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Purpose: To investigate the relationship between jaw function, patient and treatment variables, and radiation dosimetry of the mandibular muscles and joints in children and young adults receiving radiation for soft-tissue and bone sarcomas., Methods and Materials: Twenty-four pediatric and young adult patients with head-and-neck sarcomas were treated on an institutional review board-approved prospective study of focal radiation therapy for local tumor control. Serial jaw depression measurements were related to radiation dosimetry delivered to the medial and lateral pterygoid muscles, masseter muscles, and temporomandibular joints to generate mathematical models of jaw function., Results: Baseline jaw depression was only influenced by the degree of surgical resection. In the first 12 weeks from initiation of radiation, surgical procedures greater than a biopsy, administration of cyclophosphamide containing chemotherapy regimes, and large gross tumor volumes adversely affected jaw depression. Increasing dose to the pterygoid and masseter muscles above 40 Gy predicted loss of jaw function over the full course of follow-up., Conclusions: Clinical and treatment factors are related to initial and subsequent jaw dysfunction. Understanding these complex interactions and the affect of specific radiation doses may help reduce the risk for jaw dysfunction in future children and young adults undergoing radiation therapy for the management of soft-tissue and bone sarcomas., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background/purpose: The aim of this study was to retrospectively analyze the clinical presentation, histology, treatment, and outcomes of children with vaginal tumors who were treated at a single institution., Methods: A retrospective review of medical records and pathologic materials of all children with vaginal tumors treated at St Jude Children's Research Hospital between 1970 and 2009 was conducted., Results: Eighteen patients (median age, 3.7 years; range, 0.1-15 years) were identified. Three different histologies were found: rhabdomyosarcoma (RMS; n = 13), germ cell tumor (n = 3), and clear cell adenocarcinoma (n = 2). Bleeding or blood-tinged discharge was the most common clinical presentation (66%), followed by a protruding mass (39%). Vaginal and uterine salvage was 44.4% (8 of 18 patients). Thirteen patients (72.2%) remain disease-free, with a median follow-up of 23.2 years (range, 2-39 years). Four patients (22.2%) died of disease progression (1 RMS, 2 germ cell tumor, and 1 clear cell adenocarcinoma), and 1 patient with RMS died of colon cancer 12 years after the primary diagnosis had been made., Conclusions: Vaginal tumors are extremely rare in the pediatric population. Early recognition of symptoms like bleeding and a protruding vaginal mass may prevent morbidity and mortality. Our findings confirm the good prognosis of vaginal RMS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To estimate radiation therapy planning margins based on inter- and intrafractional uncertainty for pediatric brain and head and neck tumor patients at different imaging frequencies., Methods: Pediatric patients with brain (n = 83) and head and neck (n = 17) tumors (median age = 7.2 years) were enrolled on an internal review board-approved localization protocol and stratified according to treatment position and use of anesthesia. Megavoltage cone-beam CT (CBCT) was performed before each treatment and after every other treatment. The pretreatment offsets were used to calculate the interfractional setup uncertainty (SU), and posttreatment offsets were used to calculate the intrafractional residual uncertainty (RU). The SU and RU are the patient-related components of the setup margin (SM), which is part of the planning target volume (PTV). SU data was used to simulate four intervention strategies using different imaging frequencies and thresholds., Results: The SM based on all patients treated on this study was 2.1 mm (SU = 0.9 mm, RU = 1.9 mm) and varied according to treatment position (supine = 1.8 mm, prone = 2.6 mm) and use of anesthesia (with = 1.7 mm, without = 2.5 mm) because of differences in the RU. The average SU for a 2-mm threshold based on no imaging, once per week imaging, initial five images, and daily imaging was 3.6, 2.1, 2.2, and 0.9 mm, respectively., Conclusion: On the basis of this study, the SM component of the PTV may be reduced to 2 mm for daily CBCT compared with 3.5 mm for weekly CBCT. Considering patients who undergo daily pretreatment CBCT, the SM is larger for those treated in the prone position or smaller for those treated under anesthesia because of differences in the RU., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients., Patients and Methods: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered., Results: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths., Conclusions: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Background: The authors studied the survival and long-term morbidities of children with nasopharyngeal carcinoma (NPC)., Methods: This was a retrospective review of children with NPC who were treated at St. Jude Children's Research Hospital between 1961 and 2004. Prognostic factors and long term effects of therapy were analyzed., Results: Fifty-nine patients (median age, 14.1 years) were identified. Most were male (66.1%) and black (54.2%) and had lymphoepithelioma (93.2%). Thirty-five patients had stage IV disease (59.3%), 20 patients had stage III disease (33.9%), and 4 patients had stage II disease (6.8%). All patients received radiotherapy (RT) to the primary tumor, and most received cervical RT (98.3%) and chemotherapy (88.1%). The 15-year survival and event-free survival (EFS) rates were 67.2% ± 7.5% and 63.5% ± 7.8%, respectively. Five patients (8.5%) developed subsequent malignancies 8.6 to 27 years after NPC diagnosis. EFS was improved in patients who were diagnosed after 1980 (74.8% ± 10% vs 45.5% ± 10.1%; P = .031), in patients who had stage III disease compared with patients who had stage IV disease (79.3% ± 9.6% vs 56.2% ± 11.8%; P = .049), in patients who received cisplatin (81% ± 10.7% vs 45.8% ± 9.7%; P = .013), and in patients who received ≥ 50 grays of RT (71.4% ± 9.3% vs 43.8% ± 11.6%; P = .048). White patients had higher distant failure rates than black patients (41.7% ± 10.4% vs 15.6 ± 6.5%; P = .045). The 15-year cumulative incidence (CI) of any morbidity was 83.7% ± 5.4%, the CI of sensorineural hearing loss was 52.9% ± 6.7%, the CI of primary hypothyroidism was 42.7% ± 6.6%, and the CI of growth hormone deficiency (GHD) was 14.1% ± 4.7%. Dose-response relations were observed between the RT dose and primary hypothyroidism and GHD., Conclusions: The outcome of children with NPC improved over the past 4 decades with the use of cisplatin-based chemotherapy and higher RT doses. However, many survivors had long-term treatment-related morbidities., (© 2010 American Cancer Society.)

The purpose was to quantify the setup margin for pediatric patients with neuro-blastoma using cone beam CT imaging (CBCT) and ultrasound localization. Ten patients, with a median age of 4.3 years (1.8 to 7.9) underwent daily pretreatment localization CBCT and every other day post-treatment CBCT to calculate interfractional and intrafraction movement. Localization was based on CBCT to treatment planning CT registration in the lumbar spine region. Each subject was treated in the supine position under IV general anesthesia using intensity-modulated radiation therapy. Patients were repositioned based on the daily pretreatment CBCT. Required setup margins based on inter- and intrafraction positioning errors were calculated based on weekly and daily imaging scenarios. Four patients had ultra-sound localization of the kidneys performed before the CBCT. Correlation between daily CBCT and ultrasound was investigated. A lateral, longitudinal and vertical setup margin of 5.4, 5.6, and 5.9 mm is required without daily CBCT. When daily CBCT was incorporated, the setup margin was reduced to 1.5, 2.1, and 1.7 mm. There was no correlation between the suggested ultrasound shifts and the shifts based on the CBCT. Daily localization based on CBCT of the lumbar spine can reduce the required setup margin for neuroblastoma patients, thereby reducing normal tissue exposure for this young patient population. The internal margin needs further investigation before PTV reduction can be made. Ultrasound localization was highly variable and not correlated to CBCT shifts.

