Children's Cancer Group Research Articles

Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival

AbstractIn Children's Cancer Group (CCG) study 2891, patients who were recently diagnosed with acute myelocytic leukemia (AML) were assigned randomly to standard- or intensive-timing induction chemotherapy. Patients in first complete remission (CR1) and who had a human leukocyte antigen (HLA)–identical, related donor or a donor disparate at a single class I or II locus were nonrandomly assigned to receive a bone marrow transplant (BMT) by using oral busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). Methotrexate only was given for graft-versus-host disease (GVHD) prophylaxis. One hundred fifty patients received transplants. Grade 3 or 4 acute GVHD occurred in 9% of patients. Patients younger than 10 years had a lower incidence of grade 3 or 4 GVHD (4.6%) compared with patients 10 years or older (17.4%) (P = .044). Disease-free survival (DFS) at 6 years was 67% and 42% for recipients of intensive- and standard-timing induction therapies, respectively. Multivariate analysis showed that receiving intensive-timing induction therapy (P = .027) and having no hepatomegaly at diagnosis (P = .009) was associated with favorable DFS, and grades 3 and 4 acute GVHD were associated with inferior DFS. Multivariate analysis showed that grades 1 or 2 GVHD (P = .008) and no hepatomegaly at diagnosis (P = .014) were associated with improved relapse-free survival (RFS). Our results show that children older than 10 years are at higher risk for developing severe GVHD; acute GVHD is associated with favorable RFS.

Parental exposure to medical radiation and neuroblastoma in offspring

Previous studies have suggested an association between parental medical radiation exposure and increased incidence of certain childhood cancers. We investigated the relationship between medical radiation and risk of neuroblastoma in offspring using data from a North American case-control study. Cases were children diagnosed with neuroblastoma from 1 May 1992, to 30 April 1994, at Children's Cancer Group and Pediatric Oncology Group institutions throughout the United States and Canada. One matched control per case was selected using random-digit dialling. Telephone interviews were conducted with parents to collect data on any medical radiation examinations and treatments in the 2 years before conception or during pregnancy. We included 500 maternal and 339 paternal matched pairs. Overall, no association was found between maternal exposure to radiation and neuroblastoma risk (odds ratio [OR] = 1.0; 95% confidence interval [CI]: 0.7, 1.3). Analysis of maternal exposure by specific anatomical site showed no association for gonadal sites [OR = 1.0; 95% CI = 0.5, 2.0]. Little association was found with paternal radiation exposure [OR = 1.2; 95% CI = 0.8, 1.8]. No consistent exposure-response gradient was found based upon the number of maternal or paternal medical radiation examinations. The data presented here, coupled with the lower radiation doses currently used, indicate that any further study of this question will require larger studies with improved exposure assessment.

Maternal medication use and neuroblastoma in offspring.

The association between a mother's use of specific medications during pregnancy and lactation and neuroblastoma in her offspring was evaluated in a case-control study. Newly diagnosed cases of neuroblastoma (n=504) in the United States and Canada were identified between 1992 and 1994 at 139 hospitals affiliated with the Pediatric Oncology Group or the Children's Cancer Group clinical trial programs. One age-matched control was sampled from the community of each case by means of random digit dialing. Exposure information was ascertained retrospectively from mothers in a structured telephone interview. Odds ratios were estimated using conditional logistic regression, with adjustment for maternal sociodemographic factors. The results did not support an association between neuroblastoma and maternal exposure to diuretic agents, antiinfective agents, estrogens, progestins, sedatives, anticonvulsant drugs, or drugs that may form N-nitroso derivatives. Mothers of cases were more likely to report using medications containing opioid agonists while they were pregnant or nursing than were mothers of controls (odds ratio=2.4, 95% confidence interval: 1.3, 4.3). Specifically, more mothers of cases reported using medications containing codeine while pregnant or nursing than did mothers of controls (odds ratio=3.4, 95% confidence interval: 1.4, 8.4). This preliminary finding may be due to bias, confounding, or chance, and additional studies are needed for confirmation.

