Children's Cancer Group Research Articles

Very high-dose methotrexate (33.6 g/m2) as central nervous system preventive therapy for childhood acute lymphoblastic leukemia: results of National Cancer Institute/Children's Cancer Group trials CCG-191P, CCG-134P and CCG-144P

Between 1977 and 1991, the Children's Cancer Group and the National Cancer Institute conducted three trials of very high-dose methotrexate (33.6 g/m2; VHD-MTX) in place of cranial radiation (CRT) as central nervous system (CNS) preventive therapy, and assessed efficacy, acute toxicity and long-term neurocognitive outcome. CCG-191P compared VHD-MTX to CRT plus intrathecal methotrexate (IT-MTX) in 181 patients and demonstrated equivalent survival. However, patients treated with CRT had poorer performance on neurocognitive testing over time. CCG-134P evaluated the addition of intensified systemic and intrathecal therapy to VHD-MTX in 128 patients with high-risk acute lymphoblastic leukemia (ALL) and demonstrated reduced CNS relapse compared to the CCG-191P trial, but equivalent survival. CCG-144P compared VHD-MTX to IT-MTX alone in 175 patients with average-risk ALL and demonstrated equivalent survival. VHD-MTX was associated with significant toxicities, particularly neutropenia, transient hepatic dysfunction and sepsis. VHD-MTX achieved similar survival to other CNS-directed therapies without the long-term impact on intelligence, but with substantial acute toxicities.

Radiation-Induced Osteosarcoma and Papillary Carcinoma of the Thyroid

This article describes a patient with dual radiation-induced malignancies after treatment of neuroblastoma. A 12-year-old boy with a history of neuroblastoma was treated with chemotherapy, I-131 MIBG, and radiotherapy at age 4. He was disease-free for 8 years, but then developed left shoulder pain resulting from osteosarcoma. A thyroid malignancy was discovered during the evaluation. The patient was treated with thyroidectomy and then chemotherapy according to a Children's Cancer Group Study protocol. Radiation-induced sarcoma should be suspected whenever a patient who has received radiation several years previously presents with pain or swelling in the irradiated area.

Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children's Cancer Group study

We assessed the outcome of children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) receiving contemporary risk-based therapy by evaluating clinical and biologic features and outcome of children with ALL, with or without DS, enrolled in Children's Cancer Group (CCG) protocols between 1983 and 1995. Comparison of characteristics of children with ALL with (ALL-DS; n = 179) or without (ALL-NDS; n = 8268) DS showed no differences in initial white blood cell (WBC) count, central nervous system disease, and risk group. Children with ALL-DS did not present with unfavorable translocations and were older than 1 year of age at diagnosis with ALL. Event-free (56% vs 74%; P < .001) and disease-free (55% vs 73%; P < .001) survival at 10 years was significantly lower in the standard-risk ALL-DS population compared with ALL-NDS, but not in high-risk ALL-DS population (event-free survival, 62% vs 59%; P = .9; disease-free survival, 64% vs 59%; P = .9), and these differences persisted regardless of treatment era (early era [1983-1989] vs recent era [1989-1995]). Multivariate analysis revealed that presence of DS demonstrated an independent significant adverse prognostic effect for the standard-risk population, but not for the high-risk patients. These results suggest that intensification of therapy for patients with ALL-DS is needed to maintain outcome comparable with those of ALL-NDS patients.