Background: Bone marrow biopsy is considered essential for the staging and risk-adapted treatment of Hodgkin's lymphoma with unfavorable risk features. We reviewed the cases of pediatric Hodgkin's lymphoma in our institution to determine the impact of bone marrow involvement on treatment, relapse, and survival., Design and Methods: We reviewed the clinical characteristics and outcome of 383 patients treated for Hodgkin's lymphoma at St. Jude Children's Research Hospital between August 1990 and August 2008. The 5-year survival estimates for patients with and without bone marrow involvement were compared., Results: Of 228 patients who had a bone marrow biopsy at diagnosis, 21 had bone marrow involvement. Bone marrow findings changed the disease stage in only seven patients (3.1%): from IB to IVB (n=1), from IIA (with bulky disease) to IVA (n=1), from IIB to IVB (n=1), and from IIIB to IVB (n=4). One patient's risk assignment changed from intermediate to unfavorable risk without his chemotherapy being altered. No statistically significant difference was observed between patients with stage IV Hodgkin's lymphoma who did (n=21) and did not (n=61) have bone marrow involvement in 5-year relapse-free survival (89.6± 7% versus 73.9±6.1%; P=0.25) or 5-year overall survival (95.2±8.2% versus 87.3±4.9%; P=0.82)., Conclusions: Although bone marrow involvement changed the stage in 3.1% of pediatric Hodgkin's lymphoma patients, it did not change risk-adapted treatment or prognosis. We conclude that bone marrow biopsy need not be performed at diagnosis in patients who have unfavorable risk features, although this finding should be confirmed by larger prospective studies.

Background: Pediatric Hodgkin lymphoma (HL) is a highly curable disease; however, prognostic factors for the survival of patients who develop recurrent disease have not been clearly defined., Methods: This was a retrospective analysis of 50 pediatric patients with HL who relapsed or progressed between 1990 and 2006 and who were retrieved with intense cytoreductive treatment regimens followed by autologous stem cell transplantation and radiation therapy. A Cox proportional hazards model was used to determine risk factors for second treatment failure and death., Results: The median patient age was 16.1 years (range, 4.9-22.1 years) at the time of HL diagnosis. Fifteen patients developed progressive disease during therapy, 14 patients relapsed early, and 21 patients relapsed late. Patients who remained alive at the time of this study had been followed for a median of 4.4 years (range, 1.2-16.6 years). The 5-year overall survival rate for patients who had an inadequate response (n = 14) to initial salvage therapy was only 17.9% (95% confidence interval [CI], 3.1%-42.5%) compared with 97.2% (95% CI, 81.9%-99.6%) for patients who responded (n = 36; P < .0001). In a multivariate Cox regression analysis of overall survival, an inadequate response to initial salvage therapy was the only significant variable (hazard ratio, 43.6; 95% CI, 5.4-354; P = .0004)., Conclusions: The current results indicated that pediatric patients with relapsed HL who have an inadequate response after initial primary salvage chemotherapy have a very poor prognosis and should be considered for novel therapies directed at biologic or immunologic targets., (© 2010 American Cancer Society.)

Purpose: To provide a radiation pneumonitis risk estimate and investigate the correlation of clinical and dosimetric factors in pediatric patients receiving chest irradiation., Methods and Materials: A total of 122 patients diagnosed with sarcoma or Hodgkin lymphoma who received radiotherapy to the chest were evaluated for symptomatic radiation pneumonitis (Common Toxicity Criteria Grade 1 with respiratory symptom or higher grade). Pneumonitis data were collected from either prospective toxicity screenings as part of a clinical trial or through chart review. Dosimetric parameters including V(10)-V(25), mean lung dose, binned lung dose, and tissue complication probability models were used, as well as clinical features to correlate with the development of pneumonitis., Results: The 1- and 2-year cumulative incidence of symptomatic radiation pneumonitis for all patients was 8.2% and 9.1%, respectively. Nine patients experienced symptomatic Grade 1 toxicity, and 2 experienced Grade 2. From univariate analysis, chemotherapy containing bleomycin (chi(2) test, p = 0.027) and V(24) (logistic regression, p = 0.019) were the clinical and dosimetric factors that resulted in statistically significant differences in the occurrence of pneumonitis. The probability of pneumonitis increased more dramatically with increasing V(24) in patients receiving bleomycin than in those who did not. Adult tissue complication models did not differentiate pediatric patients with radiation pneumonitis from those without., Conclusions: The incidence of symptomatic radiation pneumonitis in pediatric patients is low and its severity mild. Parameters frequently used in adult radiation oncology provide some guidance as to risk, but pediatric patients warrant their own specific models for risk assessment, incorporating dosimetry and clinical factors., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: The number of long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasing; however, few studies have addressed their long-term pulmonary function., Methods: The authors examined 660 baseline and follow-up pulmonary function tests in 89 long-term survivors of pediatric hematologic malignancies and allo-HSCT., Results: At least 1 abnormal lung parameter was seen in 40.4% of baseline tests and developed in 64% of post-allo-HSCT tests (median follow-up: 8.9 years). Abnormal baseline values in ratio of forced expiratory volume in 1 second and forced vital capacity (FEV(1)/FVC), FEV(1), residual volume (RV), functional residual capacity (FRC), and FVC were associated with abnormal post-allo-HSCT values. The following pulmonary function values declined significantly with time: FEV(1)/FVC, forced mid-expiratory flow (FEF(25%-75%)), total lung capacity (TLC), diffusion capacity corrected for hemoglobin (DLCO(corr)), RV, FRC, and RV/TLC. Older age at the time of allo-HSCT was associated with lower FEV(1)/FVC, FEF(25%-75%), and DLCO(corr) and higher RV/TLC. Patients who experienced respiratory events within 1 year post-allo-HSCT had lower FEV(1) and FVC values and higher RV/TLC from their baseline pulmonary function tests. Female patients had reduced FVC, TLC, and RV values but higher FEV(1)/FVC. Pulmonary dysfunction was also associated with high-risk hematological malignancies and peripheral blood HSC product., Conclusions: Abnormal pulmonary functions in allo-HSCT survivors are prevalent, which underscore the need for risk-adapted continual monitoring and improved preventive and management strategies., ((c) 2010 American Cancer Society.)

Purpose: The purpose of the study was to compare outcomes of pediatric patients with high-risk metastatic neuroblastoma who received radiotherapy (RT) with those of patients who did not., Patients and Methods: We reviewed the records of 63 patients with newly diagnosed metastatic neuroblastoma treated at our institution (1989-2001) to investigate their characteristics at presentation, dose and field of RT, treatment response, and failure patterns., Results: Seventeen patients received RT, and 46 did not. In the RT group, a greater percentage of patients had residual disease before consolidation than did those in the no-RT group (88.2% vs 69.6%, P = .008). Gross total resection was achieved less often in the RT group (65% vs 89%, P = .055), but the 5-year cumulative incidences of local failure were similar (35.3% +/- 12.4% vs 32.6% +/- 7.1%). Although there was no difference in 5-year event-free survival, overall survival was better in the no-RT group (47.8% +/- 7.2% vs 23.5% +/- 9.2%, P = .026)., Conclusion: The addition of RT to the therapy of a group of patients with more residual locoregional disease appeared to improve the local failure rate to approximately that of patients with less residual disease. Radiotherapy may provide even greater benefit to those with less residual disease before consolidation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: There is renewed attention to primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for locoregional tumor control and its impact on overall survival., Methods and Materials: Between July 2000 through August 2006, a total of 44 pediatric patients with NB received radiation therapy (RT) with curative intent using computed tomography (CT)-based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and locoregional tumor control were measured from the start of RT to the date of death or event as determined by CT/magnetic resonance imaging/meta-iodobenzylguanidine. The influence of age at irradiation, gender, race, cumulative radiation dose, International Neuroblastoma Staging System stage, treatment protocol and resection status was determined with respect to locoregional tumor control., Results: With a median follow-up of 34 months +/- 21 months, locoregional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of locoregional control reached borderline statistical significance (p = 0.06). Age (p = 0.5), dose (p = 0.6), resection status (p = 0.7), and International Neuroblastoma Staging System stage (p = 0.08) did not influence overall survival., Conclusions: Overall survival in high-risk neuroblastoma is influenced by locoregional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose, and the effects of systemic therapy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To demonstrate the safety and efficacy of limited margin radiotherapy in the local control of pediatric and young adult patients with high-grade nonrhabdomyosarcoma soft tissue sarcoma (NRSTS)., Methods and Materials: Pediatric patients with high-grade NRSTS requiring radiation were treated on an institutional review board approved prospective institutional study of conformal/intensity-modulated/interstitial brachytherapy using a 2-cm anatomically constrained margin., Results: A total of 32 patients (median age, 15.3 years; range, 2-22 years) received adjuvant (27 patients) or definitive (5 patients) irradiation. With a median follow-up of 32 months, the 3-year cumulative incidence of local failure was 3.7% for patients undergoing irradiation after surgical resection. Four patients experienced local failure; the mean dose to the volume of recurrence was >or=97% of the prescribed dose., Conclusions: Delivery of limited margin radiotherapy using external beam or brachytherapy provides a high rate of local tumor control without marginal failure. Further follow-up is required to determine whether normal tissue effects are minimized using this approach., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Radiation related effects in children and adults limit the delivery of effective radiation doses and result in long-term morbidity affecting function and quality of life. Improvements in our understanding of the etiology and biology of these effects, including the influence of clinical variables, dosimetric factors, and the underlying biological processes have made treatment safer and more efficacious. However, the approach to studying and understanding these effects differs between children and adults. Using the pulmonary and skeletal organ systems as examples, comparisons are made across the age spectrum for radiation related effects, including pneumonitis, pulmonary fibrosis, osteonecrosis, and fracture. Methods for dosimetric analysis, incorporation of imaging and biology as well a length of follow-up are compared, contrasted, and discussed for both organ systems in children and adults. Better understanding of each age specific approach and how it differs may improve our ability to study late effects of radiation across the ages.

