A prospective study of cerebral, frontal lobe, and temporal lobe volumes and neuropsychological performance in children with primary brain tumors treated with cranial radiation.

BACKGROUND: Cranial radiation therapy (RT) is an important component in the treatment of pediatric brain tumors. However, it can result in long-term effects on the developing brain. This prospective study assessed the effects of cranial RT on cerebral, frontal lobe, and temporal lobe volumes and their correlation with higher cognitive functioning. METHODS: Ten pediatric patients with primary brain tumors treated with cranial RT and 14 age- and sex-matched healthy children serving as controls were evaluated. Quantitative magnetic resonance imaging and neuropsychological assessments (language, memory, auditory and visual processing, and vocabulary) were performed at the baseline and 6, 15, and 27 months after RT. The effects of age, the time since RT, and the cerebral RT dose on brain volumes and neuropsychological performance were analyzed with linear mixed effects model analyses. RESULTS: Cerebral volume increased significantly with age in both groups (P = .01); this increase in volume was more pronounced in younger children. Vocabulary performance was found to be significantly associated with a greater cerebral volume (P = .05) and a lower RT dose (P = .003). No relation was observed between the RT dose and the cerebral volume. There was no difference in the corresponding neuropsychological tests between the 2 groups. CONCLUSIONS: This prospective study found significant relations among the RT dose, cerebral volumes, and rate of vocabulary development among children receiving RT. The results of this study provide further support for clinical trials aimed at reducing cranial RT doses in the pediatric population. Cancer 2017;161-168. © 2016 American Cancer Society.

A prospective study of corpus callosum regional volumes and neurocognitive outcomes following cranial radiation for pediatric brain tumors.

PURPOSE/OBJECTIVE(S): Cranial radiation therapy (CRT) may disrupt the corpus callosum (CC), which plays an important role in basic motor and cognitive functions. The aim of this prospective longitudinal study was to assess changes in CC mid-sagittal areas, CC volumes, and performance on neuropsychological (NP) tests related to the CC in children following CRT. MATERIALS/METHODS: Twelve pediatric patients were treated with CRT for primary brain malignancies. Thirteen age-matched healthy volunteers served as controls. Brain MRIs and NP assessment emphasizing motor dexterity, processing speed, visuomotor integration, and working memory (visual and verbal) were performed at baseline and at 6, 15, and 27 months following completion of CRT. Linear mixed effects (LME) analyses were used to evaluate patient NP performance and changes in regional CC volumes (genu, anterior body, mid-body, posterior body, and splenium) and mid-sagittal areas over time and with radiation doses, correcting for age at CRT start. RESULTS: The mean age at CRT was 9.41 (range 1.2-15.7) years. The median prescription dose was 54 (range 18-59.4) Gy. LME analysis revealed a significant decrease in overall CC volumes over time (p < 0.00001), with no overall effect of radiation dose. Analysis of individual CC regions demonstrated a significant decrease in all regional volumes over time (p < 0.00001) in patients, with no effect of radiation dose. Only in the splenium was there a trend toward a dose-dependent effect (p = 0.093). Patients had significantly reduced NP performance across visits-most notably in motor dexterity and visual working memory (both p < 0.0001). CONCLUSIONS: These prospective data demonstrate a significant decrease in CC regional volumes after CRT, with associated decline in neurocognitive function, most notably in manual dexterity, attention, and working memory. Further prospective study of larger cohorts of patients is needed to establish the relationship between CRT dose, neuroanatomical, and functional changes in the CC.

Correction to: A prospective study of corpus callosum regional volumes and neurocognitive outcomes following cranial radiation for pediatric brain tumors.

AbstractThe published version of this article unfortunately contained an error. Author "E. Mark Mahone" has been published incorrectly by capturing "Mark Mahone" as family name when it should only be "Mahone". Given in this article is the corrected name.

Management of pediatric intracranial low-grade gliomas: long-term follow-up after radiation therapy.