ALL in children with Down syndrome

Comment on Whitlock et al, page [4043][1] In this issue of Blood, Whitlock and colleagues from the Children's Cancer Group (CCG) present the largest series to date confirming prior observations that children with Down syndrome (DS) and standard-risk acute lymphoblastic leukemia (ALL) have an

Phase II study of high‐dose chemotherapy before radiation in children with newly diagnosed high‐grade astrocytoma

High-grade astrocytomas (HGA) carry a dismal prognosis and compose nearly 20% of all childhood brain tumors. The role of high-dose chemotherapy (HDCT) in the treatment of HGA remains unclear. In a nationwide study, The Children's Cancer Group (CCG) prospectively evaluated 102 children with HGA and postoperative residual disease for efficacy and toxicity of four courses of HDCT before radiotherapy (RT). Patients were randomly assigned to one of three couplets of drugs: carboplatin/etoposide (Regimen A), ifosfamide/etoposide (Regimen B), or cyclophosphamide/etoposide (Regimen C). After HDCT, all patients were to receive local RT followed by lomustine and vincristine. Twenty-six patients were excluded after central neuroradiographic review (n = 8) or pathology review (n = 18). Of 76 evaluable patients (median age, 11.95 yrs; range, 3-20 yrs), 30 patients relapsed during HDCT, and 11 others did not complete HDCT because of toxicity. Nonhematologic serious toxicities were common (29%), and 21% of patients did not receive RT. Objective response rates were not associated with amount of residual disease and did not statistically differ between regimens: 27% (Regimen A), 8% (Regimen B), and 29% (Regimen C). Overall survival (OS) was 24% +/- 5% at 5 years and did not differ between groups. Median time to an event was longest for Regimen A (283 days compared with 83 and 91 days for Regimens B and C, respectively). The five-year, event-free survival (EFS) rate for all patients was 8% +/- 3% and 14% +/- 7% for Regimen A (P = 0.07). OS and EFS were not affected by histologic grade. Patients who responded to HDCT had a nominally higher survival rate (P = 0.03 for trend). The authors conclude that these commonly used HDCT regimens provide no additional clinical benefit to conventional treatment in HGA, regardless of the amount of measurable residual tumor.

Quality of Life in Survivors of Childhood and Adolescent Acute Myelogenous Leukemia (AML) Does Not Differ by Treatment (Bone Marrow Transplant (BMT) vs. Chemotherapy). A Report from the Children's Oncology Group (COG).

Childhood and adolescent AML requires intensive therapy. Beginning in 1979, the Childrens Cancer Group (CCG) randomized patients with newly-diagnosed AML to allogeneic bone marrow transplantation (alloBMT) based solely on the availability of an HLA-identical sibling donor. Two decades of successive CCG trials using a similar design have shown a significant survival advantage for alloBMT. To determine whether BMT was associated with a diminished quality of life (QOL) in long-term survivors compared to those who had been treated with chemotherapy alone (chemo), we conducted a cross-sectional telephone survey study of AML survivors. To be eligible, survivors must have been enrolled on a CCG AML study (beginning in 1979), have survived at least five years, and reside in the US or Canada. QOL was measured using the Medical Outcomes Study Short Form 36 (SF-36) and the Child Health Questionnaire (CHQ). 206 survivors completed the study, including 124 treated with chemo, 54 treated with alloBMT and 28 treated with autologous BMT (autoBMT). Median age at diagnosis was 3 years (range, 0–20), median age at survey was 19 years (range 8–39) and median time from diagnosis was 13.4 years. 48% were male, and 87% were white. QOL summary scores for the 82 survivors treated with BMT did not differ from those of the 124 treated with chemo (see table). Also, the adjusted summary scores did not differ by treatment after adjustment for other factors, such as age at diagnosis, race, gender, relapse, etc. None of the physical or mental SF-36 or CHQ subscale domains significantly differed by treatment, although physical subscale domains trended to be better in the chemo group. Multivariate analyses found that females had significantly lower physical and mental scores, that relapse significantly diminished the physical summary score, and that age at diagnosis was positively and significantly associated with higher mental summary score. Our data suggest that survivors of childhood and adolescent AML have similar overall QOL scores, regardless of whether they were treated with BMT or chemo. In addition, the QOL scores in most physical and mental health domains were high, suggesting that AML survivors as a group enjoyed good QOL. These data suggest that QOL in long-term survivors is not diminished by BMT and that the primary concern in assigning treatment remains survival.QOL Summary ScoresTreatmentPhysical ScoreMental ScoreMean95% CIp-valueMean95% CIp-valueAll49.3(48.0,50,7)49.9(48.4,51.3)BMT (n=82)49.0(46.8,51.1)0.6851.3(49.0,53.6)0.11Chemo (n=124)49.6(47.8,51.3)48.9(47.0,50.8)

Clonal Involvement of the CD34+CD33− Progenitor Population by Leukemic Cells Harboring FLT3/ITD Correlates with High Risk of Relapse in Pediatric Acute Myeloid Leukemia.