Aims: To investigate the relationship between the maximum grade of skin toxicity, radiation dose and clinical variables in children receiving treatment for sarcomas involving the bone and soft tissue., Materials and Methods: Between January 2003 and July 2006, 82 patients with musculoskeletal tumours on an Institutional Review Board (IRB)-approved prospective study at St. Jude Children's Research Hospital received three-dimensional conformal or intensity-modulated radiation therapy for local tumour control. Radiation dermatitis was graded according to the National Cancer Institute's Common Toxicity Criteria version 2.0 during and after radiation therapy. The dose to the skin was calculated for each patient from the radiation treatment plan., Results: The radiation doses delivered to the primary tumour ranged from 4140 to 7020cGy, with a mean dose of 5040cGy. The maximum recorded grade of skin toxicity was: grade 0: seven patients (8.6%); grade 1: 26 patients (31.7%); grade 2: 37 patients (45.1%); grade 3: 10 patients (12.2%); grade 4: two patients (2.4%). A significant association for increased grade of skin toxicity was observed between dose (P<0.01), volume of skin treated above 4000cGy (P=0.03), use of a bolus (P<0.01), Caucasian race (P<0.01) and related pain (P<0.01)., Conclusions: These findings suggest that the delivered dose, use of a bolus, the volume treated, and race may be used in the clinical setting to predict patients at risk for skin toxicity. Alterations in treatment technique and early therapeutic intervention may help to reduce or eliminate radiation-induced skin side-effects and associated pain.

To compare FDG PET/CT and bone scans for the management of young patients with Hodgkin lymphoma (HL). Eighteen patients, aged 7-24 years, with HL received bone and PET scans within 2 weeks--11 at diagnosis and 7 at known or suspected relapse (37 scan pairs). In six patients (nine scan pairs) both studies were positive. In four patients (five scan pairs), PET showed involvement not evident on bone scan. In four patients (four scan pairs), one of the studies was equivocal and the other negative. In one patient, bone scan showed abnormal uptake in a benign lesion. In nine patients (19 scan pairs), both studies were negative. All osseous metastases identified on bone scan were present on PET. Many additional sites of bony involvement were identified on PET. The bone scan may be safely eliminated.

Background: Predictors of outcome have not been established for pediatric visceral and body wall nonrhabdomyosarcoma soft tissue sarcomas (NRSTS)., Methods: The study used a retrospective review of clinical features and outcome of 61 patients with visceral and body wall NRSTS evaluated at our institution between March 1962 and December 1999., Results: Median age at diagnosis was 9.9 years (range, birth to 17.4 years). Tumors were greater than 5 cm in 43 (70%), high grade in 33 (54%), invasive in 25 (41%), and metastatic at presentation in 14 (23%) patients. Visceral tumors (n = 27) were more likely than body wall tumors (n = 34) to be greater than 5 cm (93% vs 53%; P < .001) and invasive (70% vs 18%; P < .001) and were less likely to be resected at diagnosis (44% vs 85%; P = .001). Estimated 10-year event-free survival (EFS) and overall survival (OS) for the entire cohort were 45.5% +/- 6.9% and 56.8% +/- 6.7%, respectively. The 10-year EFS and OS were better for patients with body wall sites than for those with visceral sites (61.8% +/- 8.5% and 67.5% +/- 8.2% vs 24.2% +/- 9.4% and 43.0% +/- 10.3%; P = .004 and P = .004). The 10-year estimated cumulative incidence (CI) of local recurrence was higher for patients with visceral sites than for those with body wall sites (64.3% +/- 9.8% vs 26.5% +/- 7.7%; P = .004), whereas CI of distant recurrence was similar for the 2 sites (15.2% +/- 7.2% vs 23.5% +/- 7.4%; P = .39)., Conclusions: Pediatric patients with visceral NRSTS are more likely to have invasive, large, and unresectable tumors compared to those with body wall tumors. More than two thirds of visceral NRSTS recur locally, and fewer than half of patients with visceral tumors survive.

Purpose: The incidence of pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) of the groin and axilla is unknown, and the optimal surgical approach to these patients is unclear., Methods: We conducted a retrospective study of patients treated at St Jude Children's Research Hospital from January 1962 to March 2007 for NRSTSs of the groin and axilla. Demographic variables, tumor pathology, clinical management, and outcome were reviewed., Results: Of the 300 patients treated for NRSTSs, only 10 had tumors of the axilla or groin (6 of whom had synovial sarcoma). Surgical interventions included wide resection of the tumor (n = 7), marginal resection (n = 1), subtotal resection (n = 1), and biopsy only (n = 1). Six patients underwent lymph node sampling; all were negative for tumor. Short- and long-term surgical complications were rare. Four patients received adjuvant chemotherapy (n = 3) and/or radiotherapy (n = 2). At a median follow-up of 8.5 years, 7 of the 10 were surviving free of disease. Two of these patients died of tumor progression (1 with metastases at diagnosis and 1 with an unresectable tumor at diagnosis), and one patient who was free of NRSTS died of secondary breast carcinoma., Conclusions: Pediatric NRSTSs of the axilla and groin are rare, but outcomes are similar to those of other patients with NRSTS. Wide local excision of the tumor with preservation of good limb function should be the surgical goal and may be sufficient therapy in some cases.

We undertook this study to estimate the event-free survival (EFS) of patients with newly diagnosed supratentorial primitive neuroectodermal tumor (SPNET) treated with risk-adapted craniospinal irradiation (CSI) with additional radiation to the primary tumor site and subsequent high-dose chemotherapy supported by stem cell rescue. Between 1996 and 2003, 16 patients with SPNET were enrolled. High-risk (HR) disease was differentiated from average-risk (AR) disease by the presence of residual tumor (M(0) and tumor size > 1.5 cm(2)) or disseminated disease in the neuraxis (M(1)-M(3)). Patients received risk-adapted CSI: those with AR disease received 23.4 Gy; those with HR disease, 36-39.6 Gy. The tumor bed received a total of 55.8 Gy. Subsequently, all patients received four cycles of high-dose cyclophosphamide, cisplatin, and vincristine with stem cell support. The median age at diagnosis was 7.9 years; eight patients were female. Seven patients had pineal PNET. Twelve patients are alive at a median follow-up of 5.4 years. The 5-year EFS and overall survival (OS) estimates for all patients were 68% +/- 14% and 73% +/- 13%. The 5-year EFS and OS estimates were 75% +/- 17% and 88% +/- 13%, respectively, for the eight patients with AR disease and 60% +/- 19% and 58% +/- 19%, respectively, for the eight with HR disease. No deaths were due to toxicity. High-dose cyclophosphamide-based chemotherapy with stem cell support after risk-adapted CSI results in excellent EFS estimates for patients with newly diagnosed AR SPNET. Further, this chemotherapy allows for a reduction in the dose of CSI used to treat AR SPNET without compromising EFS.