Fertility in women treated with cranial radiotherapy for childhood acute lymphoblastic leukemia.

Fertility impairments among women treated during childhood for cancer are known to occur after some, but not all, types of anticancer therapy. Although leukemia is the most common cancer of childhood, until now fertility in survivors has not been comprehensively assessed. We investigated functional impairment of fertility in women who were long-term survivors of acute lymphoblastic leukemia (ALL) with a retrospective cohort study. Proven fertility (defined as ever pregnant) was evaluated by self-report among 182 females treated on protocols of the Children's Cancer Group (age at interview, 22.6 years on average) and 170 controls drawn from among the survivors' female siblings (23.4 years). The interview included psychosocial inventories designed to detect mood problems. Significant fertility deficits were noted in female survivors treated with cranial radiotherapy (CRT) at any dose around the time of menarche (relative fertility (RF)) = 0.27, 95% CI = 0.09, 0.82, P = 0.03). Controlling for marital status, mood at interview, and many fertility-related situations did not change the association. This study provides evidence for fertility deficits after treatment for ALL with CRT, and, in addition, for the first time, suggests that girls treated around the time of menarche are especially at risk. Clinical confirmation of these results is needed. If gonadal damage occurs in women receiving these treatments, their risk for further sequelae, such as osteoporosis and heart disease, may be significantly raised, requiring active management and intervention.

Deletion of 7p or monosomy 7 in pediatric acute lymphoblastic leukemia is an adverse prognostic factor: a report from the Children's Cancer Group.

Monosomy 7 or deletions of 7q are associated with many myeloid disorders; however, the significance of such abnormalities in childhood acute lymphoblastic leukemia (ALL) is unknown. Among 1880 children with ALL, 75 (4%) had losses involving chromosome 7, 16 (21%) with monosomy 7, 41 (55%) with losses of 7p (del(7p)), 16 (21%) with losses of 7q (del(7q)), and two (3%) with losses involving both arms. Patients with losses involving chromosome 7 were more likely to be > or =10 years old, National Cancer Institute (NCI) poor risk, and hypodiploid than patients lacking this abnormality. Patients with or without these abnormalities had similar early response to induction therapy. Event-free survival (EFS) and survival for patients with monosomy 7 (P<0.0001 and P=0.0007, respectively) or del(7p) (P<0.0001 and P=0.0001, respectively), but not of patients with del(7q), were significantly worse than those of patients lacking these abnormalities. The poorer EFS was maintained after adjustment for a Philadelphia (Ph) chromosome, NCI risk status, ploidy, or an abnormal 9p. However, the impact on survival was not maintained for monosomy 7 after adjustment for a Ph. These results indicate that the critical region of loss of chromosome 7 in pediatric ALL may be on the p-arm.

Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children's Cancer Group Study CCG-E08.

Among pediatric non-Hodgkin lymphomas, the most frequent type is small noncleaved-cell lymphoma (including Burkitt and Burkitt-like). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia (ALL); however, chromosome abnormalities have not been evaluated for prognostic value in pediatric Burkitt and Burkitt-like lymphomas. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 19 patients were enrolled with cytogenetic analysis of Burkitt or Burkitt-like lymphoma and simultaneously enrolled on treatment protocols CCG-503 or CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included an age range of 2 to 14 years (median 8 years) and a male:female ratio of 14:5. All patients had advanced disease (stages III and IV, or ALL). Disease relapsed in five patients (event-free survival 74%, median follow-up 10.4 years). Chromosome abnormalities were identified in 18 patients (95%) including t(8;14)(q24.1;q32) in 12 (63%); t(8;22)(q24.1;q11.2) in 1 (5%); partial duplication of 1q in 7 (37%); and 13q32 abnormalities in 2 (11%). In patients who had relapses, in addition to the t(8;14)(q24. ;q32), two had abnormalities of 13q32 and two had partial duplication of 1q. CMYC translocations were absent in Burkitt-like lymphomas from all three patients. Burkitt and Burkitt-like lymphomas in children have a high frequency of chromosome abnormalities. Burkitt lymphoma abnormalities often involve CMYC translocations, usually a t(8;14)(q24.1;q32). Additional chromosome abnormalities that involved 13q32 and partial duplication of 1q were associated with poor prognosis. Burkitt-like lymphomas were not associated with CMYC translocations. Further studies are warranted in larger cohorts of children and adolescents with Burkitt and Burkitt-like lymphomas.

