Treatment results for patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III and IV, 1984-1997: a report from the Children's Oncology Group.

PURPOSE: To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984-1997. METHODS: Chart review and standard statistical procedures. PATIENTS AND TUMORS: Patients were 1-18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA +/- C with RT; 41 received VA +/- C alone. RT was assigned, not randomized. RESULTS: Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, < or = 5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors >5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients. CONCLUSION: Patients with Stage 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT.

Prenatal X-ray exposure and rhabdomyosarcoma in children: a report from the children's oncology group.

The association between antenatal diagnostic X-ray exposure and risk of rhabdomyosarcoma in children was assessed in a national case-control study of 319 rhabdomyosarcoma cases and 319 matched controls. Data were collected by telephone interviews of subjects' parents. Overall, an odds ratio (OR) of 1.9 [95% confidence interval (CI), 1.1-3.4] was found for any X-ray examination of the mother during pregnancy. Risk was greatest for X-ray exposure during the first trimester (OR, 5.7; 95% CI, 1.2-27.8) and was also increased for the third trimester (OR, 2.0; 95% CI, 0.9-4.6), whereas second trimester exposure was not associated with increased risk. A nonsignificant increase in risk was found for any X-rays of the abdomen, pelvis, chest, or back. Increased risk was significantly associated with "other" X-ray exposures (relative risk, 2.9; 95% CI, 1.1-7.7), primarily composed of dental X-rays. The association was strongest between embryonal rhabdomyosarcoma and first trimester exposure (relative risk, 10.5; 95% CI, 1.5-458.4). This observation regarding embryonal rhabdomyosarcoma, and our previous report of an increased frequency of major malformations in rhabdomyosarcoma are compatible with findings from animal studies in which Ptc heterozygous knockout mice exhibited an increased risk of radiation-induced development defects and of spontaneously occurring embryonal rhabdomyosarcoma.

Primary renal sarcomas in the Intergroup Rhabdomyosarcoma Study Group (IRSG) experience, 1972-2005: A report from the Children's Oncology Group.

PURPOSE: To describe clinical and pathologic characteristics and outcome of patients with renal sarcomas. PATIENTS/METHODS: The IRSG database includes newly diagnosed patients <21 years old with rhabdomyosarcoma (RMS) or undifferentiated sarcoma (UDS). We identified patients with renal sarcoma and reviewed their charts. RESULTS: Ten of the 5,746 eligible IRSG patients enrolled from 1972 to 2005 had primary renal embryonal RMS (N = 6) or UDS (N = 4). Anaplasia was present in six (60%) of the tumors. Patients' ages ranged from 2.6 to 17.8 years. Tumor diameters ranged from 7 to 15 cm (median, 12 cm). At diagnosis, seven patients had localized disease: four underwent complete removal of tumor (Group I), two had microscopic residual (Group II), and one had gross residual tumor (Group III). Three patients had distant metastases (Group IV) in lungs and bone. Nine patients received vincristine, actinomycin D and cyclophosphamide (VAC). Two Group I patients received no radiation therapy (XRT); others received XRT to the primary tumor and to some metastatic sites. Nine patients achieved complete disappearance of tumor, six due to the initial operation. Tumors recurred in lung (N = 2) or brain (N = 1) in Group IV patients; each died within 16 months. The Group III patient died of Aspergillus pneumonia. The six Group I and II patients survive, continuously disease-free, at 2.7-17.3 years (median, 4.7 years). CONCLUSIONS: Patients with renal sarcomas often present with large tumors, many of them containing anaplastic features. Removing all gross disease at diagnosis, if feasible, is a critical component of treatment to curing patients with renal sarcoma.

Results in patients with cranial parameningeal sarcoma and metastases (Stage 4) treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols II-IV, 1978-1997: report from the Children's Oncology Group.

PURPOSE: Determine outcome of patients with cranial parameningeal sarcoma and concurrent metastases treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols II-IV. PATIENTS: We identified 91 patients in the database, which includes newly diagnosed subjects <21 years old with rhabdomyosarcoma (RMS) and undifferentiated sarcoma, and reviewed their charts in detail. RESULTS: The 54 males and 37 females were <1-19 years at diagnosis. Primary sites were nasopharynx-nasal cavity, middle ear/mastoid and parapharyngeal area ("better" sites, 55%), paranasal sinus and infratemporal-pterygopalatine area ("worse" sites, 42%), and other (3%). Sixty-eight percent of informative patients had direct intracranial extension. Major metastatic sites at diagnosis were lung (63%), bone marrow (33%), and bone (27%). Treatment included vincristine, actinomycin D, and cyclophosphamide (VAC) chemotherapy and radiotherapy to the primary tumor and up to five metastatic sites/tissues. OUTCOME: The estimated 10-year failure-free survival (FFS) rate was 32% (95% confidence interval [CI]: 22%, 42%). Sixty patients had progressive disease (N = 49) or death as a first event (N = 11); another developed myelodysplastic syndrome and died. Sites of first progression/relapse were distant (55%), local (12%), CNS extension (8%), mixed (6%), and uncertain (18%). Factors indicating likelihood of 10-year FFS included tumor arising in "better" versus "worse" sites (FFS 46% vs. 18%, P = 0.02) and embryonal versus other histology (FFS 37% vs. 19%, P = 0.06). CONCLUSIONS: Cure was possible for some patients with metastatic cranial parameningeal sarcoma. Patients with the best outlook had embryonal RMS located in the nasopharynx/nasal cavity, middle ear/mastoid, or parapharyngeal region. Distant metastases were the most frequent type of recurrence, indicating that more effective systemic agents are needed to eliminate residual disease.

