Children's Cancer Group Research Articles

Intensively Timed Induction (ITI) Chemotherapy in Adults with Acute Myelogenous Leukemia (AML).

The Children's Cancer Group (CCG) demonstrated that children with AML have longer event free survival (EFS) and disease free survival (DFS), 42 +/− 7% and 55 +/− 9%, at a minimum of two years off of therapy when randomly assigned to ITI rather than standard chemotherapy (Woods, et al Blood 1996 Jun 15;87(12):4979–89). This led us to administer an almost identical regimen of ITI chemotherapy to 50 adults less than 50 years of age with untreated AML, excluding patients (pts) with inv16 or t(8;21). Each pt who remains alive in 1st complete remission (CR) has been followed for more than 3 years: the risk of relapse decreases sharply after this time (de Lima, et al. Blood 1997 Dec 15;90(12):4719–24). Daunorubicin 20 mg/m2/day intravenously (IV) on days 1–4 and 11–14, cytarabine 200 mg/m2/day IV on days 1–4 and 11–14, etoposide 100 mg/m2/day IV on days 1–4 and 11–14 and dexamethasone 6 mg/m2/day PO days 1–4 and 11–14 were given initially along with intrathecal cytarabine 70 mg on day 1 and 11 (DCTER regimen). G-CSF started on day 7 and continued until the ANC was more than 1000 for 2 days. The day 11 chemotherapy was given unless there was hypotension or clinical colitis. All pts started therapy in a protected environment. Pts in CR after the above chemotherapy repeated the induction course. After recovery, cytarabine 3 g/m2 every 12 hours for four doses was infused on days 0–3 and on days 12–15. L-asparaginase 6000 IU/m2 IV was given at hour 18 on days 3 and 15. The cytarabine and L-asparaginase were repeated upon recovery of the granulocyte count. The study was ongoing from 2/15/02 to 8/10/04. The 50 pts, median age 41 years, represented 62% of all pts eligible during this time period. Table 1 compares results in the 50 DCTER pts with the results in 35 non-core binding factor AML pts, median age 41 years, given idarubicin/cytarabine (IA) for induction and consolidation without intensive timing. The results in the IA pts treated from 1991–1993 were similar to those treated 1994–2001 (proportion alive in CR 16% and 19%). The lower CR rate in pts given DCTER reflected an increased death rate in the first 12 weeks after starting treatment. This was counterbalanced by a higher rate of potential cure, considering all 85 pts (95% confidence interval for the true difference [−.09, .34] suggesting that a difference of 26% is as plausible as no difference since .26 and 0 are each equidistant from the midpoint of the confidence interval). A larger cohort is needed to know if the higher early risk associated with DCTER is potentially justified by a better long-term prognosis.Table 1PatientsPerformance Status >1Unfavorable CytogeneticsCRProportion alive in CR at 3 yearsDCTER5014%24%69%30%IA350%23%80%17%

Failure of Asparagine (ASN) Depletion, Not Inadequate Asparaginase (ASNase) Activity, Predicts Relapse in Standard Risk (SR) Childhood Acute Lymphoblastic Leukemia (ALL): A Children's Oncology Group (COG) Report.

