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Purpose To estimate the rate of disease control after conformal radiation therapy using reduced clinical target volume (CTV) margins and to determine factors that predict for tumor progression. Methods and Materials Eighty-eight children (median age, 8.5 years; range, 3.2-17.6 years) received conformal or intensity modulated radiation therapy between 1998 and 2009. The study group included those prospectively treated from 1998 to 2003, using a 10-mm CTV, defined as the margin surrounding the solid and cystic tumor targeted to receive the prescription dose of 54 Gy. The CTV margin was subsequently reduced after 2003, yielding 2 groups of patients: those treated with a CTV margin greater than 5 mm (n=26) and those treated with a CTV margin less than or equal to 5 mm (n=62). Disease progression was estimated on the basis of additional variables including sex, race, extent of resection, tumor interventions, target volume margins, and frequency of weekly surveillance magnetic resonance (MR) imaging during radiation therapy. Median follow-up was 5 years. Results There was no difference between progression-free survival rates based on CTV margins (>5 mm vs ≤5 mm) at 5 years (88.1% ± 6.3% vs 96.2% ± 4.4% [ P =.6386]). There were no differences based on planning target volume (PTV) margins (or combined CTV plus PTV margins). The PTV was systematically reduced from 5 to 3 mm during the time period of the study. Factors predictive of superior progression-free survival included Caucasian race ( P =.0175), no requirement for cerebrospinal fluid shunting ( P =.0066), and number of surveillance imaging studies during treatment ( P =.0216). Patients whose treatment protocol included a higher number of weekly surveillance MR imaging evaluations had a lower rate of tumor progression. Conclusions These results suggest that targeted volume reductions for radiation therapy using smaller margins are feasible and safe but require careful monitoring. We are currently investigating the differences in outcome based on host factors to explain the results.

Purpose P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006. Patients and Methods After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233). Results Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT. Conclusion The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.

More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects.To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy.Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012.The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy.Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low.Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed.Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival.clinicaltrials.gov Identifier: NCT00145600.

BACKGROUND 5-Fluorouracil (5-FU) activity for various carcinomas of adults has been enhanced through the synergistic effect of leucovorin. Few pediatric studies of 5-FU in pediatric patients have been previously reported. METHODS Fifty-eight patients were treated with a 4-hour infusion of leucovorin, 400 mg/m2, administered daily for 5 days every 3-4 weeks. 5-Fluorouracil was administered by bolus injection 1 hour into each leucovorin infusion. Eleven adolescent patients with colorectal carcinoma, Stage 3 or 4, were treated with therapeutic intent, and other patients with a variety of drug-resistant pediatric solid neoplasms received similar treatment. RESULTS Patients with measurable disease of colorectal carcinoma responded favorably to 5-FU/leucovorin. Stable disease activity was seen with other tumor types. Specifically, there were no objective responses in 12 patients with Ewing's Sarcoma or 11 with osteosarcoma. There were 4 deaths in this study from causes related to toxicity. Nonfatal grade 3/4 toxicities included mucositis, rash, myelosuppression, nausea, vomiting, diarrhea, and infection. CONCLUSION The authors do not plan further evaluation of 5-FU/leucovorin in additional pediatric patients with colon cancer or other heavily pretreated malignant solid tumors and are presently treating their patients with colon carcinoma with 5-FU/leucovorin/interferon-alpha 2a.

Background: The use of interstitial, intracavitary, and permanent placement of radioactive isotopes has become a common practice in adult oncology patients based on numerous reports indicating improved local control and survival when used.1–4 These same irradiation techniques and treatments have been infrequently used for children with malignant disease despite known dose localization properties that allow for highly focal irradiation delivery with rapid reduction of the dose in nearby normal tissues. The noted benefit of decreased late complications noted in the adult series is also attractive, especially when considering the treatment of children. Methods: Between May, 198,1 and December 15, 1992, 46 children with non-CNS primary malignancy received 50 brachytherapy applications for primary therapy (n = 11 sites), as a boost in conjunction with external beam irradiation (n = 16 sites), or as treatment of recurrent disease or a second malignant neoplasm in a previously irradiated region that precluded further external irradiation or for metastatic disease (n = 23 sites). The most common tumor histologies were rhabdomyosarcoma (n = 14), soft tissue sarcoma (n = 10) and retinoblastoma (n = 10). Patient age at implantation ranged from 8 weeks to 24 years; follow-up was maintained in all patients and has ranged from 2–115 months (median, 39 months). Results: Forty-three of 50 sites receiving brachytherapy have maintained continuous disease free intervals, ranging from 2 to 115 months postimplantation (median, 41 months). The seven local failures occurred 2–20 months postimplant (median, 6 months). Severe complications occurred in 12 patients, two which were life threatening but resolved without further incident. Conclusions: Based on this ongoing clinical investigation, the authors recommend brachytherapy for selected pediatric malignancies and continue to evaluate the various factors associated with local control, local failures, and complications. Cancer 1994; 74: 733-9.

PURPOSE To evaluate survival and neurodevelopmental outcomes following radiation therapy in infants and young children with residual or progressive medulloblastoma after primary chemotherapy. PATIENTS AND METHODS Thirteen young patients (< or = 36 months old) with medulloblastoma were treated with preirradiation multiagent chemotherapy and maximal surgical resection. Patients were scheduled to receive radiation therapy at the time of documented disease progression or upon completion of chemotherapy with residual disease. All patients underwent neurodevelopmental evaluation at the time of diagnosis, before receiving radiation therapy, and at yearly intervals posttreatment. RESULTS Two patients completed the scheduled chemotherapy with residual disease and received delayed radiation therapy. The remaining 11 patients had either local or leptomeningeal progression during chemotherapy (median time to progression, 5 months). Six patients had a complete response (CR) to radiation therapy, and three of these children are alive 48 to 104 months postdiagnosis. Of the five patients who had progressive disease (PD) during radiation therapy or residual imaging abnormalities after treatment, only one is alive (with stable enhancing leptomeningeal abnormalities) 48 months postirradiation. Two additional survivors were rendered disease-free by surgical resection before radiation therapy and are without evidence of disease at 91 and 107 months after diagnosis. Thus, six of 13 patients are alive at 48 to 107 months postdiagnosis. Neurodevelopmental scores tended to be below age norms at diagnosis; scores improved during chemotherapy, but then decreased during posttreatment follow-up evaluation. CONCLUSION Radiation therapy appears to produce long-term disease-free survival in a proportion of very young patients who have progressive or residual medulloblastoma during or after primary chemotherapy. However, neurodevelopmental deficits are frequent among long-term survivors.