Staged informed consent for a randomized clinical trial in childhood leukemia: impact on the consent process.

Children Cancer Group (CCG) 1991 is the first childhood acute lymphoblastic leukemia trial within CCG that allowed the utilization of a staged approach to the consent process. One hundred and forty subjects participated in the Project on Informed Consent which compared the primary outcome measures in the consent process of patients enrolled in CCG-1991 with those enrolled in other CCG leukemia studies. The parents' trust scores were higher for the CCG-1991 compared with other protocols. Eighty percent of parents enrolled in CCG-1991 understood the distinction between the randomized clinical trial and the standard treatment arm, compared with 62.5% in the other studies, P = 0.05. Multiple other outcome measures suggested a positive impact from staged informed consent. Our results suggest that a consent process with a staged approach can help investigators obtain a more truly informed consent. Future research is needed to confirm the benefits of the staged approach to the informed consent process.

Pilot Study of Idarubicin-Based Intensive-Timing Induction Therapy for Children With Previously Untreated Acute Myeloid Leukemia: Children's Cancer Group Study 2941

Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891. On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891. Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P <.001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P =.007), mean duration of course 1 by a week (P =.002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P =.02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P =.004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891. In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.

Fertility of long-term male survivors of acute lymphoblastic leukemia diagnosed during childhood.

Fertility impairments among men treated during childhood for cancer are known to occur after some, but not all, types of anti-cancer therapy. This is the first study to evaluate proven fertility among adult male survivors of childhood acute lymphoblastic leukemia (ALL). In a retrospective cohort study, proven fertility (ever fathered a pregnancy) was evaluated by self-report among 213 men treated for ALL before age 18 on protocols of the Children's Cancer Group (CCG). Controls (N = 145) were drawn from among male siblings. Overall, with a proportional hazards analysis, proven fertility of male survivors was not different from that of controls (relative fertility (RF) = 0.95, 95% CI 0.63-1.43). However, married men treated before age 10 with high dose (24 cGy) cranial radiotherapy (RT), without spinal RT, had only 9% of the fertility of controls (Relative risk, RR = 0.09, 95% CI 0.01-0.82). High dose cranial RT at older ages was not associated with a statistically significant fertility deficit (RR = 0.56, 95% CI 0.25-1.28). In this first study of proven fertility among men treated for childhood leukemia, the majority of survivors showed no evidence of fertility impairment compared to controls. However, men treated at a young age with high dose cranial RT may have impaired fertility. These results suggest that further investigation of men with these treatments is needed to confirm and extend these findings.

Self-concept in adult survivors of childhood acute lymphoblastic leukemia: a cooperative Children's Cancer Group and National Institutes of Health study.