Background: Positron emission tomography (PET) and gallium scans facilitate diagnosis and staging, evaluation of response to therapy, and monitoring for relapse in Hodgkin lymphoma (HL), but have not been compared in pediatric HL., Procedure: We performed concurrent PET and gallium scans on 44 pediatric HL patients at diagnosis, early response, off chemotherapy, and off-therapy evaluations. PET and gallium scans were compared to each other and to computed tomography (CT) alone to determine whether either modality led to a change in stage or modified the results of the early response evaluation, which was used to determine the radiation dose., Results: PET upstaged four patients at diagnosis (2 from stage I to II, one II to III, and one III to IV), but did not lead to a change in therapy in any of them. It changed response category in two patients at early response evaluation, leading to a change in radiation dose for 1 patient (25.5 Gy instead of 15 Gy to the spleen). Gallium did not change the stage of treatment for any patient. The negative predictive values for eventual lymphoma relapse of PET and gallium scans at off therapy were 89% and 83%, respectively; the positive predictive value of PET at off therapy is 29%., Conclusion: PET appears to be superior to gallium in pediatric HL; future studies will determine the optimal timing of PET to assess early response and the utility of quantitative interpretation of the avidity of specific nodal sites.

Background: Children treated for sarcoma are at risk of treatment-associated deficits in bone mineral density (BMD). We investigated the severity of risk factors for BMD deficits in this patient population., Procedure: Using signed-rank test and logistic regression analysis, we retrospectively analyzed the relation of treatment variables and other potential risk factors to BMD (using quantitative computed tomography (QCT)) of 99 patients treated for pediatric sarcoma who had completed therapy at least 1 year previously., Results: The study group (38% rhabdomyosarcoma (RMS), 25% osteosarcoma (OS), 24% Ewing-family tumors, and 12% non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS)) represented 22% of the sarcoma survivors treated between 1982 and 2003 who remained in follow-up at St. Jude. These patients underwent QCT between July 1, 1997 and February 5, 2003. Their median age was 8.7 years (range, 0.2-21.3 years) at diagnosis and 17.4 years (range, 3.3-30.2 years) at the time of BMD measurement; 58% were male and 82% Caucasian. Median BMD Z-score was -0.75 (range, -3.33-3.02), and median BMD was 168.0 mg/cc (range, 89.2-264.8 mg/cc). Risk of BMD deficit increased significantly with younger age at diagnosis (P = 0.044) and higher cumulative cyclophosphamide dose (P = 0.007). Patients with lower extremity primary disease had a significantly lower risk of BMD deficits than others. We found no association between BMD and body habitus, primary disease, lifestyle factors, or endocrinopathy., Conclusion: A significant subset of sarcoma survivors are at risk of BMD deficits warranting prospective study of BMD to verify our results and refine risk factors contributing to BMD deficits., ((c) 2008 Wiley-Liss, Inc.)

Background: Approximately 5% of children with Wilms tumor present with bilateral disease. The treatment challenge is to achieve a high cure rate while maintaining adequate long-term renal function. The authors of this report assessed the feasibility and outcome of nephron-sparing surgery in patients with bilateral Wilms tumor who were treated at a single institution., Methods: A retrospective review was performed of all children who were treated at St. Jude Children's Research Hospital for synchronous, bilateral Wilms tumors from 1999 through 2006. Imaging studies, surgical techniques, and pathology reports were reviewed. The outcomes evaluated included surgical complications, tumor recurrence, renal function, and patient survival., Results: Twelve patients with synchronous, bilateral Wilms tumors were identified, including 10 patients who underwent successful bilateral nephron-sparing procedures. One patient who presented with renal failure and anaplastic histology underwent bilateral nephrectomies, and 1 patient with intra-atrial tumor extension underwent an ipsilateral nephrectomy/thrombectomy and subsequent contralateral partial nephrectomy. Postoperative complications included persistent urine leak in 3 patients, macroscopic residual tumor in 2 patients, and pyelonephritis in 1 patient. Long-term complications included local tumor recurrence in 2 patients, intestinal obstruction in 2 patients, ureteropelvic junction obstruction in 1 patient, and renal failure in 1 patient. The overall survival rate was 83% (mean follow-up, 3.9 years); both patients who died had bilateral, diffuse, anaplastic histology., Conclusions: All patients who had bilateral Wilms tumors with favorable histology, except for 1 patient who had extensive tumor thrombus, underwent successful bilateral partial nephrectomies. Complications were minimal, and long-term renal function and survival were excellent. From this experience, the authors concluded that bilateral nephron-sparing surgery should be considered for all patients who have bilateral Wilms tumor with favorable histology, even if preoperative imaging studies suggest that the lesions are unresectable.

Background: Patients are at risk of second malignancies (SM) after treatment for Ewing sarcoma family of tumours (ESFT)., Methods: We performed a retrospective review of 237 patients with ESFT treated at our institution from September 1979 through to February 2004. Cumulative incidence (CI) of SM by the type of malignancy and treatment was estimated., Results: Twelve patients with SM were identified. Secondary leukaemia (SL) developed in 8 patients (2 ALL, 6 MDS/AML), a median 2.6 years (range 1.4-19.6 years) after diagnosis of ESFT. Four patients had secondary solid tumours, a median 8.0 years (range 7.4-9.4 years) after the ESFT diagnosis. Five- and 10-year estimates of the CI of SM were 3.0+/-1.1% and 4.7+/-1.5%, respectively. Patients treated on recent protocols with higher cumulative doses or an increased dose intensity of alkylators and epipodophyllotoxins and the use of G-CSF had a higher estimated CI of SL than those in earlier studies (5-year CI 6.4+/-2.4% versus 0.0+/-0.0%, respectively, P=0.004)., Conclusions: Patients with ESFT are at risk for SM after treatment. The cumulative incidence of SM is higher with the current treatment protocols and may be related to the intensification of chemotherapeutic agents.

Purpose: To estimate the effects of radiotherapy and clinical factors on vertebral growth in patients with medulloblastoma and supratentorial primitive neuroectodermal tumors treated with craniospinal irradiation (CSI) and chemotherapy., Methods and Materials: The height of eight individual or grouped vertebral bodies (C3, C3-C4, T4, T4-T5, C6-T3, T4-T7, L3, L1-L5) was measured before and after CSI (23.4 or 36-39.6 Gy) in 61 patients. Of the 61 patients, 40 were boys and 21 were girls (median age, 7 years; range, 3-13 years), treated between October 1996 and October 2003. Sagittal T(1)-weighted magnetic resonance images were used for the craniocaudal measurements. The measurements numbered 275 (median, 5/patient; range, 3-7). The median follow-up after CSI was 44.1 months (range, 13.8-74.9 months)., Results: Significant growth was observed in all measured vertebrae. Excluding C3-C4, the growth rate of the grouped vertebrae was affected by age, gender, and CSI dose (risk classification). The risk classification alone affected the growth rates of C3 (p = 0.002) and L3 (p = 0.02). Before CSI, the length of all vertebral bodies was an increasing function of age (p <0.0001). The C3 length before CSI was affected by gender and risk classification: C3 was longer for female (p = 0.07) and high-risk (p = 0.07) patients., Conclusion: All vertebrae grew significantly after CSI, with the vertebrae of the boys and younger patients growing at a rate greater than that of their counterparts. The effect of age was similar across all vertebrae, and gender had the greatest effect on the growth of the lower cervical and upper thoracic vertebrae. The effect of the risk classification was greatest in the lumbar spine by a factor of < or = 10.