Internal tandem duplication of the FLT3 gene (FLT3/ITD) has been associated with high risk of relapse in acute myeloid leukemia (AML) yet nearly 25–30% of the patients with FLT3/ITD have long-term disease free survival with conventional chemotherapy. We hypothesized that FLT3/ITD AML patients with poor clinical outcome may have disease that involves less mature hematopoietic precursors than patients with favorable outcome. To test this hypothesis, we isolated less mature, CD34+CD33− and more mature, CD34+CD33+ precursor cells from 24 pediatric AML patients enrolled on Children's Cancer Group clinical trials CCG-2891 and 2961 previously identified as having a FLT3/ITD. Granulocyte/monocyte colonies (CFU-GM) were grown in methylcellulose, harvested, and analyzed for the presence of FLT3/ITD after 14 days of growth. Twenty patients yielded sufficient cells and growth of CFU-GM colonies for analysis. FLT3/ITD was detected in CFU-GM colonies derived from CD34+CD33+ cells in all patient samples (median 80% of colonies tested per patient, range 6–100%). In contrast, FLT3/ITD was detected in CFU-GM colonies derived from CD34+/CD33− cells in only 11 of the 20 patient samples (median 46% of colonies tested per patient, range 6–100%). Of the 9 patient samples without FLT3/ITD involvement of CD34+CD33− colonies, 8 achieved a CR, 6 of whom are long-term survivors, and one patient died of non-leukemic causes. In contrast, of the 11 patients with CD34+CD33− cell involvement, 9 either failed to achieve CR or relapsed after achieving CR, and 2 died of non-leukemic causes. Actuarial progression-free survival at 4 years from diagnosis for the patients with and without FLT3/ITD in the CD34+CD33− population was 0% vs. 68% respectively (p=0.017). As allelic ratio of the FLT3/ITD has been used to define high-risk patients within the FLT3/ITD cohort, we determined the FLT3/ITD allelic ratio in our study population and correlated it with the presence of FLT3/ITD in the CD34+CD33− population. Ten of the 11 (91%) of the patient samples with FLT3/ITD involvement of the progenitor cells had high allelic ratio compared to 5 of 9 (56%) of the patients without early cell involvement. Together these data suggest that clonal dominance of FLT3/ITD containing leukemia cells at the CD34+CD33− stage of hematopoietic development is correlated with a high risk of relapse. Further studies are required to determine whether clonal dominance at this hematopoietic stage is a variable that, independent of high allelic ratio, accounts for the poor clinical outcome seen in a subset of FLT3/ITD positive AML patients.

Outcomes in CCG-2961, a Children's Cancer Group Phase III Trial for Untreated Acute Myeloid Leukemia (AML).