Self-concept was compared between adult survivors of childhood acute lymphoblastic leukemia (ALL) and sibling controls. Adult survivor subgroups at greatest risk for negative self-concept were identified. Survivors (n = 578) aged > or =18 years, treated before age 20 years on Children's Cancer Group (CCG) ALL protocols, and 396 sibling controls completed a telephone interview and the Harter Adult Self-Perception Profile (ASPP). Survivors global self-worth scores were significantly lower than sibling controls (mean 3.09 vs. 3.18; P = 0.022). Unemployed survivors reported lower global self-worth scores than employed (mean 2.77 vs. 3.12; P = 0.0001), whereas employment status was not associated with self-worth in controls. Among survivors, predictors of negative self-concept included unemployment (odds ratio (OR) = 2.87; 95% CI: 1.50-5.50), and believing that cancer treatment limited employability (OR = 3.17; 95% CI: 1.79-5.62). Unemployment increased the odds for negative self-concept among survivors who received combinations of central nervous system (CNS) irradiation (CRT) and intrathecal methotrexate (IT-MTX), except high CRT with no or low dose IT-MTX. Employed survivors who perceived that treatment limited their employability showed increased odds of negative self-concept for all treatment groups compared to those who did not. Minority ethnic group membership was a borderline significant predictor of negative self-concept (OR = 1.79; 95% CI: 0.94-3.33). Global self-worth was significantly lower in ALL survivors than sibling controls, however, 81% of survivors had positive self-concept. Survivor subgroups most vulnerable to negative self-concept were the unemployed survivors, believing that cancer treatment affected employability, and ethnic minority group members. Targeted intervention may have greater clinical relevance for these subgroups.

Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group.

To describe features of patients with acute myeloid leukemia presenting with extramedullary leukemic tumors (EML). Among 1,832 patients entered on Children's Cancer Group's chemotherapy trials with acute myeloid leukemia, 199 patients had EML, defined as any leukemic collection outside the bone marrow cavity. Three patient groups were denoted: group 1 (n=109) with EML involving skin (with or without other sites of EML), group 2 (n=90) with EML in sites other than skin, and group 3 (n=1,633) without EML. The incidence of EML was 10.9%. Group 1 patients tended to be younger, had higher white blood cell counts, were more often CNS positive, had FAB M4 or M5 subtypes, and possessed more abnormalities of chromosome 11 than group 3 patients. Group 2 patients were younger, more often had the FAB M2 subtype, and had a higher incidence of t(8;21)(q22;q22) abnormality than group 3, but had similar white blood cell counts and incidence of CNS positivity at diagnosis. For group 1 the 5-year event-free survival was 26%, significantly worse than for group 3 at 29%. Event-free survival was better for group 2 patients (5-year estimate 46%), which remained a favorable prognostic factor by multivariate analysis. The authors retrospectively determined whether 118 (59%) of the EML patients received localized radiotherapy to the site of EML: 42 did and 76 did not. There were no differences in estimated event-free survival between patients who did and did not receive radiotherapy. Non-skin (group 2) EML appeared to be an independent favorable prognostic factor. Localized radiotherapy to the site of EML at the end of induction chemotherapy did not improve outcome.

Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular.

Ganglioneuroblastoma, nodular (GNBn) comprises one of the categories of peripheral neuroblastic tumors. All tumors in this category, according to the original International Neuroblastoma Pathology Classification, are classified into an unfavorable histology group. Subsequently, it has been reported that GNBn can be divided into two prognostic subsets, a favorable subset (FS) and an unfavorable subset (US). Histology slides from 70 patients who were enrolled in Children's Cancer Group studies 3881 and 3891 and who had a diagnosis of GNBn were reviewed jointly by the members of International Neuroblastoma Pathology Committee (INPC): 1) to confirm the diagnosis of GNBn, 2) to identify the FS and US by applying the same age-linked criteria that were used to distinguish the favorable histology group and unfavorable histology group in conventional neuroblastoma tumors from the neuroblastomatous component of GNBn tumors, and 3) to verify the significant prognostic difference between these two subsets. The patients had been used in a previous study, and survival data for the patients were updated since the time of their last report. The review clarified and illustrated morphologic characteristics of classical GNBn and it variants. The diagnosis of GNBn was confirmed in 67 of 70 patients. There were 22 patients with GNBn in the FS and 45 patients with GNBn in the US. The estimated survival differences between the FS and US patients with GNBn were statistically significant (8-year event free survival rate: 86.1% vs. 32.2%; P = 0.0003; overall survival rate: 90.5% vs. 33.2%; P = 0.0003). This study confirmed the recently defined prognostic subsets of GNBn. The INPC proposes to modify the International Neuroblastoma Pathology Classification by distinguishing the FS and the US among patients with GNBn tumors.