Background: Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. The individual contributions of each treatment component cannot be analyzed separately; improvements in local and systemic control can influence each other., Patients and Methods: We reviewed the records of 220 patients treated on institutional protocols from 1979 to 2004. Factors predictive of local and distant recurrence were analyzed., Results: The median age at diagnosis was 13.7 years. Ninety-five patients relapsed at a median of 1.6 years. The 5-year overall survival estimate was 63.5% +/- 3.5%. The estimated 5-year cumulative incidence (CI) of local failure was 25.1% +/- 3.0%. Local failure was associated with treatment era (P < 0.001), tumor size (P = 0.037) and type of local control (P = 0.021). Systemic treatment intensification improved local control. The estimated 5-year CI of distant recurrence was 22.5% +/- 2.9%. Patients with localized disease (P < 0.001), smaller tumors (P = 0.018) and those who received surgery +/- radiation for local control (P = 0.023) had lower CI of distant failure., Conclusions: Successful treatment of ESFT requires optimal systemic and local therapy. Both treatment modalities are intertwined and the control of both local and distant disease is the result of the combined approach.

Purpose: To describe and review the radiotherapy (RT) treatment planning and delivery techniques used for pediatric sarcoma patients at St. Jude Children's Research Hospital. The treatment characteristics serve as a baseline for future comparison with developing treatment modalities., Patients and Methods: Since January 2003, we have prospectively treated pediatric and young-adult patients with soft-tissue and bone sarcomas on an institutional Phase II protocol evaluating local control and RT-related treatment effects from external-beam RT (conformal or intensity-modulated RT; 83.4%), low-dose-rate brachytherapy (8.3%), or both (8.3%). Here we describe the treatment dosimetry and delivery parameters of the initial 72 patients (median, 11.6 years; range, 1.4-21.6 years)., Results: Cumulative doses from all RT modalities ranged from 41.4 to 70.2 Gy (median, 50.4 Gy). Median D(95) and V(95) of the planning target volume of external-beam RT plans were, respectively, 93.4% of the prescribed dose and 94.6% of the target volume for the primary phase and 97.8% and 99.2% for the cone-down/boost phase. The dose-volume histogram statistics for 27 critical organs varied greatly. The spinal cord in 13 of 36 patients received dose >45 Gy (up to 52 Gy in 1 cc) because of tumor proximity., Conclusions: Planning and delivery of complex multifield external beam RT is feasible in pediatric patients with sarcomas. Improvements on conformity and dose gradients are still desired in many cases with sensitive adjacent critical structures. Long-term follow-up will determine the risk of local failure and the benefit of normal tissue avoidance for this population.

Purpose: Limiting the neurocognitive sequelae of radiotherapy (RT) has been an objective in the treatment of medulloblastoma. Conformal RT to less than the entire posterior fossa (PF) after craniospinal irradiation might reduce neurocognitive sequelae and requires evaluation., Methods and Materials: Between October 1996 and August 2003, 86 patients, 3-21 years of age, with newly diagnosed, average-risk medulloblastoma were treated in a prospective, institutional review board-approved, multi-institution trial of risk-adapted RT and dose-intensive chemotherapy. RT began within 28 days of definitive surgery and consisted of craniospinal irradiation (23.4 Gy), conformal PF RT (36.0 Gy), and primary site RT (55.8 Gy). The planning target volume for the primary site included the postoperative tumor bed surrounded by an anatomically confined margin of 2 cm that was then expanded with a geometric margin of 0.3-0.5 cm. Chemotherapy was initiated 6 weeks after RT and included four cycles of high-dose cyclophosphamide, cisplatin, and vincristine., Results: At a median follow-up of 61.2 months (range, 5.2-115.0 months), the estimated 5-year event-free survival and cumulative incidence of PF failure rate was 83.0% +/- 5.3% and 4.9% +/- 2.4% (+/- standard error), respectively. The targeting guidelines used in this study resulted in a mean reduction of 13% in the volume of the PF receiving doses >55 Gy compared with conventionally planned RT. The reductions in the dose to the temporal lobes, cochleae, and hypothalamus were statistically significant., Conclusion: This prospective trial has demonstrated that irradiation of less than the entire PF after 23.4 Gy craniospinal irradiation for average-risk medulloblastoma results in disease control comparable to that after treatment of the entire PF.

Radiation therapy is often used to achieve local control of pelvic Ewing sarcoma in children. The effects of radiation on the female reproductive tract have been well documented in adults with gynecological malignancies, but the long-term consequences of pelvic radiation in pre-pubertal or adolescent girls are not as well described. We report a case of hematometrocolpos developing in an adolescent previously treated with chemotherapy and radiation therapy for pelvic Ewing sarcoma. We describe the clinical presentation, radiographic features, gross pathology, treatment strategies, outcome, as well as putative predisposing factors and preventative interventions., ((c) 2007 Wiley-Liss, Inc.)

Background: Pleural effusion is uncommon at diagnosis of neuroblastoma in children. Because the presence of malignant cells in pleural fluid may significantly change the management and outcome of patients with neuroblastoma, we retrospectively analyzed a cohort of neuroblastoma patients who presented with pleural effusion at the time of diagnosis to determine the incidence, presentation, stage, treatment, and outcome of these patients., Methods: We reviewed the presenting features of 295 patients with the diagnosis of neuroblastoma who received treatment at St. Jude Children's Research Hospital between 1991 and 2005. Patients were chosen for further analysis if pleural effusion had been identified on chest radiographs or computed tomography (CT) scans at diagnosis, Results: Thirty-one out of 295(10.5%) patients with neuroblastoma had pleural effusion identified at time of presentation. International neuroblastoma staging system (INSS) risk stratification was high risk in 29 cases and intermediate risk and low risk in 1 case each. The primary site of disease was abdomen in 26 patients; mediastinum in 5. We conducted cytologic analysis of pleural fluid of nine patients; the specimen of seven contained malignant cells. Eighteen of 31 patients died of progressive or recurrent disease., Conclusion: In patients with neuroblastoma, pleural effusion is usually associated with unfavorable biologic features and high-risk disease. Pleural fluid should be examined cytologically and at a time when the results would change the risk stratification. There was no statistically significant difference in the survival rate of the patients with high-risk neuroblastoma with or without malignant pleural effusion., (2007 Wiley-Liss, Inc)

Background: Advances in systemic and local therapies have improved outcomes for patients with the Ewing sarcoma family of tumors (ESFT). As new treatments are developed, a critical review of data from past treatment eras is needed to identify clinically relevant risk groups., Methods: The authors reviewed the records of 220 patients with ESFT who were treated on protocols at St. Jude Children's Research Hospital from 1979 to 2004. Two treatment eras were defined. Factors predictive of outcome were analyzed to identify distinct risk groups., Results: The median age at diagnosis was 13.7 years (range, 1.1-25.2 years). Metastatic disease was associated with tumors measuring >8 cm (P = .002) and axial location (P = .014). The 5-year overall survival (OS) estimate (63.5% +/- 3.5%) did not appear to differ by protocol. Tumor stage and size were found to be the only independent predictors of outcome. Treatment era and type of local control therapy were found to influence the outcome of patients with localized disease. Four risk groups were defined: favorable risk (age <14 years with localized, nonpelvic tumors), intermediate risk (localized, age >/=14 years, or pelvic tumors), unfavorable-pulmonary (isolated lung metastases), and unfavorable-extrapulmonary (extrapulmonary metastases). The 5-year OS estimates for these groups were 88.1% +/- 4.4%, 64.9% +/- 5.2%, 53.8% +/- 9.4%, and 27.2% +/- 7.3%, respectively (P < .001). The incidence of therapy-related leukemia was significantly higher during the second treatment era, when more intensified regimens were used (6.1% +/- 2.7% vs 0% +/- 0%; P = .005)., Conclusions: Risk stratification schemes such as this should be used to prospectively evaluate novel risk-based therapies. Studies of biologic pathways may help to refine this model.

This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.