A clone expressing the 3′ end of the RESA gene of the Palo Alto isolate of Plasmodium falciparum was isolated by screening a λ expression library of Mung bean nuclease-digested genomic DNA fragments with antibodies from malaria patients. The DNA sequence of the RESA gene of this isolate has seven single-base changes compared to that seen in the Papua New Guinean isolate FC27. Six of the seven mutations cause amino acid substitutions. The same amino acid sequence as the Palo Alto sequence is found in the Ghanaian isolate NF7. To determine whether these are the only changes in this region of the molecule, we performed PCR analyses on 12 blood samples from malaria patients from Indonesia, The Palo Alto form of the RESA gene was detected in 10 of the samples and the FC27 form of the gene was detected in the other 2 samples. No other forms of the RESA gene were found, suggesting that RESA exists in two alleles for the examined region of the gene. These results indicate that there are two major allelic forms of RESA present in this part of Indonesia.

Desmoplastic infantile gangliogliomas are massive cystic tumors, typically occurring in the cerebral hemispheres of infants. They are remarkable pathologically for a prominent desmoplasia and, in some cases, for a cellular mitotically active component that can be readily interpreted as a malignant neoplasm. Four children less than 1 year of age were diagnosed with desmoplastic infantile gangliogliomas in the Pediatric Oncology Group infant brain tumor study (Protocol number 8633). All had been diagnosed by their respective institutions as having malignant tumors, i.e., Grade III astrocytoma, malignant meningioma, leptomeningeal fibrosarcoma, and gliosarcoma. All had increased intracranial pressure, and two had seizures. The tumors were extremely large, with one measuring 12 x 9 x 9 cm. None had evidence of metastatic disease. One patient had a gross total resection, and the other three had debulking procedures. All four children were treated with chemotherapy (cyclophosphamide, vincristine, cisplatinum, etoposide) for periods ranging from 12 to 24 months. Of those with postoperative measurable disease, one child had a complete response, one a partial response, and one had stable disease at the conclusion of chemotherapy. No child received radiation therapy. All children are alive with progression-free survivals after diagnosis of more than 36, 42, 48, and 60 months, respectively. Although desmoplastic infantile gangliomas are rare, recognition of this tumor type is essential because, despite their massive size and pathologically malignant appearance, they may have a relatively benign clinical course. If total surgical resection can be achieved, further therapy may not be indicated. In those patients in whom residual disease is present, chemotherapy appears to be an effective form of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

To identify bone abnormalities related to total-body irradiation (TBI) in long-term survivors of bone marrow transplantation (BMT) for childhood leukemia.The authors obtained skeletal surveys of 10 survivors of childhood leukemia, ages 5-27 years, who had undergone BMT 7-9 years previously. Pretransplantation "conditioning" regimens were composed of chemotherapy and TBI in doses of 12 or 14.4 Gy.Of the six survivors who received TBI before age 8 years, five had osteochondromas and three had metaphyseal growth abnormalities. One also had slipped femoral capital epiphysis. Findings in the four remaining patients, who received TBI at ages 12-19 years, were less severe and less clearly related to TBI (mild scoliosis in two cases, avascular necrosis of the femoral condyles in one, and a femoral enchondroma in one).Skeletal abnormalities, previously recognized as sequelae of local external-beam irradiation in children, may occur in long-term survivors of BMT who have received TBI. Younger patients appear to be at the greatest risk.

Background. The combined modalities of surgery, chemotherapy, and radiation therapy have greatly improved the survival rate in childhood paratesticular rhabdomyosarcoma, but the incidence of complications and late side effects is a cause for concern. Methods. We reviewed the records of 18 patients treated for paratesticular rhabdomyosarcoma at St. Jude Children's Research Hospital between 1962 and 1989. Patients with Group I disease were treated with orchiectomy, retroperitoneal lymph node dissection, and multiagent chemotherapy; more advanced cases also received radiation therapy with concurrent chemotherapy. Results. Sequelae included esophageal and common bile duct stricture, inguinal nerve entrapment syndrome, and small bowel obstruction. Short stature was found in all children whose spines were irradiated via para-aortic fields (34–37 Gy) prior to puberty. Two of 18 patients died from treatment complications and one from progressive disease. Conclusions. Multimodality treatment offers an excellent prognosis in paratesticular rhabdomyosarcoma, but is associated with significant morbidity and mortality rates. A discussion of therapy components and their application to disease stages suggests possible approaches to optimizing treatment for this therapy-sensitive malignancy.