CCG-2961 tested an intensively timed induction therapy consisting of cytarabine (AC), etoposide, thioguanine, dexamethasone, idarubicin and daunorubicin. Patients in remission after induction were randomized to a second induction course (Arm A) or a 3-drug combination of fludarabine, AC, and idarubicin (Arm B). Course 3 for patients with related donors was bone marrow transplantation (BMT); for those without donors, high dose AC/l-asparaginase. After Course 3 patients without donors were randomized to 14 infusions of Interleukin 2 (IL2) over 18 days or follow-up. CNS prophylaxis was intrathecal AC. Eligibility included all subtypes of de novo AML except acute promyelocytic leukemia and AML in patients with Down syndrome. CCG-2961 opened in Oct.1996 and closed in Dec. 2002. The DSMC suspended the study between Oct. 1999 and May 2000 while the 2961 Committee developed supportive care policies to reduce treatment-related mortality (TRM). CCG-2961 enrolled 900 de novo patients aged 3 days to 21 years, with 495 and 405 patients accruing pre-and post suspension respectively. Remission induction rate is 88.5%. With median follow-up of 3.6 years (range: 0 – 8.1 years), event-free survival (EFS) at 3 years is 44±3% and survival (OS) 57±3%. Disease-free survival (DFS) following Course 2 Arms A and B are not different, although relapse is significantly higher in Arm A (7.3% .vs. 3.1% P=0.018) and TRM more common in Arm B (7.9% vs.4.2% P=0.059), despite 7 less days of neutropenia in Arm B (P<0.001). DFS is 65±9% for patients with a donor versus 50±5% for patients without a donor (P=0.005); respective OS, 74±8% and 66±5% (P=0.221). However, among 98 patients in CR1 with t(8;21) or inv(16) cytogenetics, outcomes in those without and with a donor were no different: DFS (61±12% vs. 72±18%, P = 0.49) and OS (78±10% vs. 77±17%, l P= 0.85). DFS with and without IL2 is 55±9% and 60±8%(P=0.606). Outcomes improved progressively over time. EFS pre- and post-suspension are 41±4% and 47±5%(P=0.038); OS, 52±5% and 63±5%(P=0.005); TRM is 17±3% pre- and 12±3% post-suspension (P=0.039). Factors predictive of inferior EFS are age >17 years, Afro-American and Hispanic ethnicity, body mass index <10th or >95th percentile for age, absence of related marrow donor, WBC > 50,000/mm3, karyotype with −7/7q, −5/5q- or > cytogenetic 5 abnormalities, FLT3/ITD, >15 % morphologic blasts on day 14 or >0.5% immunologically detectable blasts at the end of induction. CCG-2961 confirms the efficacy and high TRM of intensively timed therapy. Neither fludarabine nor IL2 increases DFS or OS, and availability of a donor does not improve outcomes in those with favorable cytogenetics.

Results of the Japanese Childhood Acute Myeloid Leukemia 99 Protocol for Down Syndrome and Acute Myeloid Leukemia.

Purpose: Recent multi-institutional studies have reported that children with Down syndrome (DS) and acute myeloid leukemia (AML) have a favorable outcome with less intensive chemotherapy. Based on our previous trial (Kojima, et al: Leukemia ; 14:786, 2000), the Japanese Childhood AML Cooperative Study Group conducted the AML-Down protocol study designed for children with DS and AML.Patients and Method: Between February 2000 and June 2004, 72 children (44 boys, 28 girls; median age, 1 year; range, 7 months to 7 years) were enrolled in this study. The median white blood cell count was 5,800/10−9 L. The median follow-up period was 3 years (range, 9 months to 5 years). Acute megakaryocytic leukemia (M7) was diagnosed most often (90%). The treatment regimen consisted of 5 cycles of Ara C 100mg/m2 (1-hour infusion) x 7 days, THP-ADR 25mg/m2 x 2 days, and etoposide 150mg/m2 x 3days. No prophylaxis against CNS leukemia was included.Results: Among the 72 children, 69 achieved complete remission (CR) after 1 to 2 cycles of induction therapy, with no deaths occurring during the induction period. One of 3 patients with induction failure achieved CR after another intensified chemotherapy. Eight patients relapsed during chemotherapy. One relapsed while off therapy and successfully entered a second remission after an intensified chemotherapy, followed by an allogeneic bone marrow transplant. There was no CNS relapse alone, although 1 patient relapsed in the bone marrow and CNS simultaneously. Eight relapsed patients and 2 refractory patients died without achieving a remission. The cause of death was pneumonia in 4 patients and disease progression in 7 patients. One patient died from pneumonia during the first CR. The CR rate, 3-year survival rate, and event-free survival (EFS) rate were 97.2%, 84.4%, and 83.0%, respectively. In a univariate analysis of factors that predict EFS, we found that the presence of monosomy 7 cytogenetic abnormality at diagnosis, and response to induction therapy were predictive factors for EFS. Neither age older than 2 years nor higher white blood cell count at diagnosis were statistically significant risk factors. Children with monosomy 7 had more adverse outcomes than those without monosomy 7 (41.7% vs 86.4%, p=0.02).Discussion: Our AML protocol specified for children with DS and AML does not include high-dose Arac and is much less intensive than other protocols used for treatment of these children. However, this less intensive regimen leads to an excellent outcome. In contrast to a previous study reported from CCG (Children's Cancer Group) in the United States, age was not a significant risk factor. However, monosomy 7 is a poor prognostic factor in children with AML, whether or not they have DS. Our study strongly suggests that children with DS and AML can be treated successfully with a less intensive chemotherapy regimen that does not include high-dose Arac.