Purpose: To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420., Experimental Design: Pharmacokinetic measurements were done in plasma (days 1, 2, 3, and 8 of therapy) and, concurrently, in plasma and CSF (before and at 1, 2, 4, 8, and 24 h after dose on day 34 of therapy) in an 8-year-old patient diagnosed with glioblastoma who received local irradiation and oral erlotinib in a phase I protocol. CSF samples were collected from a ventriculoperitoneal shunt, which was externalized because of infection. Erlotinib concentrations were determined by liquid chromatography/mass spectrometry. CSF penetration of erlotinib and OSI-420 were estimated by a compartmental model and by calculating the ratio of CSF to plasma 24-h area under concentration-time curve (AUC(0-24))., Results: This patient was assigned to receive erlotinib at a dose level of 70 mg/m(2), but the actual daily dose was 75 mg (78 mg/m(2)). Erlotinib and OSI-420 plasma pharmacokinetic variables on days 8 and 34 overlapped to suggest that steady state had been reached. Whereas erlotinib and OSI-420 AUC(0-24) in plasma on day 34 were 30,365 and 2,527 ng h/mL, respectively, the correspondent AUC(0-24) in the CSF were 2,129 and 240 ng h/mL, respectively. Erlotinib and OSI-420 CSF penetration were 7% and approximately 9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was approximately 130 ng/mL (325 nmol/L)., Conclusions: The plasma pharmacokinetics of erlotinib in this child overlapped with results described in adults. Oral administration of erlotinib achieves CSF concentrations comparable with those active against several cancer cell lines in preclinical models.

Purpose: To estimate potential differences in volumetric bone growth in children with sarcoma treated with intensity-modulated (IMRT) and conformal (CRT) radiation therapy using an empiric dose-effect model., Methods and Materials: A random coefficient model was used to estimate potential volumetric bone growth of 36 pelvic bones (ischiopubis and ilium) from 11 patients 4 years after radiotherapy. The model incorporated patient age, pretreatment bone volume, integral dose >35 Gy, and time since completion of radiation therapy. Three dosimetry plans were entered into the model: the actual CRT/IMRT plan, a nontreated comparable IMRT/CRT plan, and an idealized plan in which dose was delivered only to the planning target volume. The results were compared with modeled normal bone growth., Results: The model predicted that by using the idealized, IMRT, and CRT approaches, patients would maintain 93%, 87%, and 84%, respectively (p = 0.06), of their expected normal growth. Patients older than 10 years would maintain 98% of normal growth, regardless of treatment method. Those younger than 10 years would maintain 87% (idealized), 76% (IMRT), or 70% (CRT) of their expected growth (p = 0.015). Post hoc testing (Tukey) revealed that the CRT and IMRT approaches differed significantly from the idealized one but not from each other., Conclusions: Dose-effect models facilitate the comparison of treatment methods and potential interventions. Although treatment methods do not alter the growth of flat bones in older pediatric patients, they may significantly impact bone growth in children younger than age 10 years, especially as we move toward techniques with high conformity and sharper dose gradient.

Purpose/objective: This study aimed to develop objective models of radiation effects on musculature in children with soft tissue sarcoma using treatment dosimetry and clinical and quantitative magnetic resonance imaging (MRI) parameters that may be used to guide treatment planning or predict side effects., Methods: In the initial 13 patients undergoing external beam radiation therapy (RT) on a Phase II study of conformal or intensity-modulated RT for the treatment of soft tissue sarcoma approved by an Institutional Review Board, we evaluated quantitative MRI changes in the musculature to assess radiation-related treatment effects. Patients with soft tissue sarcoma, including Ewing's sarcoma, had quantitative T1, T2 and dynamic enhanced MRI (DEMRI) performed before, during (Week 4) and after RT (Week 12). Regions of interest were selected in consistent locations within and outside the high-dose regions (on ipsilateral and contralateral sides when available). Mean RT dose, T1, T2 and DEMRI parameters were calculated and modeled using a mixed random coefficient dose model., Results: The mean doses to the high- and low-dose regions were 56.4 Gy (41.8-75.3 Gy) and 13.0 Gy (0.1-37.5 Gy), respectively. Compared with tissues distant from the tumor bed, maximal enhancement was significantly increased in tissues adjacent to the tumor/tumor bed prior to RT (60.6 vs. 44.2, P=.045) and remained elevated after 12 weeks. T1 was significantly elevated in tissues adjacent to the tumor bed prior to RT (942.4 vs. 759.0, P=.0078). The slope of longitudinal change in T1 was greater for tissues that received low-dose irradiation than those that received high-dose irradiation (P=.0488). The effect of dose on the slope of T2 was different (P=.0333) when younger and older patients are compared., Conclusions: Acute affects of irradiation in muscle are quantifiable via MRI. These models provide evidence that quantifiable MRI parameters may be correlated with patient parameters of radiation dose and clinical factors including patient age. Long-term follow-up will be required to determine if acute changes correlate with clinically significant late effects.

Background: Unlike osteosarcoma, the Ewing sarcoma family of tumors (ESFT) has rarely been reported as secondary malignant neoplasms after treatment of childhood cancer. ESFT arising as a second cancer was reviewed and characterized at our childhood cancer center., Methods: A retrospective review was undertaken of 11,183 patients age <21 years who were treated for a primary cancer between March 1962 and December 2003 at St. Jude Children's Research Hospital. All cases of ESFT were confirmed to have a rearranged EWS gene., Results: Six cases of ESFT (1.3% of 479 second cancers) were identified in patients previously treated for lymphoma (n = 3), leukemia (n = 1), retinoblastoma (n = 1), or Wilms tumor (n = 1). None of these patients had a family history suggestive of a familial cancer syndrome. The median time between diagnosis of primary cancer and diagnosis of ESFT was 5.9 years (range, 3.1-18.3 years). ESFT occurred in typical anatomic locations: rib (n = 2), chest wall soft tissues (n = 2), pelvis (n = 1), and extremity (n = 1). One tumor arose at the margin of a previous radiotherapy field and 1 arose distant from previous radiotherapy fields; all other patients had not received radiotherapy. Three patients are alive at the time of this report, including 2 whose ESFT was diagnosed more than 8 years ago., Conclusions: ESFT occurs rarely after treatment of a primary cancer during childhood, and most cases do not appear to be related to radiation therapy. Long-term survival can be achieved in some patients, and therefore secondary ESFT should be treated with curative intent., (Copyright 2006 American Cancer Society.)

Purpose: Hypothyroidism frequently occurs after treatment for pediatric Hodgkin's lymphoma, but race has not been investigated as a risk factor for this delayed toxicity. The aim of this study was to determine whether race is an independent risk factor for hypothyroidism in survivors of pediatric Hodgkin's lymphoma., Patients and Methods: To identify differences between black and white patients in the development of hypothyroidism after treatment for Hodgkin's lymphoma, we conducted a retrospective study of consecutively treated pediatric patients with newly diagnosed Hodgkin's lymphoma treated at St Jude Children's Research Hospital (Memphis, TN) from January 1980 through December 2002. Clinical or biochemical hypothyroidism was defined by an above normal thyroxine-stimulating hormone concentration or by the need for thyroid hormone replacement therapy., Results: The 461 patients (388 white patients, 73 black patients) where followed for a median of 11.3 years (range, 1.8 to 24.9 years). Hypothyroidism developed in 196 (43%) of 461 patients after a median of 2.9 years (range, 0.7 to 11.3 years) after diagnosis of Hodgkin's lymphoma. Hypothyroidism developed in 47% of white patients but in only 21% of black patients (hazard ratio = 2.7; 95% CI, 1.6 to 4.6). After adjusting for other risk factors for hypothyroidism (thyroid radiation dose, sex, and nodular sclerosis histology), the risk of hypothyroidism in white patients was 2.5 times (95% CI, 1.5 to 4.3 times) the risk in black patients (P < .001)., Conclusion: White patients have a higher risk of hypothyroidism after neck irradiation for pediatric Hodgkin's lymphoma than black patients.