In order to describe the status of long-term survivors of brain stem glioma, neuropsychological and behavioral measures were obtained a median of 2.5 (range 1.5-5.6) years after diagnosis from 16 survivors of 51 consecutively diagnosed children with brain stem glioma between 1983 and 1991. Among 11 children with dorsally exophytic tumors, 7 were treated with surgery alone (SRG) and 4 received conventionally fractionated local cranial radiation therapy (CFRT; 54-56 Gy) to the brain stem following surgery, 3 of these because of recurrent disease. Five others with diffusely infiltrative brain stem tumors received hyperfractionated radiation therapy (HFRT; 70.2 Gy) to the brain stem; 4 following biopsy or limited resection and 1 without prior surgery. IQs of children in the CFRT (mean 89, SD 24.4) and HFRT (mean 85, SD 12.7) groups were not significantly different. Children in the SRG group had significantly higher IQs (mean 100, SD 11.0) and fewer neurologic deficits than those who had received CFRT or HFRT. However, after statistically controlling for severity of neurologic deficits, treatment had no effect on IQ. The severity of residual neurologic deficits accounted for 42% of the variance in IQ scores; children with fewer neurologic problems scored higher. Additional studies are required to evaluate the potential neuropsychological benefits of equivalent total doses of HFRT compared to CFRT.

Purpose : To systematically analyze the spatial uncertainties associated with each step of the stereotactic radiosurgery (SRS) procedure and the overall spatial accuracy in the treatment delivery. Methods and Materials : A special test device has been designed and fabricated to permit accurate simulation, localization and treatment portal verification of a SRS target. This device with simulated targets dispersed in 3-D space can be rigidly attached to the BRW CT or angio frame for localization, to the BRW phantom base for target coordinate determination, and to the floor stand for portal verification. The setup allows evaluation of the accuracy of each procedure separately as well as the overall accuracy in the delivery of SRS treatment. Results : Biplanar film localizations reveal a systematic error in the phantom base pointer of the order of 0.1 mm that is applied as a correction to the measured target coordinates. Targets localized by planar film angiography had a mean positional error of 0.38 ± 0.1 mm compared to 1.0 ± 0.7 mm for digital angiography localization. The positional accuracy associated with CT localization was superior when a 2 mm vs. 4 mm slice thickness was used (0.9 ± 0.3 mm vs. 1.6 ± 0.5 mm error). Cumulative mean errors, including inaccuracies associated with treatment setup, were 1.0 ± 0.4 mm for radiographic localization, 1.2 ± 0.5 mm for CT with a 512 × 512 matrix and 2 mm slice thickness, and 2.0 ± 0.6 mm for CT at a 4 mm slice thickness (256 × 256 matrix). Larger errors would be expected in the clinical setting. Conclusion : Spatial errors in stereotactic radiosurgery are best estimated using a systematic approach to isolate independent contributing factors. The accuracy in target localization determines the overall accuracy of SRS procedure, provided the mechanical accuracy of the treatment apparatus is assured. Biplanar treatment portal verification with a fiducial localization frame is an accurate method of verifying the target coordinates before delivering treatment.

A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children

Investigations of long-term outcomes have been instrumental in designing safer and more effective contemporary therapies for pediatric hematological malignancies. Despite the significant therapeutic changes that have occurred over the last five decades, therapy modifications largely represent refinements of treatment protocols using agents and modalities that have been available for more than 30 years. This review summarizes major trends in the evolution of treatment of pediatric hematological malignancies since 1960 to support the relevance of the study of late effects of historical therapeutic approaches to the design and evaluation of contemporary treatment protocols and the follow-up of present-day survivors.

Diffuse intrinsic pontine glioma (DIPG) nearly exclusively affects children. The prognosis of DIPGs has remained grim despite more than three decades of clinical research and numerous clinical trials. More than 90% of the children with DIPG will succumb within 2 years of diagnosis. The tumor's incidence is still undefined, but data suggest 100-150 affected children annually in the US. The single proven effective treatment modality in DIPG remains radiation therapy. For the majority of patients however this treatment is only of transient effectiveness. Recent breakthroughs in the understanding of the molecular biology of DIPG have raised new hope and opened new avenues for therapeutic options. The advancement of basic and translational research and cooperation was the objective of the Toronto Think Tank, as new approaches are urgently needed.

Chronic inflammation is known to facilitate carcinogenic transformation in various tissues. 5-iodo-6-amino-1,2-benzopyrone (INH2BP), a novel inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (pADPRT) has recently been shown to regulate a variety of cellular signal transduction pathways and to abrogate in vivo tumorigenicity by a Ha-ms transfected endothelial cell line. Here we have investigated the effect of INH2BP on the activation by endotoxin (bacterial lipopolysaccharide, LPS) on the production of the inflammatory mediators tumor necrosis factor alpha (TNF alpha), interleukin-10 (IL-10) and interleukin-6 (IL-6), nitric oxide (NO) and prostaglandins in vitro and in vivo. In addition, we studied the effect of INH2BP on the activation of mitogen-activated protein kinase (MAP kinase) and nuclear factor kappa B (NF-kappa B) in vitro. In cultured J774 and RAW 264.7 macrophages, LPS induced the production of prostaglandin metabolites, the release of TNF and the expression of the inducible isoform of NO synthase (iNOS). The production of prostaglandins and of NO were inhibited by INH2BP in a dose-dependent manner, while the short-term release of TNF alpha was unaffected. INH2BP markedly suppressed LPS-mediated luciferase activity in RAW cells transiently transfected with a full length (-1,592 bp) murine macrophage iNOS promoter-luciferase construct, but not in a deletional construct consisting of -367 bp. In vivo, INH2BP pretreatment inhibited the induction of iNOS by LPS in rats, did not affect the LPS-induced TNF and IL-6 response, but enhanced LPS-induced IL-10 production. INH2BP pretreatment markedly improved the survival of mice in a lethal model of endotoxin shock. Our results demonstrate that INH2BP has potent anti-inflammatory actions in vitro and in vivo.