Long-term results of children with acute myeloid leukemia: a report of three consecutive Phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891

The Children's Cancer Group (CCG) conducted three Phase III prospective clinical trials for children with de novo acute myeloid leukemia between the years 1979 and 1995. A total of 1903 eligible children ages birth to 21 years of age were enrolled on CCG 251 (n=485), CCG 213 (n=532) and CCG 2891 (n=886). Follow-up is ongoing, with medians of 7.9, 10.9 and 8.6 years, respectively. These three clinical trials developed dose- and time-intensive induction regimens based upon high-dose cytarabine and daunomycin and randomly assigned patients to allogeneic bone marrow transplantation in first remission if an HLA-matched related donor was identified. Despite dose- and time-intensive induction regimens, remission induction rates remained relatively stable at 77-78%. However, overall survival, event-free survival and disease-free survival (DFS) increased for patients receiving intensive-timing induction therapy in comparison to patients who received standard-timing induction, regardless of the type of postremission therapy. Outcomes were best for patients receiving intensive-timing induction followed by matched related donor allogeneic transplantation with DFS of 65+/-9% at 6 years. These three clinical trials have established a strong foundation for the development of future studies focusing on further risk group stratification and the development of novel, molecularly-targeted therapies.

Favorable Prognosis for Patients 12 to 18 Months of Age With Stage 4 Nonamplified MYCN Neuroblastoma: A Children's Cancer Group Study

The long-term survival of children between age 12 and 24 months with stage 4 neuroblastoma and nonamplified MYCN (MYCN-NA) has not been defined previously. Survival for stage 4 MYCN-NA neuroblastoma patients enrolled onto Children's Cancer Group (CCG) protocols 321P2 (1986 to 1991) and 3891 (1991 to 1996) was analyzed. Treatment consisted of intensive alkylator-based induction chemotherapy with or without autologous bone marrow transplantation (ABMT) with or without 13 cis-retinoic acid. Survival was analyzed by age strata less than 12, 12 to 18, 18 to 24, and more than 24 months at diagnosis. Patients younger than 12 months were treated on the moderate-intensity CCG protocol 3881. Forty-three patients with stage 4 MYCN-NA disease enrolled onto CCG-321P2 (n = 17) or CCG-3891 (n = 26) were between 12 and 24 months of age at diagnosis. After a median follow-up of 94 months (range, 4 to 140 months), the 6-year event-free survival (EFS) for the 12- to 18-month age group was superior to that of the 18- to 24-month age group (74% +/- 8% v 31% +/- 12%; P = .008). The EFS for children older than 24 months with stage 4 MYCN-NA neuroblastoma was 23% +/- 3%, and for children younger than 12 months was 92% +/- 3%. Children diagnosed with stage 4 MYCN-NA neuroblastoma in the second year of life form a transitional group between infants and older children in terms of prognosis. Patients between 12 and 18 months of age have significantly better long-term survival than that of older children treated with intensive chemotherapy with or without ABMT. These patients may not benefit from additional intensification of therapy beyond that provided in earlier clinical trials and may even maintain this high survival rate with less intensive therapy.