Reduced Folate Carrier and Dihydrofolate Reductase Expression in Acute Lymphocytic Leukemia May Predict Outcome: A Children's Cancer Group Study

Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome. Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies. Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance. These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.

Community and home care services provided to children with cancer: a report from the Children's Cancer Group Nursing Committee--Clinical Practice Group.

A survey directed to home care providers was conducted by the Children's Cancer Group Nursing Committee--Clinical Practice Group. The purpose of the survey was to (a) assess the treatments, resources, and counseling services provided to children with cancer and (b) query what are their informational needs in servicing this specialized population. The survey found that there are many chemotherapy, biotherapy, and supportive therapies being provided in the home. There are also variations in the experiences of the agencies and home care providers in delivering these services. There were numerous informational needs identified by the agencies. The survey results were discussed with the Clinical Practice Group and several themes were expressed: (a) safety, (b) protocol adherence, (c) making the home into a hospital, and (d) meeting the informational needs of the home care providers.

Outcome of children with centrally reviewed low‐grade gliomas treated with chemotherapy with or without radiotherapy on Children's Cancer Group high‐grade glioma study CCG‐945

The objectives of the current study were to determine the outcome of children who were treated with chemotherapy and radiotherapy on the Children's Cancer Group (CCG) high-grade glioma protocol (CCG-945) who were diagnosed with low-grade gliomas on post hoc central pathologic review and to identify clinical and biologic features associated with prognosis. Between 1985 and 1991, 250 children with institutionally classified high-grade gliomas were enrolled on CCG-945. Patients older than 24 months with intracranial lesions were assigned randomly to receive either lomustine, vincristine, and prednisone (control regimen) or the 8-drugs-in-1-day regimen (experimental regimen); younger patients and those with primary spinal cord tumors were assigned nonrandomly to the experimental regimen. Central independent review by 5 neuropathologists led to a reclassification of low-grade glioma in 70 patients, who were the focus of the current study. The study involved 42 males and 28 females (median age, 7.7 years) with a median follow-up of 10.4 years. At 5 years, the progression-free survival (PFS) rate was 63% +/- 6%, and the overall survival (OS) rate was 79% +/- 5%, compared with a PFS rate of 19% +/- 3% (P < 0.0001) and an OS rate of 22% +/- 3% (P < 0.0001) in the remainder of the cohort. Significantly poorer 5-year PFS was seen in children younger than 24 months, those with fibrillary astrocytoma, and those with posterior fossa tumors. Patients demonstrated a modest improvement in PFS but no improvement in OS compared with children with low-grade gliomas who were treated with contemporary chemotherapy-alone approaches. The current report calls attention to the importance of central pathologic review in large multiinstitutional trials of children with gliomas and suggests that aggressive front-line combined chemoradiotherapy does not confer a survival advantage in this highly selected population of patients.

Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group.