Background: Children with diffuse brainstem glioma (BSG) commonly undergo novel therapies because their outcome is poor with radiation therapy (RT). Although recent clinical trials using new biologic agents documented intratumoral hemorrhage (IH) among several children with BSG, to the authors' knowledge little is known regarding this phenomenon. In the current study, the authors assessed the characteristics and estimated the cumulative incidence of IH among children with BSG., Methods: All available brain imaging studies and medical records of 48 consecutive patients with newly diagnosed BSG treated at the study institution over a 10-year interval (1992-2002) were reviewed. Treatment was comprised of RT and various regimens of conventional chemotherapy; none of these patients received biologic agents. At the time of last follow-up, all patients had died of tumor progression., Results: The authors reviewed 319 imaging studies (251 magnetic resonance imaging scans and 68 computed tomography scans). IH was present in 6.25% of patients at the time of diagnosis. The 6-month and 12-month cumulative incidence estimates of IH regardless of the associated symptoms were 15.5% +/- 5.5% and 24.4% +/- 6.5%, respectively. The same estimates for symptomatic cases were 8.9% +/- 4% and 17.8% +/- 6%, respectively. All cases of IH at the time of diagnosis and 78% of symptomatic cases that developed after diagnosis were located in necrotic areas., Conclusions: Although IH is uncommon at the time of diagnosis, symptomatic IH may occur among nearly 20% of children after the diagnosis of BSG. The uniform occurrence of IH among patients treated with various chemotherapeutic regimens and its association with necrotic areas suggests that tumor biology plays a significant role in this event., ((c) 2006 American Cancer Society.)

Background: Survivors of Hodgkin lymphoma and other patients who receive neck irradiation are at increased risk of thyroid cancer. Ultrasonography provides an inexpensive and non-invasive method of thyroid screening, but the clinical significance of thyroid nodules detected by ultrasound screening is uncertain., Procedure: We reviewed the demographics, clinical characteristics, method of detection, and outcome of patients who developed thyroid nodules after treatment for pediatric Hodgkin lymphoma at our institution. One radiologist reviewed all imaging studies., Results: Sixty-seven children treated for Hodgkin lymphoma from 1962 to 2001 developed thyroid nodules. The study group represented 9,024 person-years of follow-up after the diagnosis of Hodgkin lymphoma and 581 person-years after diagnosis of a thyroid nodule. A median of 10.5 years (range, 0.2-24.8 years) elapsed between the diagnoses of Hodgkin lymphoma and thyroid nodule(s). All but one patient had received neck irradiation for Hodgkin lymphoma, with a median thyroid radiation dose of 35 Gy (range, 12-45 Gy). Thyroid nodules were found to be malignant in seven patients (10%), at a median of 16.2 years (range, 8.4-23.7 years) after diagnosis of Hodgkin lymphoma. Only one malignancy was found through screening ultrasonography. All patients with thyroid cancer remained disease-free at 0.4-16.2 years of follow-up., Conclusions: Thyroid nodules are common in Hodgkin lymphoma survivors treated with neck irradiation, but the majority of these lesions have an indolent clinical course and do not undergo malignant transformation. Only patients with a palpable mass or clinical symptoms need more extensive evaluation, including Doppler-flow ultrasonography and fine-needle aspiration.

Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.

Purpose: Refinement in managing pediatric Hodgkin's disease (HD) requires understanding of factors associated with local treatment failure. This study defines the cumulative incidence (CI) of local failure (LF) and prognostic factors for pediatric patients treated for HD with combined-modality therapy (CMT)., Patients and Methods: We enrolled 195 patients onto two prospective studies at St Jude Children's Research Hospital between 1990 and 2000. Patients received CMT with chemotherapy (vinblastine, doxorubicin, methotrexate, and prednisone [VAMP]; vinblastine, etoposide, prednisone, and doxorubicin; or VAMP/cyclophosphamide, vincristine, and procarbazine) and involved-field radiation therapy delivered to initial site(s) of disease on the basis of early response. Sites of disease involvement, treatment, and sites of failure were confirmed from the patients' medical record, imaging, and radiotherapy treatment records. We estimated the overall survival, event-free survival, and CI of LF., Results: With a median follow-up of 7.6 years, the CI of LF was 10.9% and 11.6% at 5 and 10 years, respectively. Twenty-seven (14%) of 195 patients experienced recurrence of HD, and 22 (81%) of those experienced LF. Bulky mediastinal disease greater than one third transthoracic diameter predicted a higher incidence of LF, but did not predict failure in the mediastinum. Male sex, low initial hemoglobin, and bulky mediastinal disease were prognostic indicators of LF. Attenuation of radiation dose to 15 Gy based on response provides excellent infield control., Conclusion: CMT provides excellent local disease control in children and young adults with HD. LF remains a primary site of disease recurrence, with male sex, low initial hemoglobin, and bulky mediastinal disease predicting for LF.

Purpose: To document the spectrum and severity of late effects in female survivors of pelvic rhabdomyosarcoma., Patients and Methods: We reviewed the demographic, diagnostic, treatment, and outcome data of the 26 females treated for pelvic rhabdomyosarcoma at our institution between March 1962 and December 1996 who survived free of disease for 5 or more years. Adverse effects that occurred 5 or more years after diagnosis were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0., Results: The most common tumor sites were vagina (n = 7), pelvis/retroperitoneum (n = 6), and bladder (n = 4). All patients received chemotherapy (alkylating agent, n = 23; doxorubicin, n = 16); 22 received radiotherapy (median dose, 46 Gy). Median follow-up of the 23 survivors was 20.3 years. Late effects occurred in 24 patients, 23 of whom had grade 3/4 late effects (median grade 3/4 late effects per patient, three; range, zero to 14). Fourteen patients (54%) required surgery for late complications. The 22 patients who had received radiotherapy had a greater median number of late effects per patient than did the remaining four (9.5 v one; P = .002). The median number of late effects per patient was higher in the 12 patients treated during or after 1984 than in the 14 treated earlier (12.5 v 6.5; P = .041)., Conclusion: The burden of late effects in girls treated for pelvic rhabdomyosarcoma is significant and does not seem to be diminishing with advances in treatment. Prospective studies are needed to better assess the impact of these late effects on quality of life and functional outcome, and to refine the treatment approach to pelvic rhabdomyosarcoma.

Purpose: To model the effects of external beam irradiation on the developing flat bones of pediatric patients undergoing radiation therapy (RT) for tumors involving the musculoskeletal system., Methods and Materials: Patients with image-guided RT plans including areas adjacent to facial or pelvic flat bones underwent retrospective contouring of nontumor involved flat bones ipsilateral and contralateral to the treatment side. Radiation dose-volume information and bone volume data (initial and the most recent follow-up) were analyzed in 15 paired flat bones from 10 patients (ages 1.0-17.0 years). The models to predict bone growth after completion of RT (v(post)) were based on initial bone volume (v(pre)), the patient's age, time to follow-up (t), and the dose-volume parameter (v(Int35+))., Results: We developed a dose effects model as follows: Log (v(post) / v(pre)) = beta(time)t + beta(age group)t + beta(dose)t v(Int35). The dose-volume parameter v(Int35) predicted significantly for alterations in growth in younger patients, but not for older patients. The predictability of the fitted model for relative change in bone growth improved in the younger age group with the addition of the dose-volume term v(Int35) (correlation coefficient of r = 0.5510 to r = 0.6760 with the addition v(Int35))., Conclusions: Our model accurately predicted flat bone growth and is notable for the inclusion of radiation dose-volume information, which is now available in the image-guided RT era. Further refinement of this model in a prospective patient population is underway.