Introduction: The mechanisms of treatment failure in ALL are poorly understood. Attention has focused on the intrinsic resistance of the leukemic blast. ASNase contributes importantly to response and outcome in ALL. In about 1/3 of 1st relapse patients, we found inadequate ASN depletion, i.e., ASN > 3 mmoles on Day 14 of Induction (11 days following a single dose of pegylated ASNase) and an inferior re-induction rate (Pediatr Blood Cancer 2006; 47:141). Patients with relapse have a superior re-induction rate with qwk rather than conventional qow pegylated ASNase (Blood 2000; 96:1709). In the present study, we hypothesized that inadequate ASN depletion with standard ASNase dosing leads to relapse in newly diagnosed children with ALL.Methods: Between 1997 and 1998, 118 children with NCI standard risk ALL were enrolled on Children's Cancer Group CCG-1962 study after informed consent (Blood 2002; 99:1986). By random allocation, patients received either native ASNase 6,000 IU/m2 tiw × 9 in Induction and × 6 in each of 2 Delayed Intensification (DI) phases (n=59, 15 relapses, 1 2nd malignancy) or a single dose of pegylated ASNase 2500 IU/m2 (n=59, 10 relapses) in Induction and each of 2 DI phases. All ASNase was administered intramuscularly and begun on Day 3–5 of Induction and each DI phase. Multiple samples were obtained for each patient and cooled promptly to prevent ex-vivo deamination, which may lead to falsely low, not falsely high ASN values. We examined the incidence of relapse by 8 years in patients ranked by ASN concentration and ASNase activity.Results: The overall 4-year EFS is 84%. Overall, 17/ 31 patients (55%) in the highest Day 14 ASN tertile relapsed compared to 7/ 75 (9%) in the lower two tertiles (p<0.001). The median Day 14 ASN for relapse and remission patients was 3.8 and 0.1 [native ASNase] and 4.9 and 0.63 mmoles [pegylated ASNase]. Day 7 ASN was less informative. ASNase activity was not predictive of outcome.Conclusion: In vivo, asparagine (ASN) depletion reflects a balance between ASNase activity and ASN production, which may vary for an individual over time and among individuals. ASN depletion on Induction Day 14, 9–11days after ASNase administration, predicts outcome in children with SR ALL receiving either native or pegylated ASNase. ASNase activity is not predictive. Failure to achieve adequate ASN depletion in Induction may contribute to relapse in childhood ALL.ASN ConcentrationInduction DayPegylated ASNaseNative ASNaseDay 7 ASNμmolesRelapses/ totalμmolesRelapses/ total1st tertile> 1.143/ 16> 0.996/ 162nd tertile0.03–1.124/ 160.04–0.733/173rd tertile0.012/ 190.014/23DAy 14 ASN1st tertile> 2.789/ 17> 2.628/ 142nd tertile0.18–2.680/ 170.23–0.273/ 153rd tertile0.01–0.071/ 170.013/ 26ASNase ActivityInduction DayPegylated ASNaseNative ASNaseDay 7 ActivityIU/mlRelapses/ totalIU/mlRelapses/ total1st tertile≤0.643/17≤0.235/192nd tertile0.65–0.922/180.24–0.513/183rd tertile0.93–1.634/170.52–1.135/19DAy 14 Activity1st tertile≤ 0.312/17≤ 0.235/182nd tertile0.34–0.664/180.24–0.424/193rd tertile0.68–1.254/170.42–1.245/18

Polymorphisms in the MGMT Gene as Predictors of Leukemia Risk and Response to Therapy in Children with AML.

Approximately 40% of patients treated with chemotherapy for pediatric AML will relapse after initial treatment and 8–10% will die of toxic side effects of chemotherapy. This highly variable response to standardized treatment protocols is due in part to genetic variation among patients in the metabolism of chemotherapeutic agents and in the response to the DNA damage they induce. We have analyzed polymorphisms in the coding region of the DNA alkylation repair gene O6-Methylguanine-DNA Methyltransferase (MGMT) in 356 patients with de novo pediatric AML to determine whether naturally occurring MGMT variant alleles correlate with leukemia susceptibility, treatment efficacy, and the incidence of adverse effects of chemotherapy. The polymorphism rs2308321 (Ile143Val) has been shown to modify biochemical properties of the MGMT protein, with altered substrate specificity of the rare valine allele (G genotype) compared with the isoleucine allele (A genotype) (Margison et al, Carcinogenesis , 26;1473, 2005). All patients were treated on Children's Cancer Group protocols 2941 and 2961. Outcomes were examined stratified by genotype. All patients received intensively timed induction therapy with IDA-DCTER (idarubicin, dexamethasone, Ara-C, thioguanine, etoposide and daunomycin) given on days 0 to 3 followed by DCTER given on days 10 to 13. On recovery of ANC and platelet counts, patients were randomized to consolidation therapy with a further course of IDA-DCTER/DCTER or IDA-FLAG (idarubicin, fludarabine, Ara-C and G-CSF). Patients received intensification with a single course of high dose Ara-C and L-asparaginase unless a family donor was available when allogeneic transplant was performed after busulfan and cyclophosphamide. Black children were significantly more likely to have a homozygous wild-type AA genotype than white children (p=0.002). When compared to a healthy control population, there was no correlation between MGMT polymorphisms and the risk of AML overall. However, in a case-case comparison of genetic sub-types of AML, children with a variant allele (AG or G/G genotype) were significantly more likely to have monosomy 7 than AA cases (9% vs 1%; p=0.01); in contrast, children with trisomy 8 were significantly more likely to have an AA genotype (8% vs 0%; p=0.028). The presence of at least one G allele was associated with a significant reduction in the incidence of relapse. There was no effect on treatment-related mortality (TRM). In a multivariate Cox model adjusted for race, the increased risk of relapse (RR) associated with the variant G allele remained significant (hazard ratio 1.72 95% CI 1.03–2.86; p=0.037). These results suggest that genotyping at the rs2308321 polymorphism in the MGMT gene could be useful in the risk stratification of patients with AML prior to therapy.A/AA/G+G/GN% ± 2 SEN% ± 2 SEp-value5yr OS from end of course 128054 ± 67671 ± 110.0315yr RR from end of course 128043 ± 67627 ± 110.0145yr TRM from end of course 128014 ± 47614 ± 80.11