This was a retrospective analysis of outcome based on cytogenetics for a Children's Cancer Group phase 3 trial of acute myelogenous leukemia (AML) (CCG-2891). A retrospective analysis of outcome for newly diagnosed children with AML and myelodysplastic syndrome (MDS) was performed using data collected from CCG-2891. The authors identified 11 patients whose blasts carried t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q among 470 eligible patients entered with acceptable, centrally reviewed cytogenetics. A bone marrow specimen was used for each case of cytogenetic analysis in which 20 banded (either G-banded or Q-banded) metaphases were completed on each subject. All 11 patients had characteristic monocytoid morphology (M4 or M5) and tended to be young (0.1-7.9 years; median 0.9 years). All 11 patients entered remission, but remissions tended to be short; 9 patients relapsed within 12 months (median 4 months). The relapse rate of 82% was significantly higher for this group of patients compared with 46% for the group at large. The relapse rate for this group of patients having t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was also significantly higher compared with subjects with other 11q23 chromosomal abnormalities. The CNS relapse rate of 55% was higher for this group of patients compared with 3% for all other patients in the study. The CNS relapse rate was higher for the subjects who had t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q compared with subjects with all other chromosome 11 abnormalities. Three children survived, two in second remissions (4.7 and 6.3 years after relapse) and one in first remission (7.0 years after diagnosis). Survival and event-free survival for the patients with t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from all other patients with cytogenetics. Similarly, the survival and event-free survival for the patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from the 11q23 group of subjects. Further research is needed to determine the various changes that are occurring at the molecular level for patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 to gain insight into the mechanisms causing this clinical phenotype associated with a poor prognosis.

CYP3A genotypes and treatment response in paediatric acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer with a cure rate of approximately 80%. Relapse occurs despite treatment stratification based on clinical criteria. Relapse risk in ALL may be related to simple nucleotide polymorphisms (SNPs) of enzymes that metabolize chemotherapeutic agents. We evaluated whether SNPs in the cytochrome P450 3A family (CYP3A4*1B, CYP3A5*3 and CYP3A5*6) were associated with relapse risk on a national Children's Cancer Group (CCG) paediatric ALL trial (CCG-1891). CCG-1891 enrolled 1204 patients, and obtained both relapse and toxicity data prospectively. One hundred and twenty-four relapsed patients and 409 non-relapsed patients were assayed for each SNP. CYP3A variants were not associated with an increased risk of relapse. However, patients with the CYP3A4*1B and CYP3A5*3 genotypes had a decreased risk of peripheral neuropathy that was statistically significant on univariate analysis. After correction for multiple comparisons, the association between CYP3A*1B and CYP3A5*3 genotypes approached, but did not reach, statistical significance. CYP3 genotypes may not significantly modify the risk of relapse in childhood ALL, but may modify the risk of toxicity.

Prospective clinical trials of intracranial low-grade glioma in adults and children

Over the last decade, the results of 5 prospective clinical trials of intracranial low-grade glioma (LGG) have been published, 4 in adults with supratentorial LGG and 1 in children with infra- and supratentorial LGG. The data from the more than 1600 patients treated on these studies are summarized herein. European Organization for Research and Treatment of Cancer study 22845 randomized 311 adults to postoperative observation or radiation therapy (RT). There was no difference in the 5-year overall survival (OS) rate between the 2 arms. Irradiated patients had a significantly improved 5-year progression-free survival (PFS) rate. European Organization for Research and Treatment of Cancer study 22844 randomized 379 adults to low-dose (45 Gy) versus high-dose (59.4 Gy) RT. Similarly, an intergroup study conducted by the North Central Cancer Treatment Group, Radiation Therapy Oncology Group, and Eastern Cooperative Group randomized 203 adults to low-dose (50.4 Gy) versus high-dose (64.8 Gy) RT. There was no difference in the 5-year OS or PFS rates between the 2 dose groups in either study. A Southwest Oncology Group study randomized 54 adults with incompletely resected LGG to RT alone or RT plus CCNU (lomustine) chemotherapy. There was no difference in outcome between the 2 treatment arms. Important prognostic factors for OS in these 4 adult trials included extent of surgical resection, histology, tumor size, and age. An intergroup study of the Children's Cancer Group and Pediatric Oncology Group enrolled 660 pediatric patients with management based on the extent of surgical resection: Children who underwent gross total tumor resection were observed postoperatively, whereas those who had subtotal resection or biopsy were either observed or administered RT at the discretion of their physician. Survival was most impacted by several prognostic factors, primarily extent of resection. Besides extent of resection, other prognostic factors that were consistent in predicting survival in these 5 clinical trials included patient age and tumor location, size, and histology. The data from these 5 studies indicate that for intracranial LGG in adults, postoperative RT is associated with improved 5-year PFS but not OS rates compared to postoperative observation. Radiation doses of 45 to 54 Gy result in 5-year OS and PFS rates that are similar to those for higher doses. The strategies of chemotherapy alone and RT plus chemotherapy are under investigation. For pediatric LGG, extent of surgical resection is the most important prognostic factor associated with favorable 5-year OS and PFS. Radiation therapy and chemotherapy are generally used in the settings of incomplete resection and recurrent disease, and these strategies are being investigated in prospective clinical trials. The schemata from recently completed and ongoing studies in both adult and pediatric intracranial LGG are reviewed.

