers; MTX clearance was always impaired if both markers were elevated. If neither urinary NAG nor serum creatinine concentrations increased, the risk of impaired MTX excretion was negligible. Our findings demonstrate that urinary NAG and serum creatinine levels, measured before MTX administration, can be used to identify patients who will have difficulty in clearing the drug.

Fifty-two previously untreated patients with localized Ewing's sarcoma of bone were treated with nonintensive chemotherapy in combination with surgery or radiation therapy (RT). RT was delivered to limited volumes in a dose dependent on the initial response to induction chemotherapy (30 to 35 Gy v 50 to 55 Gy). Fifty of the 52 patients achieved complete or partial responses with induction chemotherapy, with one nonresponding patient rendered free of tumor with surgery. Fifty patients were evaluable for local control of tumor and overall response to protocol therapy. Seventeen relapses have occurred; three metastatic, four local plus metastatic, and ten local. Two factors predicted worse disease-free survival: high WBC count (P = .03) and size of primary tumor (P = .05). Of the 14 local recurrences, 12 occurred in 28 patients who presented with primary tumors greater than 8 cm in size while only two of 22 patients with lesions less than 8 cm had local recurrence. The Kaplan-Meier estimate of disease-free survival at 3 years is 82% for those with small lesions and 64% for those with larger lesions. Site of primary was of no prognostic value (P = .27). The 5-year survival estimate for all patients is 80% (median time on study, 3.3 years).

Hypoxanthine:guanine phosphoribosyltransferase (HPRT) activity was measured in 14 human osteosarcomas to test whether a subset of these tumors was deficient in the purine salvage pathway enzyme and thus provide a rationale for therapy with methotrexate-thymidine rescue. All tumors contained HPRT activity within the range previously reported for xenografts of human osteosarcoma. Three patients received methotrexate (3.375 g/m2/24 hours) as a 72-hour continuous infusion with thymidine rescue (2.0 g/m2/24 hours) beginning 24 hours after the start of the methotrexate infusion. The methotrexate-thymidine infusion was well tolerated by all patients with no significant toxicity; however, there were no responses. We conclude that osteosarcomas are not deficient in HPRT activity. Therefore, the previously reported rationale for therapy of osteosarcoma with methotrexate-thymidine based on lack of activity of this enzyme is not valid. This combination, although well tolerated, is inconvenient and requires prolonged hospitalization. Therefore, without a valid rationale it cannot be recommended for therapy of patients with osteosarcoma.