PURPOSE To assess the value of tumor-cell ploidy as a predictor of survival in medulloblastoma. PATIENTS AND METHODS Ploidy determinations were based on the flow-cytometric analysis of cellular DNA content in fresh tumor specimens taken from 34 consecutively treated children with newly diagnosed medulloblastoma. Patients were assigned a high or low risk of failure depending on tumor size and invasiveness, and the presence or absence of metastatic disease. Treatment consisted of radiotherapy, with or without chemotherapy, according to institutional or cooperative group protocols. RESULTS Univariate analysis of candidate prognostic factors showed that only tumor-cell ploidy and clinical risk group had a statistically significant influence on survival. Patients with hyperdiploid stem lines (n = 9) had significantly longer survival times (P = .04) than did those with diploid lines (n = 20). The estimated 5-year survival probabilities (+/- SE) for these two subgroups were 89% +/- 11% and 48% +/- 13%, respectively. Although clinical risk status (high v low) showed essentially the same predictive strength as ploidy, the two features identified largely nonoverlapping subgroups. Thus, within the clinical high-risk group, it was possible to distinguish hyperdiploid patients whose 5-year survival rate (83% +/- 15%) was comparable to that of patients with localized, low-risk tumors. CONCLUSION This prospective study indicates that both ploidy and clinical risk group are important prognostic factors in medulloblastoma. Their combined use at diagnosis would distinguish patients who require more aggressive therapeutic intervention (diploid, clinical high-risk group) from those who could be expected to benefit most from standard treatment.

Background. Children diagnosed with medulloblastoma whose tumor involves the brain stem or has spread through the cerebrospinal fluid pathways to other areas of the brain or spinal cord have a poor prognosis despite therapy with surgery, craniospinal irradiation (CSI), and chemotherapy. Preradiation chemotherapy may improve the outlook for these patients. Methods. To further study the role and feasibility of preradiation chemotherapy, children between the ages of 4 and 21 years diagnosed with advanced medulloblastoma and measurable disease were enrolled in the Pediatric Oncology Group 8695 study. Patients were treated with a 9-week course of vincristine, cisplatin, and cyclophosphamide followed by CSI. Imaging films were reviewed centrally for eligibility and response to chemotherapy. Toxicity to chemotherapy and radiation as well as delays and modifications in subsequent CSI were recorded. Results. Thirteen of 30 fully evaluable patients achieved complete or partial response (43%) to chemotherapy. Toxicity was mostly fever and neutropenia after cyclophosphamide, which is predictable and tolerable. Radiation therapy was delivered in full doses and volumes in most patients but was delayed in its start in most patients. Central review of films revealed frequent use of different imaging modalities at baseline and after therapy, making accurate assessment of tumor response difficult. Conclusion. Preradiation chemotherapy with vincristine, cisplatin, and cyclophosphamide is active in patients with advanced medulloblastoma but should be modified to minimize the risk of progressive disease while on therapy and to avoid delays in starting radiation therapy. Consistent use of the same neuroimaging modality is essential in documenting response.

Between November 1989 and October 1992, 28 consecutive patients with glioblastoma multiforme (n = 18) or anaplastic astrocytoma (n = 10; includes one patient with oligodendroglioma with anaplastic astrocytoma component) were treated with interstitial iodine 125 (60 Gy over 6 days) and with concomitant cisplatin (via infusion on days 2-6 of the implant), then followed by hyperfractionated external beam irradiation (110 cGy delivered twice daily; 66 Gy planned total dose). Of 26 patients (60%) who received both 125I and HEBI, 15 are alive with no evidence of recurrent disease at a median follow-up of 18 months post-125I (range: 11 to 34 months). Four other disease-free patients succumbed to nontumor-related events. Two patients with local control had distant failure outside the HEBI treatment fields. Overall local control is 77%. Local failure occurred in 6 patients (23%) 2 to 11 months post-125I. Time to disease progression ranged from 4 to 18 months (median: 10 months). Survival (measured from the date of diagnosis) has ranged from 6 to 26 months (median: 15 months). All patients have maintained Karnofsky Performance Status within 20 points of their preimplant status, with the exception of a single patient who, following diagnosis of radiation necrosis and surgical intervention for symptomatic relief, had a 30-point drop in KPS. Radiation necrosis or persistent mass effect were noted by neuroimaging in seven patients, four of whom required surgical intervention following failed medical management. Ototoxicity, nephrotoxicity, peripheral nerve dysfunction, or hematologic toxicities have not been observed. This new innovative treatment approach offers a promising alternative to the normally dismal prognosis for patients with malignant gliomas.

Purpose: In September 1984, the Pediatric Oncology Group began accrual to a Phase I/II study designed to assess the efficacy and toxicity of sequentially escalated doses of hyperfractionated (twice daily) radiotherapy in children wit-h poor-prognosis brain stem tumors. Pediatric Oncology Group Study #849closed in June 1990 with a total of 136 patients on study. We report here the outcome of patients treated atthe third and final dose level (75.6 Gy), and compare the results to those obtained at the 66 and 70.2 Gy dose levels. Methods and Materials: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the midbrain, pons or medulla. Histological confirmation of diagnosis was not mandatory provided that the clinical and radiological findings were typical for brain stem glioma. Treatment consisted of radiotherapy delivered to local fields. At the third dose level, fraction sizes of 1.26 Gy were given twice dally, with a minimum interfraction interval of 6 hr to a dose of 75.6 Gy in 60 fractions over 6 weeks. Between 589 and 690, 41 patients were accrued to the study. Two were excluded from analysis leaving 39 evaluable patients, 21 male and 19 female, whose ages ranged from 3 to 15 years (median 7.5 years). Results: Following treatment, neurological improvement was reported in 30/39 (77%) of the patients. On central review of imaging studies in 29 patients, one patient was found to have had a complete response to radiotherapy, five a partial (> 50% response), and only three had non-responding or progressive disease. The median time to disease progression was 7 months; median survival time was 10 months; survival at 1 year was 39.9% (SE 8.3%) and at 2 years, 7% (SE 4.8%). The pattern of failure was local in all patients; in addition six had evidence of leptomeningeal seeding. Morbidity of treatment included an enhanced skin reaction (21%), otitis media and/or externa (26%) and steroid use > 3 months (62%). Intralesional necrosis was a frequent finding (45%) on imaging studies performed at a median time of 6 weeks post treatment. Conclusion: The results of treatment in terms of progression-free survival and overall survival are not significantly different (at p = .55 and p = .46, respectively) from those obtained at the two previous dose levels. There is no evidence that higher doses of hyperfractionated radiotherapy given as in this study improve the outlook of patients with poor-risk brain stem gliomas.

Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial.The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, or cranial-nerve palsy; they received additional intrathecal injections of chemotherapeutic agents and cranial irradiation. Patients were retrospectively classified on the basis of cerebrospinal fluid findings: 291 patients had no detectable blast cells, 42 had fewer than 5 leukocytes per microliter and blast cells, and 18 had central nervous system leukemia as defined above. The clinical characteristics and outcomes of treatment in these groups were analyzed.The five-year probability of survival free of relapses confined to the central nervous system in patients with detectable blast cells and fewer than 5 leukocytes per microliter of cerebrospinal fluid was lower than in patients without blast cells (mean [+/- SE], 87 +/- 13 vs. 96 +/- 2 percent), but was not different from the probability in patients with central nervous system leukemia at diagnosis. All such isolated relapses of leukemia in patients with detectable blast cells occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, the presence of cerebrospinal fluid blast cells with fewer than 5 leukocytes per microliter was independently related to the risk of relapse confined to the central nervous system.Patients with leukemic blast cells in their cerebrospinal fluid are at increased risk for central nervous system relapse when cranial irradiation is delayed. Such patients require intensified central nervous system treatment early in the course of therapy.

Background Among patients with malignant brain tumors, infants and very young children have the worst prognosis and the most severe treatment-related neurotoxic effects. Therefore, in 1986, the Pediatric Oncology Group began a study in which postoperative chemotherapy was given in order to permit a delay in the delivery of radiation to the developing brain. Methods Children under 36 months of age with biopsy-proved malignant brain tumors were treated postoperatively with two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. This sequence was repeated until the disease progressed or for two years in 132 children under 24 months of age at diagnosis and for one year in 66 children 24 to 36 months of age at diagnosis. After this, the patients received radiation therapy. The response to the first two cycles of chemotherapy was measured in 102 patients with residual postoperative disease. Results The first two cycles of cyclophosphamide and vincristine...

Background. The most frequent second malignant neoplasm after retinoblastoma is osteosarcoma, which may be associated with radiation therapy or arise de novo in patients with bilateral retinoblastoma. Methods. Clinical, pathologic, and diagnostic imaging findings in two patients with Ewing sarcoma (ES) and one with peripheral neuroepithelioma (PN) are presented. Results. Second malignant neoplasms located in the extremities or pelvis were seen 12–18 years after initial diagnosis of unilateral (two patients) or bilateral (one patient) retinoblastoma. The patients with unilateral retinoblastoma were treated by enucleation only; the other received ocular radiation therapy and chemotherapy. To the knowledge of the authors, this is the first documentation of round blue cell tumor after unilateral retinoblastoma. Conclusions. ES and PN should be included in the differential diagnosis of malignant neoplasms occurring after treatment of unilateral or bilateral retinoblastoma.

The ability of short-inversion-time inversion recovery (STIR) magnetic resonance imaging to depict infradiaphragmatic lymphadenopathy was evaluated in 25 consecutive patients with newly diagnosed Hodgkin disease. All patients underwent computed tomography (CT) and multiplanar STIR imaging prior to lymphography (LAG). The STIR and CT images were evaluated for paraaortic and parailiac node enlargement. Findings were compared with LAG findings, which showed the architectural pattern of the opacified lymph nodes. In the upper paraaortic region, STIR imaging showed more abnormal nodes than did CT or LAG. In the lower paraaortic and parailiac regions, lymph node enlargement was shown equally well with STIR and LAG, whereas CT showed fewer enlarged lymph nodes. LAG showed paraaortic or parailiac focal tumor infiltration in three patients with normal-size nodes, and hyperplasia in two patients with enlarged nodes. STIR imaging showed more abnormal infradiaphragmatic nodes than did CT because of improved lymph node conspicuity. STIR imaging may be a useful addition to CT for staging pediatric Hodgkin disease.

Background. Children and adolescents with unresectable rhabdomyosarcoma fare poorly when treated with contemporary chemotherapeutic regimens. Evaluation of newly developed agents in these patients is important to improve their outcome. Based on a preclinical rhabdomyosarcoma xenograft model that accurately predicted the activity of new agents, the safety and efficacy of ifosfamide was evaluated as part of a Phase II clinical trial in previously untreated children with unresectable rhabdom yosarcoma. Methods. Twenty-two children and adolescents (median age, 9 years) with newly diagnosed unresectable rhabdomyosarcoma (Intergroup Rhabdomyosarcoma Study Group III [n = 15] or IV [n = 71] received two courses of ifosfamide at a dose of 1.6 g/m2 intravenously for 5 days over a 6-week period. Then the patients were evaluated for response, and additional treatment with surgery, radiation therapy, and multiagent chemotherapy (vincristine, cyclophosphamide, dactinomycin, and doxorubicin) was administered. Results. Nineteen of 22 patients (86%) had a partial response to ifosfamide given as a single agent. No complete responses to this agent alone were observed. After administration of additional chemotherapy and local control measures (radiation therapy and surgery), the estimated proportion of patients surviving progressionfree at 2 years was 63% (95% confidence interval, 37-80%). Ifosfamide was tolerated well; the most frequent toxicity was nondose-limiting myelosuppression. Transient mild renal toxicity infrequently was observed, and no central nervous system toxicity occurred in this group of patients. Conclusions. Ifosfamide appears to have significant clinical activity in untreated patients with unresectable rhabdomyosarcomas. These findings provide an accurate estimate of the response rate to single-agent ifosfamide in this group of previously untreated patients and thus provide a foundation for its rational incorporation into multiagent clinical trials. In addition, the potential benefits of this type of new drug development were demonstrated. Cancer 1993; 71:2119-25.