Treatment of localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma: lessons learned from intergroup rhabdomyosarcoma studies III and IV.

PURPOSE: The characteristics and clinical outcomes of children and adolescents with localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma (RMS) treated on national protocols from the Intergroup Rhabdomyosarcoma Group are reported. PATIENTS AND METHODS: We conducted a retrospective review of 164 children and adolescents enrolled in the third and fourth Intergroup Rhabdomyosarcoma Studies. Variables analyzed included age, sex, primary tumor site, histologic subtype, clinical group, therapy, site and rate of treatment failure, and time to initial recurrence. RESULTS: Localized nonorbital, nonparameningeal RMS accounted for 9% of all cases of RMS. The median age at diagnosis was 5 years; the median follow-up was 6.6 years. Estimated 5-year failure-free survival (FFS) and survival (S) rates were 76% (95% CI, 69% to 83%) and 83% (95% CI, 77% to 89%), respectively. In multivariate analysis, patients with clinically involved regional nodes (N1) had worse FFS (P =.02). For patients with embryonal tumors, FFS was significantly improved, especially among patients with Group I/II without nodal disease clinical Group I, II N0. For patients with alveolar/undifferentiated histology, FFS was significantly worse in children under the age of 1 year. Actuarial estimates of recurrences at 15 years were local (19%), regional (5%), and distant (9%). CONCLUSION: More than 80% of patients with RMS of the head and neck are cured of their disease using surgery and vincristine, dactinomycin +/- cyclophosphamide with or without radiotherapy. Our results indicate that early, limited exposure to cyclophosphamide might reduce recurrence in low-risk embryonal patients and that reduced dosages might achieve comparable results with improved toxicity profiles. These hypotheses will be tested in the next generation of trials from the Soft Tissue Committee of the Children's Oncology Group.

PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group.

PURPOSE: Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue malignancy of children and adolescents. Most ARMS patients express PAX3-FKHR or PAX7-FKHR gene fusions resulting from t(2;13) or t(1;13) translocations, respectively. We wished to confirm the diagnostic specificity of gene fusion detection in a large cohort of RMS patients and to evaluate whether these alterations influence clinical outcome in ARMS. PATIENTS AND METHODS: We determined PAX3-FKHR or PAX7-FKHR fusion status in 171 childhood rhabdomyosarcoma (RMS) patients entered onto the Intergroup Rhabdomyosarcoma Study IV, including 78 ARMS patients, using established reverse transcriptase polymerase chain reaction assays. All patients received central pathologic review and were treated using uniform protocols, allowing for meaningful outcome analysis. We examined the relationship between gene fusion status and clinical outcome in the ARMS cohort. RESULTS: PAX3-FKHR and PAX7-FKHR fusion transcripts were detected in 55% and 22% of ARMS patients, respectively; 23% were fusion-negative. All other RMS patients lacked transcripts, confirming the specificity of these alterations for ARMS. Fusion status was not associated with outcome differences in patients with locoregional ARMS. However, in patients presenting with metastatic disease, there was a striking difference in outcome between PAX7-FKHR and PAX3-FKHR patient groups (estimated 4-year overall survival rate of 75% for PAX7-FKHR v 8% for PAX3-FKHR; P =.0015). Multivariate analysis demonstrated a significantly increased risk of failure (P =.025) and death (P =.019) in patients with metastatic disease if their tumors expressed PAX3-FKHR. Among metastatic ARMS, bone marrow involvement was significantly higher in PAX3-FKHR-positive patients. CONCLUSION: Not only are PAX-FKHR fusion transcripts specific for ARMS, but expression of PAX3-FKHR and PAX7-FKHR identifies a very high-risk subgroup and a favorable outcome subgroup, respectively, among patients presenting with metastatic ARMS.

Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV.