The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience.

To examine the influence of the pathology review mechanism on the results of analyses of therapeutic efficacy and biological prognostic correlates for pediatric high-grade gliomas, we evaluated the effects of using single-expert review or consensus review, as alternatives to institutional classification, in determining outcome results of a large randomized trial. The study group was the randomized cohort of Children's Cancer Group study 945, which compared efficacy of 2 chemotherapy regimens adjuvant to surgery and radiation. Trial eligibility required institutional histopathologic diagnosis of high-grade glioma. Sections of study tumors also were centrally reviewed, initially by a study review neuropathologist and subsequently by 5 neuropathologists, including the review pathologist. Reviews were independent, and reviewers were masked to clinical factors and outcomes, and consensus diagnoses of the panel were then established. Among 172 eligible patients, 42 tumors were classified as discordant on single-expert review and 51 on consensus review. Progression-free survival probabilities calculated for patients with tumors classified as high-grade gliomas by either single-expert or consensus review were inferior to those for the overall, institutionally diagnosed cohort. However, conclusions of the study regarding relative efficacy of treatment and clinical and molecular outcome correlates were unaffected by diagnosis method. Resection extent, proliferation index, and p53 expression were associated strongly with outcome, regardless of diagnosis method. However, comparisons between arms in which inclusion was determined by different review criteria for each arm caused spurious conclusions about efficacy differences between treatments. We conclude that the pathology review mechanism had little effect on within-trial comparisons of therapeutic effects or prognostic correlates in this randomized study, but strongly influenced survival distributions that were calculated for each treatment arm. These results support the implementation of expedited central review in therapeutic studies involving childhood malignant gliomas as a way to prospectively identify and exclude cases with discordant diagnoses and indicate the need for additional measures, such as molecular assessments, to increase the reproducibility of neuropathologic classification for these tumors.

Disclosure of the right of research participants to receive research results: an analysis of consent forms in the Children's Oncology Group.

The offer of return of research results to study participants has many potential benefits. The current study examined the offer of return of research results by analyzing consent forms from 2 acute lymphoblastic leukemia studies of the 235 institutional members of the Children's Oncology Group. Institutional review board (IRB)-approved consent forms from 2 standard-risk acute lymphoblastic leukemia studies (Children's Cancer Group [CCG] 1991 and Pediatric Oncology Group [POG] 9407) were analyzed independently by 2 reviewers. The authors received replies from 202 of the 235 institutions that were contacted (85%). One hundred eighty-one institutions had CCG 1991 (n = 96) or POG 9905 (n = 85) protocols that were approved by an IRB. Most institutions provided contact information for the principal investigator (n = 175; 97%) and a member of the institution's research services office (n = 154; 85%). Only 5 (2.8%) institutions provided an indication of a participant's right to receive a summary of research results; most of these institutions provided details on how (n = 5) or when (n = 5) this was to occur. All of these institutions (n = 162; 89.5%) provided a specific statement offering new information that might affect a participant's decision to continue to participate in a study. Only 2 institutional consent forms offered participants the option to receive research results, and only 10 (5.5%) consent forms contained an unambiguous, specific statement offering to provide new information after the study was closed. Few institutional review board-approved consent forms explicitly indicate the right of research recipients to receive a summary of the results of the research in which they have participated.