Evidence for an Age Cutoff Greater Than 365 Days for Neuroblastoma Risk Group Stratification in the Children's Oncology Group

In the Children's Oncology Group, risk group assignment for neuroblastoma is critical for therapeutic decisions, and patients are stratified by International Neuroblastoma Staging System stage, MYCN status, ploidy, Shimada histopathology, and diagnosis age. Age less than 365 days has been associated with favorable outcome, but recent studies suggest that older age cutoff may improve prognostic precision. To identify the optimal age cutoff, we retrospectively analyzed data from the Pediatric Oncology Group biology study 9047 and Children's Cancer Group studies 321p1-p4, 3881, 3891, and B973 on 3,666 patients (1986 to 2001) with documented ages and follow-up data. Twenty-seven separate analyses, one for each different age cutoff (adjusting for MYCN and stage), tested age influence on outcome. The cutoff that maximized outcome difference between younger and older patients was selected. Thirty-seven percent of patients were younger than 365 days, and 64% were > or = 365 days old (4-year event-free survival [EFS] rate +/- SE: 83% +/- 1% [n = 1,339] and 45% +/- 1% [n = 2,327], respectively; P < .0001). Graphical analyses revealed the continuous nature of the prognostic contribution of age to outcome. The optimal 460-day cutoff we selected maximized the outcome difference between younger and older patients. Forty-three percent were younger than 460 days, and 57% were > or = 460 days old (4-year EFS rate +/- SE: 82% +/- 1% [n = 1,589] and 42% +/- 1% [n = 2,077], respectively; P < .0001). Using a 460-day cutoff (assuming stage 4, MYCN-amplified patients remain high-risk), 5% of patients (365 to 460 days: 4-year EFS 92% +/- 3%; n = 135) fell into a lower risk group. The prognostic contribution of age to outcome is continuous in nature. Within clinically relevant risk stratification, statistical support exists for an age cutoff of 460 days.

Cognitive and Adaptive Outcome in Low-Grade Pediatric Cerebellar Astrocytomas: Evidence of Diminished Cognitive and Adaptive Functioning in National Collaborative Research Studies (CCG 9891/POG 9130)

Clinicians often assume that children with posterior fossa tumors are at minimal risk for cognitive or adaptive deficits if they do not undergo cranial irradiation. However, small case series have called that assumption into question, and have also suggested that nonirradiated cerebellar tumors can cause location-specific cognitive and adaptive impairment. This study (1) assessed whether resected but not irradiated pediatric cerebellar tumors are associated with cognitive and adaptive functioning deficits, and (2) examined the effect of tumor location and medical complications on cognitive and adaptive functioning. The sample was composed of 103 children aged 3 to 18 years with low-grade cerebellar astrocytomas, who underwent only surgical treatment as part of Children's Cancer Group protocol 9891 or Pediatric Oncology Group protocol 9130. The sample was divided into three groups based on primary tumor location: vermis, left hemisphere, or right hemisphere. Data were collected prospectively on intelligence, academic achievement, adaptive skills, behavioral functioning, and pre-, peri-, and postsurgical medical complications. The sample as a whole displayed an elevated risk for cognitive and adaptive impairment that was not associated consistently with medical complications. Within this group of children with cerebellar tumors, tumor location had little effect on cognitive, adaptive, or medical outcome. We did not replicate previous findings of location-specific effects on cognitive or adaptive outcome. However, the elevated risk of deficits in this population runs contrary to clinical lore, and suggests that clinicians should attend to the functional outcomes of children who undergo only surgical treatment for cerebellar tumors.