Proceedings of the 9th International Conference on Brain Tumor Research and Therapy: 1. Introduction; 2. Surgery; 3. Radiation therapy; 4. Chemotherapy; 5. Immunotherapy; 6. Growth-regulatory alterations; 7. Molecular genetics; 8. Brain tumor invasion; 9. Normal tissue damage; 10. Polyamines.

Purpose A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics. Patients and Methods Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m2/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21). Results Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m2/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m2/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied. Conclusion Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m2/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.

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.

Purpose To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). Methods and Materials Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. Results Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45–16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. Conclusions Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.

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. Cancer 2010. © 2010 American Cancer Society.

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.

On the basis of an extensive recursive partitioning analysis of 668 patients with newly diagnosed neuroblastoma registered on Pediatric Oncology Group (POG) studies between October 1981 and May 1987, four major subsets of patients were created. Important prognostic factors included the patient's stage of disease, age, and level of serum lactate dehydrogenase (LDH). After adjusting for these factors, no other clinical prognostic factors were significant. The implications for protocol design are that (a) fine tuning of current therapy should be sought for the two favorable disease patient subsets, while (b) novel aggressive therapies are needed for the two unfavorable disease patient subsets where the overwhelming majority are dying. This article may serve as a model for others investigating prognostic factors. The data were divided into two subsets: one was used for an exploratory analysis; the other was used to confirm the exploratory findings. Despite spite the large number of statistical tests performed, the likelihood that the findings can be attributed to chance can be dismissed as virtually zero.

PURPOSE Because of concerns about late toxicities of treatment among infants diagnosed with acute lymphoblastic leukemia (ALL), and especially the effects of cranial radiation therapy (CRT), we compared the functional and neuropsychologic status of 26 long-term survivors of ALL who were diagnosed in the first 24 months of life versus 26 children who were treated previously for Wilms' tumor. PATIENTS AND METHODS Of the children with ALL, CNS prophylaxis included no CRT in six, 18 Gy CRT in five, 20 Gy CRT in seven, and 24 Gy CRT in five. Three additional children experienced CNS relapse and received total CRT doses of 24, 40, and 44 Gy. All children received neuropsychologic testing; children with ALL also participated in diagnostic imaging studies. RESULTS As a group, the children who were treated for ALL did not differ significantly from those who were treated for Wilms' tumor on objective measures of global functional status. However, children treated for ALL had a significantly lower mean intelligence quotient (IQ) (87 v 96), poorer performance on four of six measures of visual and auditory memory, lower achievement with regard to arithmetic skills, and a greater frequency of special educational intervention than those who were treated for Wilms' tumor. IQ and auditory memory performance in the ALL group was correlated inversely with time since the completion of therapy and total CRT dose. CONCLUSIONS These results reinforce the contemporary trend of prophylactic CRT omission in very young children except for those who are at risk for CNS relapse. For infants and very young children who require CRT, evidence is presented that supports the approach for the delay of CRT until the child is older.

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal me-tastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression. Cancer 1992; 69:1061–1066.

Medulloblastoma is at once the most common and, perhaps, the most challenging malignant brain tumor in children. The disease is intricately linked to the history of radiation oncology, from the earliest observations of “radiosensitivity” to the current applications of 3-dimensional conformal and intensity modulation technologies. Pediatric oncology provided the testing ground for combined modality therapy in the 1960s; medulloblastoma has provided what may be one of the more successful models for testing applications of combined chemotherapy–irradiation in central nervous system tumors. There is increasing agreement in the literature regarding simplified recognition of features that define medulloblastoma as “favorable,” “average risk,” or “low-stage”: disease confined to the posterior fossa primary site (i.e., M0) in children over 3 years old (1–4). The role of surgical resection is important in the disease, best gauged by the degree of postoperative residual (5, 6). Even patients with previously defined “high-stage” local characteristics (i.e., significant local residual or brainstem invasion, but M0) enjoy high rates of disease control in an era when attempted gross resection is the standard and even those with “.1.5 cm residual” have had substantial resection of the primary tumors (1, 3–6). Most significant in identifying the “highrisk” or “high-stage” cohort of children is the presence of neuraxis dissemination at diagnosis (1–3, 6). In the current edition of the Journal, Kortmann and colleagues show similar outcome among M0 children with and without local disease residual, but a difference between those with and without imaging evidence of subarachnoid metastasis that is highly significant (7). Radiation therapy has been the primary therapeutic modality for the past seven decades. A contemporary estimate of the outcome following surgery and irradiation is provided by the first Pediatric Oncology Group–Children’s Cancer Group (POG–CCG) low-stage medulloblastoma trial (1986–1990). Reported initially in 1996, the update of this study shows event-free survival (EFS) of 70% at 5 years (60% at 8 years) for children with localized disease following near total or total resection and “conventional” radiation therapy: 36 Gy to the neuraxis and 54 Gy to the posterior fossa, initiated within 4 weeks of definitive surgery (8, 9). The trial documented a marginally significant benefit to the conventional radiation dose regimen at 5 years compared to the investigational reduced neuraxis-dose regimen (23.4 Gy craniospinal therapy), with no statistical difference at 8-year follow-up (9). Recent literature indicates inadequate radiation volumes, particularly about the cribriform plate, in up to 20–45% of cases; Miralbell’s detailed retrospective analysis demonstrated a significant correlation between incomplete subarachnoid coverage and an increased rate of recurrence, particularly in the supratentorial or subfrontal areas (10, 11). The Kortmann et al. series documents a prospective multiinstitutional trial conducted between 1991 and 1997, indicating inadequate irradiation at the cribriform region in 12% of cases and incomplete inclusion of the posterior fossa in 10% (7). Adequate irradiation is central to disease control in medulloblastoma. Medulloblastoma is a chemosensitive disease. Earlier controlled studies in CCG and the International Society of Paediatric Oncology (SIOP) demonstrated the efficacy of adjuvant, postirradiation chemotherapy in children with high-stage disease (12, 13). Controlled trials have failed to convincingly demonstrate a similar advantage in low-stage disease (2, 12, 13). POG and CCSG attempted to prospectively study the impact of chemotherapy in favorable disease presentations in 1993, opening a trial comparing conventional dose irradiation to reduced neuraxis-dose irradiation combined with chemotherapy. The study could not be completed due to investigator and parental biases in both directions. Subsequent published data have encouraged combined chemoradiation in most medulloblastoma presentations. Packer, in a limited-institution, single-arm trial accessioning “high-risk” cases, showed that conventional radiation therapy combined with vincristine, chloroethylcyclohexylnitrosourea (CCNU), and cisplatinum resulted in 90% 5-year EFS for M0 “high-risk” medulloblastoma (i.e., those with residual disease in the posterior fossa) (1). A recent report of an interim CCSG study in children , 10 years old with M0 presentations shows 79% 5-year progression-free survival (PFS) following reduced neuraxis-dose irradiation and the identical 3-drug regimen (4). Although not clearly superior to outcome following irradiation alone in “low-risk” settings, the study indicates disease control at least equal to that achieved with conventional radiation doses (2, 8, 9, 12, 13). Equally important, analysis of an Int. J. Radiation Oncology Biol. Phys., Vol. 46, No. 2, pp. 261–263, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter

We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved significantly (P=0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (

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 ≥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.

Purpose To report the outcome using radiation therapy (RT) for pediatric patients with high-grade spinal cord tumors. Methods and Materials A retrospective chart review was conducted that included 17 children with high-grade spinal cord tumors treated with RT at St. Jude Children's Research Hospital between 1981 and 2007. Three patients had gross total resection, 11 had subtotal resection, and 3 underwent biopsy. The tumor diagnosis was glioblastoma multiforme ( n = 7), anaplastic astrocytoma ( n = 8), or anaplastic oligodendroglioma ( n = 2). Seven patients received craniospinal irradiation (34.2–48.6 Gy). The median dose to the primary site was 52.2 Gy (range, 38–66 Gy). Results The median progression-free and overall survivals were 10.8 and 13.8 months, respectively. Local tumor progression at 12 months (79% vs. 30%, p = 0.02) and median survival (13.1 vs. 27.2 months, p = 0.09) were worse for patients with glioblastoma multiforme compared with anaplastic astrocytoma or oligodendroglioma. The median overall survival was shorter for patients when failure included neuraxis dissemination ( n = 8) compared with local failure alone ( n = 5), 9.6 vs. 13.8 months, p = 0.08. Three long-term survivors with World Health Organization Grade III tumors were alive with follow-up, ranging from 88–239 months. Conclusions High-grade spinal cord primary tumors in children have a poor prognosis. The propensity for neuraxis metastases as a component of progression after RT suggests the need for more aggressive therapy.

Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse.We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it.The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection.With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

BACKGROUND: A carboplatin-based chemotherapy regimen was used as primary postoperative therapy in infants with central nervous system (CNS) tumors to limit renal and ototoxicity and to target systemic exposure. METHODS: Fifty-three patients aged

Summary Background Therapy for ependymoma includes aggressive surgical intervention and radiotherapy administered by use of methods that keep the risk of side-effects to a minimum. We extended this treatment approach to include children under the age of 3 years with the aim of improving tumour control. Methods Between July 11, 1997, and Nov 18, 2007, 153 paediatric patients (median age 2·9 years [range 0·9–22·9 months]) with localised ependymoma were treated. 85 patients had anaplastic ependymoma; the tumours of 122 were located in the infratentorial region, and 35 had received previous chemotherapy. Patients received conformal radiotherapy after definitive surgery (125 patients had undergone gross total, 17 near total, and 11 subtotal resection). Doses of 59·4 Gy (n=131) or 54·0 Gy (n=22) were prescribed to a 10 mm margin around the target volume. Disease control, patterns of failure, and complications were recorded for patients followed over 10 years. Overall survival, event-free survival (EFS), cumulative incidence of local recurrences, and cumulative incidence of distant recurrences were assessed. Variables considered included tumour grade, tumour location, ethnic origin, sex, age when undergoing conformal radiotherapy, total radiotherapy dose, number of surgical procedures, surgery extent, and preradiotherapy chemotherapy. Findings After a median follow-up of 5·3 years (range 0·4–10·4), 23 patients had died and tumour progression noted in 36, including local (n=14), distant (n=15), and combined failure (n=7). 7-year local control, EFS, and overall survival were 87·3% (95% CI 77·5–97·1), 69·1% (56·9–81·3), and 81·0% (71·0–91·0), respectively. The cumulative incidences of local and distant failure were 16·3% (9·6–23·0) and 11·5% (5·9–17·1), respectively. In the 107 patients treated with immediate postoperative conformal radiotherapy (without delay or chemotherapy), 7-year local control, EFS, and overall survival were 88·7% (77·9–99·5), 76·9% (63·4–90·4), and 85·0% (74·2–95·8), respectively; the cumulative incidence of local and distant failure were 12·6% (5·1–20·1), and 8·6% (2·8–14·3), respectively. The incidence of secondary malignant brain tumour at 7 years was 2·3% (0–5·6) and brainstem necrosis 1·6% (0–4·0). Overall survival was affected by tumour grade (anaplastic vs differentiated: HR 3·98 [95% CI 1·51–10·48]; p=0·0052), extent of resection (gross total vs near total or subtotal: 0·16 [0·07–0·37]; p vs white: 3·0 [1·21–7·44]; p=0·018). EFS was affected by tumour grade (anaplastic vs differentiated: 2·52 [1·27–5·01]; p=0·008), extent of resection (gross total vs near total or subtotal: 0·20 [0·11–0·39]; p vs female: 2·19 [1·03–4·66]; p=0·042). Local failure was affected by extent of resection (gross total vs near total or subtotal: 0·16 [0·067–0·38]; p vs female: 3·85 [1·10–13·52]; p=0·035), and age ( vs ≥3 years: 3·25 [1·30–8·16]; p=0·012). Distant recurrence was only affected by tumour grade (anaplastic vs differentiated: 4·1 [1·2–14·0]; p=0·017). Interpretation Treatment of ependymoma should include surgery with the aim of gross-total resection and conformal, high-dose, postoperative irradiation. Future trials might consider treatment stratification based on sex and age. Funding American Cancer Society and American Lebanese Syrian Associated Charities (ALSAC).