Improved Outcome of Children with Down Syndrome (DS) and High Risk Acute Lymphocytic Leukemia (HR-ALL): A Report of CCG-1961.

Down syndrome patients with ALL (ALL-DS) have unique clinical and biologic features which can make treatment a challenge particularly in regards to toxicity. In order to evaluate the optimal treatment for ALL-DS with higher risk ALL we compared the outcomes of ALL-DS patients (n=51) enrolled on the Children's Cancer Group (CCG) 1961 protocol for HR-ALL to those of their non-DS counterparts (n=2001). CCG-1961 was open from November 1996 to May 2002 for patients with ALL age 1–9 years and WBC ≥ 50,000 or age ≥ 10 years with any WBC. Rapid early responders (RER ≤ 25% blasts on day 7 bone marrow after 4 drug induction) were randomized in a 2 × 2 design to receive intensive post-induction intensification therapy (IPII) or standard post-induction intensification therapy (SPII) and 1 or 2 delayed intensification phases. Slow early responders (SER > 25% blasts on day 7 bone marrow) were treated with IPII, and randomized to receive idarubicin or doxorubicin. No up-front therapy modifications were prescribed for DS patients (only for toxicity as per protocol). All DS patients were over 2 years of age. DS patients were more likely to have WBC ≥ 50,000 than non-DS (76% vs 53%) and less likely to have T cell immunophenotype (4% vs 23%), lymphoma syndrome (10% vs 23%) or marked splenomegaly (4% vs 12%) at diagnosis. No differences in gender, race, or extramedullary disease were noted in the DS vs non-DS patients. There were 36 RER DS patients (16 randomized to IPII and 20 SPII) and 16 SER patients. There were 6 deaths in the DS patients: 4 early in induction, 1 in consolidation, and 1 in maintenance. All deaths were associated with toxicity and/or infection and 2 patients had progressive disease. DS patients were more likely to have grade 3–4 stomatitis during intensive treatment phases (15.2% vs 1.8% during induction, 23.1% vs 2.9% during delayed intensification #1). The 5-yr event free survival (EFS) was 69.1% (se 8.4%) for DS patients and 70.4% (se 1.5%) for non-DS patients. The 5-yr overall survival (OS) was equivalent for the two groups: 77.9% (se 7.5%) for DS patients compared to 80.9% (se 1.1%) for non-DS patients. The 5 year death as a first event assessment was 88.2% (se 6.6%) (RHR 2.6) vs 95.5% (se 0.7%) for non-DS patients, consistent with an increased incidence of early toxic deaths in the ALL-DS cohort. IPII therapy for RER DS patients resulted in excellent disease control (0 BM relapses vs 5 with SPII). The 4-yr EFS for the IPII DS patients (RER + SER) was 83.7% (se 6.7%) vs 78.8% (se 11.5%) for the RER DS randomized group only. This difference may be explained by the single event in the 16 SER patients; however the small number precludes a definitive conclusion. In conclusion, HR patients with ALL-DS treated with IPII therapy on CCG-1961 have similar OS and EFS to non-DS patients. These results compare favorably with those of other studies. The early mortality due to toxicity in the DS population does not result in decreased EFS or OS as compared to the non-DS population. IPII therapy is well tolerated and effective in HR ALL-DS, as evidenced by excellent outcomes in the RER and SER groups, and should be considered a reasonable standard of care for this patient population.