Maternal hair dye use and risk of neuroblastoma in offspring*

Studies have suggested an association between maternal hair dye use and elevated risk of childhood cancer, including neuroblastoma. We analyzed data from a large case-control study to investigate the relationship between maternal hair dye use around pregnancy and risk of neuroblastoma in offspring. Cases were children with neuroblastoma diagnosed between 1992 and 1994 at hospitals in the United States and Canada participating in the Children's Cancer Group or the Pediatric Oncology Group. Random-digit dialing was used to identify one matched control for each case. Information on hair dye use was gathered from telephone interviews of 538 case and 504 control mothers. Use of any hair dye in the month before and/or during pregnancy was associated with a moderately increased risk of neuroblastoma (adjusted odds ratio (OR) = 1.6; 95% confidence interval (CI) = 1.2-2.2). Temporary hair dye use (OR = 2.0, CI = 1.1-3.7) was more strongly associated with neuroblastoma than use of permanent hair dye (OR = 1.4, CI = 1.0-2.0). Although the results of this study provide evidence of an association between maternal hair dye use and neuroblastoma, further research is necessary to evaluate effects by method of hair dye application, color, and chemical composition.

Patterns of treatment failure in infants with primitive neuroectodermal tumors who were treated on CCG‐921: A phase III combined modality study

To analyze patterns of treatment failure in infants with primitive neuroectodermal tumors (PNETs) who were treated primarily with chemotherapy in a large multi-institutional study. Sixty-five prospectively staged patients with PNET confirmed by central pathology review, who were 18 months or younger were treated on Children's Cancer Group Study 921 (CCG-921) primarily with chemotherapy. Forty-six patients had posterior fossa (PF) primary tumors and 19 patients had supratentorial (ST) primaries. Patterns of sites of initial treatment failure were analyzed and compared to failure patterns of 180 older children who had PF-PNETs, and 44 older children with ST-PNETs who were treated on the same protocol. The entire cohort of younger patients fared much worse than those older than 18 months. Cumulative 5-year relapse incidence (+/-SE) for younger patients with PF-PNETs was 64.5 +/- 8.9% for patients without metastases (M0) compared to 71.4 +/- 13.4% for patients with metastases (M+). The cumulative 5-year relapse incidences for younger patients with ST-PNETs were 64.3 +/- 13.7% for M0 patients compared to 100 +/- 33.3% for M+ patients. Relapses in these patients occurred within 2 years. The overall treatment failure rate was significantly higher for younger compared to older patients with PF-PNET and ST-PNET. There was no statistically significant difference in relapse patterns between patients with PF primary tumors and ST primaries when stratified by stage. There was no statistically significant difference in relapse patterns between M0 and M+ patients. All patients had a high risk of recurrence at primary tumor site. Younger patients who had PF primary tumors without metastasis at presentation were significantly more likely to relapse in PF than older patients. Younger patients were at significant risk of relapse in the spine, but none had it as the sole site of first relapse. Despite aggressive chemotherapy, younger children with PNETs have high rates of treatment failure and fare worse than high-risk, older patients with PF-PNETs, indicating the need to maximize local, regional, and systemic therapies.

Isochromosome 17q Is a Negative Prognostic Factor in Poor-Risk Childhood Medulloblastoma Patients

Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (<18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome. DNA from 35 medulloblastoma patients from four Children's Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses. The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age <3 tended to be associated with <3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups. Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.

Significance of HOX11L2/TLX3 expression in children with T-cell acute lymphoblastic leukemia treated on Children's Cancer Group protocols

Significance of HOX11L2/TLX3 expression in children with T-cell acute lymphoblastic leukemia treated on Children's Cancer Group protocols

Treatment of newly diagnosed children with lower-risk leukemia: A collaborative Children’s Cancer Group (CCG)/NCI pilot trial incorporating 6-thioguanine