INTRODUCTION: The treatment of pediatric intracranial low-grade gliomas (LGG) generally begins with maximal safe resection. Radiation therapy (RT) and chemotherapy are typically reserved for patients with incomplete resection and/or disease progression. We report long-term treatment outcomes and toxicities in a cohort of pediatric patients with LGG after RT. METHODS: Thirty-four patients <21 years old with intracranial LGG who were treated with RT at the Johns Hopkins Hospital were included in this retrospective analysis. Patients were evaluated for overall survival (OS), progression-free survival (PFS), recurrence patterns, and treatment toxicities using descriptive statistics, Kaplan-Meier curves, and Cox proportional hazard regressions. RESULTS: The mean age at diagnosis was 7.9 years (range 1.2-18.3 years) and mean age at RT was 9.8 years (range 3.0-28.9 years). The median follow-up time was 9.8 years after radiation (range 0.8-33.3 years). The estimated 10-year OS and PFS after RT were 92 and 74 %, respectively. Twelve patients had disease progression after RT, and all recurrences were local. Two patients died due to disease progression 2.3 and 9.1 years after RT. One patient had malignant transformation of LGG to high-grade glioma. No significant predictors of PFS were identified on uni- or multivariate analysis. Late effects of LGG and treatment seen were endocrine deficiencies in 16 patients, visual problems in 10 patients, hearing loss in 4 patients, special education requirements for 5 patients, and a vascular injury/demyelination secondary to RT in 1 patient. CONCLUSION: Our study suggests that the use of radiation in patients with intracranial LGG results in excellent OS and PFS with acceptable toxicity at long-term follow-up.

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

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

Patterns of failure after involved field radiation therapy for pediatric and young adult Hodgkin lymphoma.

BACKGROUND: Involved field radiation therapy (IFRT) is integral in curative therapy for Hodgkin lymphoma (HL), although primarily used in patients with intermediate/high-risk HL. We present failure patterns and clinical outcomes in a cohort of pediatric and young adult patients with HL treated with IFRT at the Johns Hopkins Hospital. PROCEDURE: Patients ≤40 years old with intermediate/high-risk HL who received chemotherapy and IFRT from 1997 to 2012 were included in this retrospective analysis. Patients were evaluated for failure patterns, overall survival (OS), and event-free survival (EFS) using Kaplan-Meier curves, descriptive statistics, and Cox proportional hazard regressions. RESULTS: We reviewed 74 patients (45 pediatric and 29 young adult) with a median follow-up of 4.4 years. The mean age at diagnosis was 21.4 years. Patients received a median of 29.75 Gy of IFRT (range 15-39.6 Gy). The majority of pediatric patients received ABVE-PC chemotherapy (n = 25) and <30 Gy of radiation (n = 33) while most young adults received ABVD chemotherapy (n = 24) and ≥30 Gy (n = 25). Estimated 5-year OS and EFS were 96% and 81%, respectively. Thirteen patients had recurrence; eight were pediatric. Distant relapse alone comprised 83% of failures in patients receiving ≥30 Gy. Of the seven patients who received <30 Gy and had recurrence, six had local failure as a component of their recurrence. Caucasian race (P = 0.02) and nodular sclerosing histology (P = 0.01) predicted for increased EFS. Late effects were minimal and all deaths (n = 4) were from HL. CONCLUSIONS: In this series, pediatric and young adult patients were treated with differing chemoradiation and had distinct recurrence patterns.

Diffusion tensor imaging of deep gray matter in children treated for brain malignancies.

PURPOSE: Previous DTI studies reported microstructural changes in white matter of patients receiving treatment for brain malignancies. The primary aim of this prospective pilot longitudinal study was to examine if DTI can detect microstructural changes in deep gray matter (as evaluated by the apparent diffusion coefficient, ADC) between pediatric patients treated with cranial radiation therapy and typically developing healthy children. The relationship between ADC and neurobehavioral performance was also examined. METHODS: ADC was measured at 1.5 T in the caudate, putamen, globus pallidus, thalamus, and hippocampus in nine patients (mean age 11.8 years) and nine age-matched healthy controls. The study was designed with four visits: baseline, 6-month, 15-month, and 27-month follow-ups. RESULTS: Patients had 24 % higher overall mean ADC in the hippocampus compared with controls (p = 0.003). Post hoc analyses revealed significantly elevated ADC at baseline (p = 0.003) and at the 27-month follow-up (p = 0.006). Nevertheless, patients performed normally on a verbal memory test considered to be a hippocampus-related function. Relative to controls, patients' performance on the tests of the visual-spatial working memory decreased over time (group by visit, p = 0.036). Both patients and controls showed a decline in motor speed with increasing ADC in the globus pallidus and putamen. CONCLUSIONS: Childhood brain malignancies and their treatment may affect gray matter microstructure as measured by water diffusion. Significant findings in the hippocampus but not other regions suggest that differences in tissue sensitivity to disease- and treatment-related injury among gray matter regions may exist. ADC in basal ganglia may be associated with motor performance.