PURPOSE: To identify risk factors associated with outcomes in children with metastatic rhabdomyosarcoma (RMS) treated on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV). PATIENTS AND METHODS: Patients with metastatic RMS were treated with one of two regimens that incorporated a window of either ifosfamide and etoposide (IE) with vincristine, dactinomycin, and cyclophosphamide (VAC) or vincristine, melphalan (VM) and VAC. Study end points were failure-free survival (FFS) and overall survival (OS). Clinical factors including age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease were correlated with those end points. RESULTS: One hundred twenty-seven patients were eligible for analysis. The estimated 3-year OS and FFS for all patients were 39% and 25%, respectively. By univariate analysis, 3-year OS was significantly influenced by histology (47% for embryonal v 34% for all others, P =.026) and increasing number of metastatic sites (P =.028). By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor (P =.007 and.006, respectively). The combination of embryonal histology with two or fewer metastatic sites identified a subgroup with 3-year FFS of 40% and OS of 47%. CONCLUSION: Children with group IV RMS treated on the IRS-IV study had improved OS and FFS if they had two or fewer metastatic sites and embryonal histology. This favorable subset of patients has outcomes approaching those observed in selected patients with localized, nonmetastatic disease. Thus, these patients might not be appropriate candidates for regimens that include experimental agents with substantial toxicities or unproven antitumor activity.

Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

PURPOSE: Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. IRSG D9602 protocol (1997 to 2004) objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients. PATIENTS AND METHODS: Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients. RESULTS: Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77). CONCLUSION: Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients.

Impact of tumor viability at second-look procedures performed before completing treatment on the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV, 1991-1997: a report from the children's oncology group.

PURPOSES: The aims of the study were to compare results of clinical/radiographic studies before second-look procedures (SLP) with SLP specimens from patients with gross residual sarcoma at diagnosis and to relate tumor viability to outcome. PATIENTS: Seventy-three patients underwent SLP before completing chemotherapy, with (n = 59) or without (n = 14) radiotherapy. Tumor sites were bladder/prostate (n = 27), head/orbit/parameningeal (n = 22), extremity/trunk (n = 14), and retroperitoneum/pelvis (n = 10). RESULTS: Of 14 patients, 1 (7%) with clinical/radiographic complete response (CR) had viable tumor. Of 59 patients, 35 (59%) without CR had viable tumor. Five-year failure-free survival (FFS) rates were 81% in 37 patients without viable tumor and 53% in 36 patients with viable tumor (Cox proportional hazards adjusted P = .05). Five-year FFS rates were 67% in 15 patients with clear margins and 43% in 21 patients with tumor-involved margins (n = 18) or viable gross tumor (n = 3) (Cox proportional hazards adjusted P = .04). Five-year survival was 78% to 79% among 73 patients with and 333 patients without SLP during treatment. CONCLUSIONS: Second-look procedures can show whether viable tumor is present and may be beneficial in selected patients with rhabdomyosarcoma. Disappearance of tumor (CR) usually correlated with no viable tumor at SLP. However, 41% of patients without CR had no viable tumor. Those without viable tumor had increased FFS but not survival compared to those with viable tumor.

Treatment of children and adolescents with localized parameningeal sarcoma: experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through -IV, 1978-1997.

BACKGROUND: We reviewed 611 patients with parameningeal sarcoma entered on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-II through IV (1978-1997), to delineate treatment results and evaluate prognostic factors. PROCEDURE: Primary sites were the middle ear/mastoid (N = 138), nasopharynx/nasal cavity (N = 235), paranasal sinuses (N = 132), parapharyngeal region (N = 29), and the pterygopalatine/infratemporal fossa (N = 77). Treatment was initial biopsy or surgery followed by multiagent chemotherapy and radiation therapy (XRT). Beginning in 1977, patients with cranial nerve palsy, cranial base bony erosion, and/or intracranial extension at diagnosis were considered as having meningeal involvement. They received triple intrathecal medications, whole brain XRT, and then spinal XRT. These treatments were successively eliminated from 1980 to 1991. RESULTS: The 611 patients' overall survival rate at 5 years was 73% (95% confidence interval, 70-77%). Favorable prognostic factors were: age 1-9 years at diagnosis; primary tumor in the nasopharynx/nasal cavity, middle ear/mastoid, or parapharyngeal areas; no meningeal involvement; and non-invasive tumors (T1). Thirty-five of 526 patients (6.7%) with information about presence/absence of meningeal involvement at diagnosis developed central nervous system (CNS) extension at 5-164 weeks (median, 46 weeks) after starting therapy. The estimated 5-year cumulative incidence rate of CNS extension during the study period was 5-7% (P = 0.88). CONCLUSIONS: Biopsy, XRT to the target volume, and systemic chemotherapy are successful treatments for the large majority of patients with localized parameningeal sarcoma. Carefully defining and irradiating the initial volume should reduce the risk of CNS failure. Aggressive initial surgical management of these patients is unnecessary.