Hearing Loss, Quality of Life, and Academic Problems in Long-term Neuroblastoma Survivors: A Report From the Children's Oncology Group

Among a cohort of long-term neuroblastoma survivors, our aims were to (1) assess the association between treatment intensity and parent-reported hearing loss in the child, (2) evaluate the strength of the association between hearing loss and parent-reported academic and psychosocial difficulties in the child, and (3) examine the association between parent-reported academic and psychosocial difficulties in the child and the child's self-reported quality of life. Through a mailed survey that included the Pediatric Quality of Life Inventory 4.0 and an outcomes questionnaire for parents, we evaluated 137 children (aged 8-17 years) who were previously enrolled in 1 of 2 Children's Cancer Group neuroblastoma clinical studies. Childhood survivors of neuroblastoma who had prevalent hearing loss, as reported by their parents, had at least twice the risk of an identified problem with reading skills, math skills, and/or attention and a similarly higher risk of a general learning disability and/or special educational needs than did neuroblastoma survivors without hearing loss. Consistent with this finding, hearing loss was associated with a 10-point-lower mean score in the school-functioning scale of the Pediatric Quality of Life Inventory 4.0. We also observed a clear pattern of poorer self-reported quality-of-life scores among children with parent-reported academic and psychosocial problems compared with those without such problems, particularly with school functioning, even after controlling for reported hearing loss. We found evidence that long-term neuroblastoma survivors, especially those with hearing loss, are at elevated risk for academic learning problems and psychosocial difficulties. We also found strong concordance between parent-reported learning problems in the child and indications of distress in the child's self-reported quality of life.

A Phase 1 and pharmacokinetic clinical trial of paclitaxel for the treatment of refractory leukemia in children: A Children's Oncology Group study

This report summarizes a phase 1 study conducted by the Children's Cancer Group (CCG) to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and anti-leukemia activity of paclitaxel in children with advanced stage leukemias. This study examined two dose escalation schedules of intravenous paclitaxel. Doses ranged from 250 to 500 mg/m(2) every 21 days in schedule A and 105 to 200 mg/m(2) weekly x 3 every 28 days in schedule B. Serial plasma samples for pharmacokinetic studies were obtained after the first paclitaxel dose. Sixty-three patients (median 10 years) with refractory or relapsed leukemia (ALL) (n = 39), acute myeloid leukemia (AML) (n = 19), biphenotypic (n = 4), and JCML (n = 1)) were enrolled. The DLTs in schedule A were grade 4 hypertension and hyperbilirubinemia with an MTD of 430 mg/m(2) every 21 days. The DLTs in schedule B were coagulopathy, hyperkalemia, hyperbilirubinemia, elevated SGOT (n = 1, 125 mg/m(2)), peripheral neuropathy (n = 1, 200 mg/m(2)), and typhlitis (n = 1, 200 mg/m(2)) with an MTD of 182 mg/m(2) weekly x 3 every 28 days. Among 54 evaluable patients, there was one complete response (CR), three partial responses (PR), and five patients with stable disease (SD). The mean terminal elimination half-life was 9.5 +/- 3.4 hr and the mean plasma clearance was 23 +/- 11 L/hr/m(2). Paclitaxel was tolerated at 430 mg/m(2) every 21 days and at 182 mg/m(2)/dose weekly x 3 every 28 days in pediatric patients. The objective response rate across all dose levels and schedules was <10%.