Prognostic factors in pediatric high-grade astrocytoma: the importance of accurate pathologic diagnosis.

To characterize a population of pediatric high-grade astrocytoma (HGA) patients by confirming the proportion with a correct diagnosis, and determine prognostic factors for survival in a subset diagnosed with uniform pathologic criteria. Sixty-three children diagnosed with HGA were treated at the Johns Hopkins Hospital between 1977 and 2004. A single neuropathologist (P.C.B.) reviewed all available histologic samples (n = 48). Log-rank analysis was used to compare survival by patient, tumor, and treatment factors. Median follow-up was 16 months for all patients and 155 months (minimum 54 months) for surviving patients. Median survival for all patients (n = 63) was 14 months with 10 long-term survivors (survival >48 months). At initial diagnosis, 27 patients were grade III (43%) and 36 grade IV (57%). Forty-eight patients had pathology slides available for review, including seven of ten long-term surviving patients. Four patients had non-HGA pathology, all of whom were long term survivors. The remaining 44 patients with confirmed HGG had a median survival of 14 months and prognostic analysis was confined to these patients. On multivariate analysis, five factors were associated with inferior survival: performance status (Lansky) <80% (13 vs. 15 months), bilaterality (13 vs. 19 months), parietal lobe location (13 vs. 16 months), resection less than gross total (13 vs. 22 months), and radiotherapy dose <50 Gy (9 vs. 16 months). Among patients with more than one of the five adverse factors (n = 27), median survival and proportion of long-term survivors were 12.9 months and 0%, compared with 41.4 months and 18% for patients with 0-1 adverse factors (n = 17). In an historical cohort of children with HGA, the potential for long term survival was confined to the subset with less than two of the following adverse prognostic factors: low performance status, bilaterality, parietal lobe site, less than gross total resection, and radiotherapy dose <50 Gy. Pathologic misdiagnosis should be suspected in patients who are long term survivors of a pediatric high grade astrocytoma.

Neuroimaging and neuropsychological follow-up study in a pediatric brain tumor patient treated with surgery and radiation.

Intracranial tumors are the most common neoplasms of childhood, accounting for approximately 20% of all pediatric malignancies. Radiation therapy has led directly to significant increases in survival of children with certain types of intracranial tumors; however, given the aggressive nature of this therapy, children are at risk for exhibiting changes in brain structure, neuronal biochemistry, and neurocognitive functioning. In this case report, we present neuropsychological, magnetic resonance imaging, proton magnetic resonance spectroscopic imaging, and diffusion tensor imaging data for two adolescents (one patient with ependymal spinal cord tumor with intracranial metastases, and one healthy, typically developing control) from three time points as defined by the patient's radiation schedule (baseline before the patient's radiation therapy, 6 months following completion of the patient's radiation, and 27 months following the patient's radiation). In the patient, there were progressive decreases in gray and white matter volumes as well as early decreases in mean N-acetyl aspartate/choline (NAA/Cho) ratios and fractional anisotropy (FA) in regions with normal appearance on conventional MRI. At the last follow-up, NAA/Cho and FA tended to change in the direction to normal values in selected regions. At the same time, the patient had initial reduction in language and motor skills, followed by return to baseline, but later onset delay in visuospatial and visual perceptual skills. Results are discussed in terms of sensitivity of the four techniques to early and late effects of treatment, and avenues for future investigations.

Successful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma.

We report a novel regimen for refractory post-transplant T-cell lymphoma (PTL). Our patient presented with non-Epstein-Barr virus (EBV) related, T-cell post-transplant lymphoproliferative disease (PTLD) 3.5 years after liver transplantation. Initially diagnosed as polyclonal PTLD, the disease progressed to a monoclonal, T-cell PTL that was refractory to several chemotherapy regimens but responded to a regimen consisting of fludarabine, cyclophosphamide, cytarabine, and alemtuzumab. Consolidation therapy included high-dose chemotherapy, autologous hematopoietic stem cell rescue, and radiation therapy. She remains in remission 2.5 years later. T-cell PTL is a rare disease with a poor prognosis; this regimen provides a novel, potentially curative approach for its treatment.