Background: The local management of Ewing sarcoma family of tumors (ESFT) often centers on the surgical resectability of the primary lesion and physician biases regarding differences in the morbidity between primary surgical and radiotherapeutic management., Methods: The authors retrospectively reviewed the records of 33 patients with localized ESFT who underwent surgery and received systemic chemotherapy at St. Jude Children's Research Hospital (Memphis, TN). Two multiagent systemic chemotherapy regimens were used: 14 patients received vincristine, doxorubicin, cyclophosphamide, and actinomycin D (VACA), and 19 received VACA in combination with ifosphamide and etoposide. The primary tumor was surgically resected via a wide, local excision (n = 32) or a marginal excision (n = 1)performed either at diagnosis or after 3-5 months of systemic chemotherapy. Clinical outcome and prognostic factors for disease control were reported in the current study., Results: The median follow-up for patients was 9.9 years. The 5-year and 10-year survival rates were 84.5% and 75.8%, respectively. At 5 years, the cumulative incidence of local disease recurrence was 12.5%, and the event-free survival (EFS) rate was 71.7%. The same values were found at 10 years. The site of tumor origin was a significant predictor of EFS. The survival rate of patients whose tumors arose in bone was 78.6%, and the survival rate of patients whose tumors originated in soft tissue was 25.0% (P = 0.028). No other factors investigated were predictive of outcome., Conclusions: Local disease control and overall outcome for patients with ESFT managed by multiagent systemic therapy and surgery was excellent. Local disease control rates remained near 90% at 10-year follow-up. Patients with extraosseous primary sites of disease may fare less well with this approach to therapy.

About 1,700 children in the United States are diagnosed yearly with lymphomas; Hodgkin's disease accounts for approximately half of these cases, or 6% of all childhood cancers. Contemporary therapy allows for the achievement of remission in the majority of cases. The fusion of positron emission tomography (PET) with CT provides the most accurate imaging method for disease characterization and treatment response. However, experience with 18F-FDG PET-CT is limited in pediatric Hodgkin's disease. Numerous non-oncologic processes can mimic recurrent or residual tumor. This pictorial addresses mimickers of disease such as uptake in normal structures, infections, transforming germinal canters and effects of therapy on normal tissues. It is essential for radiologists to be familiar with these findings in order to stage disease activity and therapeutic response accurately.

Background: The role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting., Methods: Patients ages 3-21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5-day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), were analyzed during Cycles 1 and 3., Results: Thirty-three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n=5) or toxicity (n=1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty-nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one-third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1-year survival rate was 48% (standard error, 8%)., Conclusions: The administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children.

Purpose: To assess the effect of radiation dose on local tumor control of the Ewing sarcoma family of tumors in 79 patients with localized disease treated at a single institution., Methods and Materials: Thirty-seven patients received vincristine, actinomycin D, cyclophosphamide, and doxorubicin, and 42 received vincristine, actinomycin D, and cyclophosphamide, with alternating cycles of ifosfamide and etoposide; all underwent definitive radiotherapy (median dose, 37.5 Gy) with either low-dose (<40 Gy) or standard dose (> or =40 Gy) radiation delivered according to the protocol. We calculated the cumulative incidence of local treatment failure, disease recurrence, and overall survival and analyzed the effect of known prognostic factors and radiation dose., Results: The cumulative incidence of local treatment failure at 10 years was 30.4% and that of disease recurrence was 40%. The overall survival rate was 64.5%. Patient age > or =14 years and tumor size > or =8 cm were adverse prognostic factors for local treatment failure; patient age > or =14 years was also associated with worse survival. Although the radiation dose alone did not predict for local treatment failure, the cumulative incidence of local failure at 10 years was 19% when tumors <8 cm were treated with <40 Gy, and no patient treated with standard doses (> or =40 Gy) developed local recurrence (p = 0.084)., Conclusion: Tumor size and patient age predict for local tumor control in patients with Ewing sarcoma family of tumors treated with systemic therapy and definitive radiotherapy. Patients treated with reduced-dose radiotherapy experienced unacceptably high rates of local recurrence.

Background: Local tumor control for patients with Ewings sarcoma family of tumors (ESFT) is favorable when the primary tumor is resectable or small. Local failure rates for patients who received combined surgery and RT were reviewed to determine outcome and prognostic factors., Procedures: We performed a retrospective review of all patients with localized ESFT treated with combined definitive surgery and RT between 1978 and 2001, at St. Jude Children's Research Hospital. Rates of local failure, survival, and prognostic factors for recurrence were determined in 39 patients who received combined local therapy. Systemic treatment included vincristine, actinomycin D, cyclophosphamide, and doxorubicin (6 patients), with the addition of ifosfamide and etoposide (33 patients)., Results: With a median follow-up of 8.7 years the 5- and 8-year survival estimates were 89.2 +/- 5.4% and 82.8 +/- 7.3%. The 8-year incidence of local failure was 10.8 +/- 5.2%. The 8-year local failure rate for patients with positive surgical margins was 17% and for negative surgical margins 5% (P = 0.25). Overall survival was improved for patients with negative surgical margins (94 vs. 71%, P = 0.052). Tumor size, site, histologic response, and radiation dose did not significantly alter the rate of local failure., Conclusions: Patients with ESFT managed with definitive surgery and irradiation have favorable local control rates. Even among patients with unfavorable prognostic factors local tumor control remained excellent., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: We conducted a phase II trial of conformal radiation therapy (CRT) for localized childhood ependymoma to determine whether the irradiated volume could be reduced to decrease CNS-related side effects without diminishing the rate of disease control., Patients and Methods: Between July 1997 and January 2003, 88 pediatric patients (median age, 2.85 +/- 4.5 years) received CRT in which doses (59.4 Gy to 73 patients or 54.0 Gy after gross-total resection to 15 patients younger than 18 months) were administered to the gross tumor volume and a margin of 10 mm. Patients were categorized according to extent of resection (underwent gross total resection, n = 74; near-total resection, n = 6; subtotal resection, n = 8), prior chemotherapy (n = 16), tumor grade (anaplastic, n = 35), and tumor location (infratentorial, n = 68). An age-appropriate neurocognitive battery was administered before and serially after CRT., Results: The median length of follow-up was 38.2 months (+/- 16.4 months); the 3-year progression-free survival estimate was 74.7% +/- 5.7%. Local failure occurred in eight patients, distant failure in eight patients, and both in four patients. The cumulative incidence of local failure as a component of failure at 3 years was 14.8% +/- 4.0%. Mean scores on all neurocognitive outcomes were stable and within normal limits, with more than half the cohort tested at or beyond 24 months., Conclusion: Limited-volume irradiation achieves high rates of disease control in pediatric patients with ependymoma and results in stable neurocognitive outcomes., (Copyright 2004 American Society of Clinical Onocology)

Background: Brain metastases of pediatric germ cell tumors are uncommon, and there is limited information regarding their incidence, clinical presentation, response to treatment, and influence on survival., Methods: The authors reviewed the experience with brain metastases from pediatric germ cell tumors at St. Jude Children's Research Hospital (Memphis, TN) over a 40-year period., Results: Between March 1962 and February 2002, 16 of 206 patients with germ cell tumors (7.8%) had brain metastases at the time of initial presentation (n = 2), later in the course of the illness (n = 12), or at autopsy (n = 2). Twelve of 16 patients (75%) had symptoms referable to the brain (nausea/emesis, headaches, or seizures), and 14 (88%) had pulmonary metastases at the time brain metastases were identified. Patients with brain metastases were more likely to have an extragonadal primary tumor (P = 0.013), advanced-stage disease at initial presentation (P = 0.016), and choriocarcinoma within the primary tumor (P < 0.001). The incidence of brain metastases was significantly lower in the second 2 decades of the study period (5 of 135 patients [3.7%]) than in the first 2 decades (11 of 71 patients [15.5%]; P = 0.005). Two of the 16 patients in the current study are long-term survivors., Conclusions: Brain metastases are uncommon in childhood germ cell tumors, and their incidence appears to be decreasing. In the current study, most patients with such metastases were symptomatic and had pulmonary metastases at the time brain metastases were identified. Patients with the highest risk of developing brain metastases include those with extragonadal tumors, those with high disease stage at initial presentation, and those with choriocarcinoma as a component of the primary tumor. The probability of survival is poor, although a small proportion of patients may become long-term survivors.