Immunophenotypic identification of possible therapeutic targets in paediatric non‐Hodgkin lymphomas: a children's oncology group report

Immunophenotypic analysis can identify protein epitopes in non-Hodgkin lymphomas (NHL) that may respond to targeted immunotherapies, such as anti-CD20 and anti-CD52. Recent studies suggest additional targets may provide therapeutic benefits in NHL. This study evaluated protein expression of CD25, CD52, CD74 and CD80 in paediatric NHL to determine possible targets for immune-based therapeutic approaches. Patient samples were derived from paediatric NHL clinical trials sponsored by the Children's Cancer Group (CCG, now the Children's Oncology Group, COG) and included Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), disseminated T- and B-cell lymphoblastic lymphoma (T-LBL and B-LBL) and anaplastic large cell (ALCL). Immunophenotypic studies were performed on formalin-fixed, paraffin-embedded diagnostic tissues. CD25 was expressed in 8% of T-LBL and 75% of ALCL cases, but not in BL, DLBCL, or B-LBL. CD52 was expressed in 99% of cases of paediatric NHL of all subtypes. CD74 was expressed in 100% of B-LBL, BL and DLBCL, but was absent in ALCL and T-LBL. CD80 was expressed in 12% of B-LBL, 6% of BL and 10% of DLBCL cases studied, but was not detected in T-cell NHL. These expression patterns suggest that CD25, CD52 and CD74 may represent potential new therapeutic targets in paediatric NHL.

Augmented Berlin-Frankfurt-Muenster (ABFM) regimen for children with standard-risk acute lymphoblastic leukemia (SR-ALL) and slow early response (SER)

9511 Background: Numerous studies have shown that SER in ALL has a negative impact on outcome. Children's Cancer Group CCG-1882 demonstrated that post-induction intensification greatly improved the outcome of children with high-risk ALL and SER. Five year event-free-survival (EFS), and overall survival (OS) for the augmented regimen was 75 ± 4% vs 55 ± 4.5%, and 78 ± 4% vs 67 ± 5% for the standard regimen, p &lt;0.001 and 02 respectively (N Engl J Med 1998; 338:1663–71). Methods: Therefore, COG-1952 and COG- 1991, studies for patients with SR-ALL, assigned the slow early responders to augmented therapy, while others were randomized according to the study design. Study eligibility criteria were similar for both, and included newly diagnosed children with National Cancer Institute SR criteria. COG-1952 accrued a total of 2,027 patients and COG-1991 accrued 3,054. In COG-1952 patients were deemed SER if their day-7 marrow had &gt;5% blasts, and their day-14 marrow &gt;25%. COG-1991 used the same criteria for SER, but also added patients whose day-7 marrow had &gt;25% blasts and their day-14 marrow had &gt;5% blasts to the SER group. This was based on the unfavorable outcome of this subgroup in COG-1952. The augmented therapy in COG-1991 like the CCG-1882 and COG-1952, was based on a COG-modified ABFM, but differed in using dexamethasone as the sole steroid and pegylated asparaginase as the asparaginase preparation, as compared to prednisone in induction and maintenance, and native E coli asparaginase. Results: Comparative groups with days 7 and 14 M3 marrows and unfavorable cytogenetics included 126 patients from COG-1991 and 81 from the COG-1952 were assigned to their corresponding ABFM regimens. Four year EFS and OS were 85% ± 5% and 90 ± 4% for CCG-1991 vs 61 ± 5.6% and 75 ± 5% for CCG-1952, p = 0.003 and 0.04 respectively. Conclusion: We conclude that the use of dexamethasone, and pegylated asparaginase greatly improves the outcome of children with NCI-SR with SER treated on a modified augmented BFM therapy, thus supporting the use of these agents in ALL therapy. No significant financial relationships to disclose.

Autologous bone marrow transplantation for children with AML in first remission

In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.

Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: Report from the Children's Oncology Group

Myelodysplastic syndromes (MDS), acute erythroleukemia (FAB M6), and acute megakaryocytic leukemia (FAB M7) have overlapping features. Children without Down syndrome or acute promyelocytic leukemia who were newly diagnosed with primary myelodysplastic syndrome or acute myeloid leukemia (AML) M6 or M7 were compared to children with de novo AML M0-M5. All children were entered on the Children's Cancer Group therapeutic research study CCG 2891. The presentation and outcomes of the 132 children diagnosed with MDS (60 children), AML FAB M6 (19 children), or AML FAB M7 (53 children) were similar. Children with AML FAB M7 were diagnosed at a significantly younger age (P = 0.001). Children with MDS, M6, or M7 had significantly lower white blood cell (WBC) counts (P = 0.001), lower peripheral blast counts (P < 0.001), and an increased frequency of -7/7q- (P = 0.003) at presentation. All three groups had significantly inferior overall survival (OS) (P < 0.001) and event free survival (P < 0.001) compared with the 748 children diagnosed with AML FAB M0-M5 when assessed from entry on study. This poor survival was largely attributable to induction death and failure. However, when assessed from successful completion of induction therapy, the 5-year OS (P = 0.090)(49.1 vs. 56.9%) and disease-free survival (DFS) (P = 0.113)(38.0 vs. 46.3%) therapy were not significantly different from other children with AML. Childhood AML FAB M6 and AML M7 resemble MDS in presentation, poor induction success rates, and outcomes.

Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia

To evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL). We retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Children's Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002. The 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% +/- 2.4% v 77% +/- 0.6% (P = .02) and 26 +/- 2.4 v 20 +/- 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesity's hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients > or = 10 years old at diagnosis; in this subset, obesity's adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients 10 years old, obesity's adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity. Obesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL.

Outcomes of primary liver cancer in children: an appraisal of experience

Introduction Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common primary liver cancers in children. Recent advances in management of pediatric liver cancer have improved disease-specific survival (DSS). This is a review of our experience with childhood liver malignancy over the past 3 decades. Materials and Methods A retrospective chart review from 1975 to 2005 identified patients who were 18 years old or younger with a histologically confirmed diagnosis of primary liver cancer. Patients were staged according to the Children's Cancer Group and Pediatric Oncology Group (CCG/POG) system. Patients were followed up prospectively through clinic visits and mail correspondence. Standard statistical methods were used for comparison, risk, and survival analyses. Results Fifty-two patients were confirmed to have primary liver cancers, where 24 (46%) patients had HB, 22 (42%) had HCC, 3 (6%) had sarcomas, and 3 (6%) had other histologies. Mean ages at presentation for HB and HCC were 3.2 and 13.1 years old, respectively. The most common presentations were abdominal mass (67%) and pain (40%). Most patients underwent major liver resection (n = 45, 87%), including: lobectomy (n = 25, 48%), and trisegmentectomy (n = 11, 21%). Three patients underwent liver transplantation (n = 3, 6%) for advanced local disease. Forty-five (87%) received primary or neoadjuvant and/or adjuvant chemotherapy. Patients had the following CCG/POG stages: I (n = 31, 60%), II (n = 6, 11.5%), III (n = 9, 17%), and IV (n = 6, 11.5%). Complete gross resection (stage I and II) was achieved in 37 (71%) patients. The perioperative mortality and morbidity rates were 0% and 29%, respectively. Patients with complete resection had significantly better 5-year DSS and median survival compared with incomplete gross resection: 62% vs 9% and 216 vs 18 months, P < .001. Patients treated during the period 1995-2005 had better 5-year DSS and median survival compared with those treated during 1975-1994: 68% vs 32% and 117 vs 27 months, P = .032. All 3 patients who underwent transplantation for conventionally unresectable disease are alive without disease recurrence (follow-up period, 1-15 years). Conclusion Complete resection of the pediatric primary liver tumors remains the cornerstone of treatment to achieve cure. Major liver resection can be performed with minimal perioperative mortality and morbidity. Patients with HB appeared to have better survival compared with patients with HCC, and there was significant improvement in the DSS of children treated in the recent decade. Liver transplantation in conjunction with chemotherapy may have an increasing role in the management of locally advanced primary liver cancers.

Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961

AbstractTo assess the impact of minimally differentiated acute myeloid leukemia (AML-M0) morphology in children, we analyzed 2 sequential Children's Cancer Group AML clinical trials. We compared presenting characteristics and outcomes of 82 CCG-2891 and CCG-2961 patients with de novo, non–Down syndrome (DS) AML-M0 with those of 1620 patients with non-M0 AML, and of 10 CCG-2891 patients with DS-associated AML-M0 with those of 179 with DS-associated non-M0 AML. Morphology and cytogenetics were centrally reviewed. The non-DS AML-M0 children had a lower white blood cell (WBC) count (P = .001) than their non-M0 counterparts and a higher incidence of chromosome 5 deletions (P = .002), nonconstitutional trisomy 21 (P = .027), and hypodiploidy (P = .002). Outcome analyses considering all children with non-DS AML demonstrated no significant differences between M0 and non-M0 patients. Analyses restricted to intensive-timing CCG-2891 and CCG-2961 demonstrated comparable complete response (CR) rates (79% and 78%) between non-DS M0 and non-M0 patients. Overall survival (OS) from diagnosis (38% ± 14% versus 51% ± 3%; P = .160) was not significantly different between the 2 groups. OS from end of induction (45% ± 17% versus 63% ± 3%; P = .038), event-free survival (EFS; 23% ± 11% versus 41% ± 3%; P = .018), and disease-free survival (DFS; 31% ± 14% versus 52% ± 3%; P = .009) were inferior in the M0 group. There was no significant outcome difference between DS-associated AML-M0 and non-M0 children. This study suggests that intensively treated non–DS-associated AML-M0 children have an inferior outcome compared with children with non-M0 AML.

A study of ovarian lesions in pre-menarche girls.

To analyze various clinical presentations and the surgical management of ovarian pathologies in pre-menarche girls. Case series. Surgical Unit B, National Institute of Child Health, Karachi, from September 2002 to August 2004. Case records of all the pre-menarche girls child having an ovarian pathology and managed during the study period were reviewed. Age of the patients, presenting symptoms, investigations performed, surgical approaches, operative findings and final histological diagnosis were noted. Ovarian lesions were classified according to WHO criteria.System proposed by the Children's Cancer Group and the Paediatric Oncology Group was used for staging of tumors. Following resection, patients with malignant tumors were followed-up by oncologist. There were 18 patients with ovarian lesions. Age range of patients was from day 1 to 13 years. Mass in abdomen was the most common presenting symptom (60% patients ) followed by pain (50%). Right ovary was involved in 12 (55%) cases and left in 6 (45%). Six patients had non-tumorous cysts, 3 had benign tumors and 9 were with malignant lesions. Of the non-tumorous cysts, 3 patients had simple follicular cysts and 2 were hemorrhagic cysts. There were 2 patients with benign teratoma and one with dermoid cyst. Four patients had malignant teratoma, 4 dysgerminoma and one yolk sac tumor. Malignant tumors were all of stage IA according to Paediatric Oncology Group staging. Ovarian tumors are rare in paediatric age group especially in pre-menarche girls. Except one, all malignant tumors were found in patients above 7 years of age. Benign (tumorous and non-tumorous) and malignant lesions occurred with equal frequency in pre-menarche girls in this study.

Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)

AbstractThe Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n = 4986) and POG (January 1986 to November 1999, n = 6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.

Anaplastic mixed gliomas and anaplastic oligodendroglioma in children: results from the CCG 945 experience

To review interpathologist diagnosis variability and survival of children treated for either anaplastic mixed glioma (AMG) or anaplastic oligodendroglioma (AO) with surgery, irradiation and chemotherapy. Two hundred and fifty patients with an institutional diagnosis of malignant glioma were enrolled on Children's Cancer Group CCG-945 between 1985 and 1991, and administered vincristine during involved field radiotherapy, then six cycles of prednisone, lomustine and, vincristine; or two cycles of "eight-drugs-in-one-day" (8-in-1) chemotherapy then involved-field radiotherapy followed by six cycles of 8-in-1 chemotherapy. Central review of institutional pathology was post hoc by five experienced neuropathologists. Twenty-six children had institutional diagnoses of AMG and four had AO. Complete resection and cerebral tumor location was associated with better overall survival (OS) in patients with institutional diagnoses of AMG. However, central review established that only nine of 26 children had AMG: either mixed oligoastrocytoma (MOA) or anaplastic mixed oligoastrocytoma (AOA) and only one had AO. Central review revealed five more patients with AMG, but none with AO. Institutional and CCG central review diagnoses of AMG or AO had poor Jaccard reliabilities of 0.29 and 0.25 respectively. Five-year EFS and OS for five children with centrally confirmed MOA was 50 +/- 20%, with four centrally confirmed AOA was 37.5 +/- 17%. After central review, small samples made tests for differences in survival between regimes impossible. Diagnosis of these tumors is challenging, with only 35% of institutional diagnoses confirmed for AMG and 25% for AO, and survival among children with these tumors is poor, despite intensive therapy. This suggests reliable diagnostic markers and new therapeutic approaches are needed.