Results of treatment of patients with superficial facial rhabdomyosarcomas on protocols of the Intergroup Rhabdomyosarcoma Study Group (IRSG), 1984-1997.

PURPOSE: We analyzed the outcome of 47 patients with superficial facial rhabdomyosarcoma (RMS) treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III, -IV-Pilot, and -IV. METHODS: We reviewed patients' records. Clinico-pathologic features, treatment, and outcome were examined to identify prognostic factors. RESULTS: Thirty-two patients were males; 35 patients were 1-9 years old at diagnosis. Tumor sites were buccal/cheek (N = 21), external nasal/nasolabial (N = 12), lip/chin (N = 9), and masseter (N = 5). Patients (46/47) had localized disease: 18 biopsy only (Group III), 17 microscopic residual tumor (Group II), and 11 complete resection without residual tumor (Group I). Eight-year estimated event-free survival (EFS) and overall survival (OAS) rates were 61% and 65%. Patients <12 months old had inferior EFS, 21%, compared to approximately 68% in older patients (P = 0.077). Eight-year EFS rates were 80% for females and 50% for males (P = 0.096). Eight-year EFS rates were 72% in 33 patients without regional lymph-nodal tumor and 39% in 14 patients with regional nodal tumor (P = 0.07). Eight-year EFS rates were 72% for 22 patients with embryonal RMS and 53% for 23 patients with alveolar RMS (P = 0.28). Location of the primary tumor was not significantly related to outcome. CONCLUSIONS: Patients with superficial facial RMS often have localized, grossly resectable lesions at the time of presentation. Favorable prognostic factors include age >12 months, female gender, embryonal histology, and no lymph-nodal tumor.

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.

Outcome analysis of childhood low-grade astrocytomas.

BACKGROUND: We aimed to determine the long-term natural history of low-grade astrocytomas (LGA) in children, with respect to pathology, and to evaluate influence of treatment on survival. PATIENTS AND METHODS: A consecutive cohort of patients < or =21 years with surgically confirmed LGA from 1965 to 1996 was assembled. All available pathology specimens were reviewed, masked to original diagnosis, patient data, and neuroimaging. RESULTS: Two hundred seventy-eight children (160 males; mean age 9.1 years; tumor location: 77 cerebrum, 62 cerebellum, 51 hypothalamic, 30 thalamus, 9 ventricle, 40 brainstem, and 9 spine) were assessed. Among 246 specimens reviewed, diagnoses were 135 pilocytic astrocytoma (PA), 27 diffuse astrocytoma (DA), 75 unclassifiable well-differentiated astrocytoma (NOS), and 9 subependymal giant cell astrocytoma. At 5 and 10 years from initial surgery, for all LGA overall survival (OS) was 87% and 83%, while progression-free survival (PFS) was 55% and 42%, respectively. Original pathology diagnoses did not predict PFS (P = 0.47), but reviewed diagnoses were significantly associated with PFS (P = 0.007). Reviewed diagnoses were highly associated with OS (P < 0.0001), with 5-year OS for PA 96%, DA 48%, and NOS 86%; these differences remained significant when stratified by location or extent of resection. Among patients with residual tumor after surgery, 5-year PFS was 48% with observation alone (n = 114), no different (P = 0.32) from that achieved with immediate irradiation (n = 86). CONCLUSION: LGA, particularly PA, have excellent long-term OS. While tumor location and resection extent affect outcome, pathologic diagnosis when carefully interpreted significantly influences long-term survival. Immediate postoperative irradiation does not confer an advantage in delaying first progression in children with residual PA.

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.

Association of Neuronal Injury in the Genu and Body of Corpus Callosum After Cranial Irradiation in Children With Impaired Cognitive Control: A Prospective Study.