Sixty children with localized osseous Ewing's sarcoma were treated between 1978 and 1988 with induction chemotherapy (cyclophosphamide, adriamycin), irradiation and/or surgery, and 10 months of maintenance chemotherapy (cyclophosphamide, adriamycin, dactinomycin, vincristine). Following induction chemotherapy, 43 patients received primary radiation therapy to limited radiation volumes defined by post-chemotherapy residual soft tissue tumor extension and initial osseous tumor extent. Irradiation was defined as low dose at 30-36 Gy (median 35 Gy) for 31 cases with objective response to induction chemotherapy and high dose at 50-60 Gy (median 50.4 Gy) for 12 patients with poor response to induction chemotherapy or with tumors greater than or equal to 8 cm. Overall event-free survival at 5 years is 59% and local tumor control is 68%. Initial failures have been local (12), simultaneous local and distant failures (7), and distant (6). In the surgical resection group, 14 patients had complete resection without radiation therapy, and 3 patients had microscopic residual plus 35-41 Gy; 100% local control has been maintained. In 43 patients with primary radiation therapy group, local tumor control is 58% (p = .004). Despite limited radiation volume, 18/19 local failures occurred centrally within the bone, well within the radiation volume. Imaging response to induction chemotherapy predicted local tumor control in the radiation therapy group: 62% with complete response/partial response versus 17% with no response/progressive disease (p less than 0.01). Local tumor control related strongly to primary tumor size in the radiation therapy group; among 31 cases receiving 35 Gy, local tumor control is 90% for lesions less than 8 cm versus 52% for tumors greater than or equal to 8 cm (p = .054). The central pattern of local failure in this experience suggests the effectiveness of limited radiation volume. The overall local tumor control rate following the tested dose level of 35 Gy appears to be inadequate, although results in selected cases with tumors less than 8 cm in greatest tumor dimension indicate potential efficacy in a yet limited experience.

Between May 1986 and February 1988, 57 patients were accrued to the second dose level of a Phase I/II Pediatric Oncology Group (POG) study exploring the use of hyperfractionated radiation therapy (HRT) in children with high-risk brain stem tumors. Local fields were treated with fraction sizes of 117 cGy given twice daily, with a minimum interfraction interval of 6 hours, to a total dose of 7020 cGy in 60 fractions over 6 weeks. Information regarding clinical status during HRT was available for 55 patients (44 [80%] improved, 6 remained stable, and 5 deteriorated). Results of initial and follow-up computed tomography (CT) scan and/or magnetic resonance imaging (MRI) were available for review for 52 patients. One patient had a complete response (CR) to treatment, 3 had a partial response (PR) (more than 50% response), and 40 remained stable, for a total response rate (CR + PR + stable) of 77%. Median time to disease progression was 6 months. Median survival time was 10 months. Survival rate was 39.6% (standard error [SE] = 6.6%) at 1 year and 23% (SE = 5.8%) at 2 years. Complications of treatment included an enhanced skin reaction in six patients and otitis media and/or externa in nine. One patient bled into tumor shortly after completion of HRT, and three had intralesional necrosis. Five patients continued taking steroids for protracted periods in the face of improved clinical and/or radiologic findings. Complications related to the use of steroids included opportunistic infections, impaired glucose tolerance, hypertension, osteoporosis, and significant mood changes. In no patient was there evidence of any late injury attributable to HRT. When compared with results of treatment with HRT at a lower dose level (6600 cGy), there appears to be a trend toward improved survival at 7020 cGy despite a less favorable patient population at the higher dose level. A second dose escalation to 7560 cGy in 60 fractions over 6 weeks has been implemented as planned.

The need for second-look surgery after chemotherapy in children with advanced germ cell tumors is controversial, particularly when levels of the tumor markers alpha-fetoprotein (AFP) or beta-human chorionic gonadotropin (beta HCG) are elevated at diagnosis. The authors evaluated the outcome of second-look surgery in relationship to tumor marker status in 27 patients with Stage III to IV disease who had completed four courses of chemotherapy. Markers were elevated at diagnosis in 19 patients. After chemotherapy, markers normalized in 12 of these patients. Second-look surgery confirmed complete response (CR) in these 12 patients, two of whom had residual masses on computed tomography (CT) scan (mature teratoma and necrotic tumor). The AFP decreased but did not normalize in seven patients; five had residual disease at second look and the other two later developed measurable disease. Of the eight patients with normal AFP at diagnosis, second look confirmed clinical CR in four. The other four patients had CT evidence of residual masses: surgery showed necrotic tissue in two cases, mature glial elements in one, and mature teratoma with glial elements in one. Thus second-look surgery added no information for treatment planning in children with elevated tumor markers at diagnosis and might best be reserved for patients without tumor markers at diagnosis and residual masses on CT scan, and those with persistent elevation of tumor markers and potentially resectable residual disease. Because of the possibility of small amount of residual tumor, second-look surgery may also be useful in patients whose markers normalize but who have residual masses on CT scans.