8539 Background: Although mercaptopurine (MP) is the thiopurine antimetabolite conventionally used in the treatment of childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is more potent than MP in vitro; and in patients, oral or intravenous TG achieves cytotoxic concentrations in CSF. We therefore performed a pilot study of TG administered orally and by 24 h continuous IV infusion (CIVI), as part of multi-agent chemotherapy, in children with standard risk ALL. Methods: Children with newly diagnosed standard risk ALL (age 1 - 10 yrs, WBC < 50k) were eligible. Treatment was based on the best regimen of the CCG 105 trial, with the addition of CIVI TG (480mg/m2) once during consolidation, twice during each interim maintenance and every 8 weeks during the first year of maintenance, and the substitution of oral TG (60mg/m2/d) for oral MP during maintenance. Red blood cell thioguanine nucleotides (TGNs) concentrations were determined periodically. Results: 58 (31 female) pts, median age 4.3 (range 1.4 - 9.9) yrs, were enrolled. The 8 year event-free survival was 84% (plateau reached at 4 yrs), with an 8 year overall survival of 88% (median potential follow-up 8.9 yrs). There were no CNS relapses and no toxic deaths. Toxicities following CIVI-TG included reversible neutropenia and elevated hepatic transaminases. Six pts experienced reversible veno-occlusive disease (VOD) while receiving oral TG. As the contribution of CIVI-TG to the later development of VOD was not known, the study was amended following the 5th case of VOD to discontinue CIVI TG and change all pts to oral MP. TGN concentrations during oral TG administration averaged 95 ng/8x108 RBC (range 12 -447), greater than observed with oral MP administration. Conclusions: Substituting TG for MP is associated with reversible VOD. However, the lack of CNS relapses in this pilot study suggests that TG may lower the risk of developing CNS leukemia. A subsequent randomized study of oral TG vs. MP was performed by the CCG based, in part, on the results of this trial. No significant financial relationships to disclose.

Low dose involved field radiation (IFRT) or no further treatment following complete response to initial chemotherapy in young adult (YA) patients 16–21 years of age with Hodgkin’s disease (HD): The Children’s Cancer Group (CCG) Experience

8513 Background: There is scant data in the literature concerning the outcome of YA pts 16–21 years of age with HD. Methods: Newly diagnosed YA HD pts (N=227) were entered on the CCG 5942 study. Following clinical staging, YA pts received risk adapted chemotherapy. Group I patients had Stage I or IIA, no bulk disease, no hilar adenopathy and < 4 nodal regions involved. Group III patients had stage 4 disease. Initial therapy for Group I patients consisted of 4 cycles of the COPP/ABV Hybrid while Group 2 patients received 6 cycles of COPP/ABV. Group III patients received two cycles each of high dose ARA-C/VP-16. COPP/ABV, and CHOP. Patients who achieved a complete response to initial chemotherapy were randomized to receive no further treatment or IFRT (2100 RADS). Patients with partial response were nonrandomly assigned to IFRT. Results: Five year EFS for YA pts was 81% ± 2.8%; 5 year survival was 91.4% ± 2.1%. Events included 3 - progressive disease, 36 - relapse, and 1 second malignancy. Sixty and 56 YA pts were randomized to IFRT or no IFRT respectively. Five pts randomized to receive IFRT received no IFRT (1 relapse) and 5 patients assigned to no IFRT received IFRT (no relapse). In an as treated analysis, 5 year EFS was 94.6% for IFRT pts versus 74% for no IFRT pts (P = .002). IFRT improved EFS for group 2 and group 3 patients. At 5 years, there is a trend for better survival for the IFRT group compared to the no IFRT group, 100% vs. 90% (P = .06). Conclusion: The 5942 study showed a significant advantage for IFRT in preventing relapse but not for survival. This effect was consistent in all age groups, including YA. High dose radiation therapy is not necessary for the treatment of YA pts with HD. No significant financial relationships to disclose.

Erratum: Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF

Correction to: Gene Therapy (2005) 12, 452–460. doi:10.1038/sj.gt.3302421 The above affiliations for the below authors were published incorrectly, the correct affiliations are given below: N Patel3, S Shousha2 2Department of Histopathology, Imperial College London, London, UK 3CR UK Children's Cancer Group, Medical Oncology Unit, Queen Mary, University of London, Charterhouse Square, London, UK