Allogeneic Bone Marrow Transplantation in First Remission for Children with Ultra-high-risk Features of Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study Report

The prognosis for childhood acute lymphoblastic leukemia (ALL) has improved dramatically over the past quarter of a century. Despite improvements in the treatment of childhood ALL, relapse still occurs in 20%-30% of patients. Although many of these relapses occur in the “standard-risk” patients, approximately 10% of these patients present at diagnosis with clinical and biological features that identify them as having a very high risk of relapse. Children (2 months to 21 years) with ≥1 ultra-high-risk feature (UHRF) of ALL in first remission treated on a frontline Children’s Cancer Group (CCG) ALL study with a matched family allogeneic donor were eligible for study entry onto CCG-1921 and an allogeneic bone marrow transplant (AlloBMT). Each patient received fractionated total body irradiation (1200 cGy) and cyclophosphamide (120 mg/kg) conditioning therapy followed by unmobilized BM from a matched family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporin. Twenty-nine patients with a median age of 8.7 years with UHRF ALL in first complete remission (CR1) received an AlloBMT from a family member. The incidence of grade II-IV acute GVHD was 20.7% and the incidence of chronic GVHD was 3.7%. AlloBMT conditioning regimen was well tolerated and only 1 patient (3%) had treatment-related mortality. Ten patients (35%) died due to progressive disease. The 5-year event-free survival (EFS) for all patients was 58.6% and patients without cytogenetic abnormalities had a 5-year EFS of 77.8%. The 5-year EFS rates for infants and non-infants were 20.0% and 66.7% (log-rank test, P = .01), respectively. Patients with Philadelphia chromosome-positive ALL had a 5-year EFS of 66.7%. The children with UHRF of ALL may benefit from AlloBMT in CR1, especially patients with primary induction failure and Philadelphia chromosome-positive ALL. Randomized prospective cooperative group studies are required to establish the role of allogeneic hematopoietic stem cell transplantation versus intensive chemotherapy in children with UHRF ALL in CR1.

The Association between Cytogenetic Abnormalities and Clinical Outcomes Based on Prognostic Factors of the Children Cancer Group (CCG) in Pediatric Patients with Acute Leukemia: Two Institutional Retrospective Studies

Results: The incidence of cytogenetic abnormalities was 51 (51.5%) in 99 patients, and 27 (39.7%) in acute lymphoblastic leukemia (ALL) patients and 24 (77.4%) in acute myelogenous leukemia (AML) patients. The most frequent cytogenetic abnormality was hyperdiploidy and t(8:21) in the ALL and AML patients, respectively. The overall survival rate (OS)/disease free survival rate (DFS) of the ALL patients was 74.0%/73.9%. The OS/DFS of the standard risk group (88.8%/85.2%) was significantly higher than that of the high-risk group (49.4%/39.3%) in the ALL patients (P=0.0005/P<0.0001). There was no significant difference in the survival rates according to the type of cytogenetic abnormalities among the ALL patients for the standard/high risk groups, based on the CCG prognostic factors. The OS/DFS of the AML patients were 43.4% and 41.7%, respectively, without significant differences of the survival rates according to the type of chromosomal abnormalities. Conclusion: There were significant differences of OS/DFS based on the risk groups in ALL patients when evaluated with the CCG prognostic factors (standard/high) and chromosomal abnormalities (good/ poor), respectively. However, there was no significant correlation between type of cytogenetic abnor- malities and clinical outcomes based on the CCG prognostic factors in children with ALL as well as with AML.

Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group

Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group

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

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