PURPOSE: Brain radiation is associated with functional deficits in children. The purpose of this study was to examine white matter integrity as measured by diffusion tensor imaging and associations with region-specific radiation dose and neuropsychological functioning in children treated with cranial irradiation. METHODS AND MATERIALS: A total of 20 patients and 55 age- and sex-matched controls were included in the present study. Diffusion tensor imaging and neuropsychological assessments were conducted at baseline and 6, 15, and 27 months after treatment. The neuropsychological assessment included motor dexterity, working memory, and processing speed. White matter regions were contoured, and the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were recorded for each participant. Linear mixed effects regression models were used to prospectively compare the associations among ADC, FA, radiation dose to contoured structures, and performance on the neuropsychological assessments over time. RESULTS: The mean prescription dose was 44 Gy (range 12-54). Across visits, compared with the controls, the patients showed a significantly increased ADC across all selected regions and alterations in FA in the dorsal midbrain and corpus callosum (genu, splenium, body). An increased radiation dose to the genu and body of the corpus callosum was associated with alterations in ADC and FA and reduced neuropsychological performance, most notably motor speed and processing. CONCLUSIONS: These prospective data suggest that subcortical white matter, especially the genu and body of the corpus callosum, could be regions with increased susceptibility to radiation-induced injury, with implications for cognitive function.

Repeat stereotactic radiosurgery for high-grade and large intracranial arteriovenous malformations.

BACKGROUND: The treatment of large and high-grade (Spetzler-Martin III-V) AVMs remains a challenge. There is a paucity of literature addressing the efficacy of radiosurgery in this group. We retrospectively analyze our experience with repeat radiosurgery with such AVMs. METHODS: Between 1989 and 2004, 14 patients with large and high-grade AVMs deemed to be nonoperative candidates were treated with repeat radiosurgery. Patients were treated either on a LINAC or gamma knife-based system at 2- to 3-year intervals with targeting of the entire nidus with each treatment. Patients who did not receive their full treatment course or follow-up at the institution were excluded. RESULTS: Mean follow-up was 18 months. The complete obliteration rate was 35.7%, with a mean volume reduction of 53% in the remaining lesions. Twenty percent of grade III and 50% of grade IV lesions experienced cure. Complications included persistent headaches (2 patients). Statistical analysis revealed no difference between obliterated and partially obliterated groups with regard to mean pretreatment volume (24.87 cm(3)), median Spetzler-Martin grade (IV), mean follow-up (30.5 months), total delivered dose (3550 cGy), mean dose per stage (13 Gy), median number of stages (2), or mean interval between treatment stages (40 months). CONCLUSION: The present study demonstrates the potential role of repeat radiosurgery in the treatment of this cohort in the context of our short follow-up. The benefits of repeat therapy could be derived from using lower doses per session and repeat targeting of the lesion in an effort to increase response and decrease complication rates.

Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study.

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/m(2) daily x 5 every 21 days) immediately after cyclophosphamide (250 mg/m(2) daily x 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 < or = 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.

Failure pattern and factors predictive of local failure in rhabdomyosarcoma: a report of group III patients on the third Intergroup Rhabdomyosarcoma Study.

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.

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.

Children from ethnic minorities have benefited equally as other children from contemporary therapy for rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group.

PURPOSE: To define the clinical characteristics of rhabdomyosarcoma (RMS) occurring in children from ethnic minorities and determine whether these children have benefited equally from advances in therapy. PATIENTS AND METHODS: This was a retrospective cohort analysis of children treated on the Intergroup Rhabdomyosarcoma Study Group protocols between 1984 and 1997. The clinical features and outcomes of 336 African-American children and 286 children from other ethnic minorities were compared with those of white children (n = 1,721). RESULTS: African-American, other ethnic group, and white children enjoyed similar 5-year failure-free survivals (FFS) of 61%, 61%, and 66%, respectively, P =.15. Compared with white children, nonwhite patients more often had (1) invasive, T2 tumors (P =.03); (2) stage 2 or 3 tumors (P =.003); (3) large tumors (more than 5 cm, P <.006); and/or (4) tumors with positive regional nodes (ie, N1, P =.002). Using Cox proportional hazards analysis, seven patient risk categories were defined with significant differences in outcome. This model was then used to search for other factors associated with FFS after adjusting for these risk categories. Only T stage and age remained associated with FFS (P =.001 and P <.001, respectively). After adjusting for T stage, risk category, and age, we explored the relationship of ethnic group to FFS and found that, compared with whites, the relative risk of failure was 1.14 for African-American patients and 1.2 for other ethnic minority patients, values that are not significantly different. CONCLUSION: Patients from ethnic minority groups more often have larger, invasive tumors with positive lymph nodes. Nevertheless, they have benefited as equally as white children from the dramatic progress in therapy of RMS.