Sharon B. Murphy

Clinical trials in children.

The imperative to undertake randomised trials in children arises from extraordinary advances in basic biomedical sciences, needing a matching commitment to translational research if child health is to reap the benefits from this new knowledge. Unfortunately, many prescribed treatments for children have not been adequately tested in children, sometimes resulting in harmful treatments being given and beneficial treatments being withheld. Government, industry, funding agencies, and clinicians are responsible for research priorities being adult-focused because of the greater burden of disease in adults, coupled with financial and marketing considerations. This bias has meant that the equal rights of children to participate in trials has not always been recognised. This is changing, however, as the need for clinical trials in children has been increasingly recognised by the scientific community and broader public, leading to new legislation in some countries making trials of interventions mandatory in children as well as adults before drug approval is given. Trials in children are more challenging than those in adults. The pool of eligible children entering trials is often small because many conditions are uncommon in children, and the threshold for gaining consent is often higher and more complex because parents have to make decisions about trial participation on behalf of their child. Uncertain about what is best, despite supporting the notion of trials in principle, parents and paediatricians generally opt for the new intervention or for standard care rather than trial participation. In this review, we explore issues relating to trial participation for children and suggest some strategies for improving the conduct of clinical trials involving children.

National cancer clinical trials: Children have equal access; adolescents do not

PURPOSE To determine whether adolescents with cancer, who in comparison to younger patients have a higher cancer incidence and lower mortality reduction, have equal access to national cancer clinical trials. METHODS The ethnic/racial distribution of 29,859 subjects < 20 years of age entered onto National Cancer Institute-sponsored clinical trials between January 1, 1991, and June 30, 1994, was compared with the expected distribution of patients of the same age in the United States. RESULTS The Childrens Cancer Group and Pediatric Oncology Group had 29,134 (97.6%) of the total study entries among < 20-year-old subjects during the 3.5 years of surveillance. The adult cooperative groups accounted for < 3% of the clinical trials entries in the 15-19-year age range. When analyzed nationally by region, the under-representation of the older adolescent subjects was universal. From other analyses, the two pediatric cooperative groups were estimated to have registered > 94% of the children < 15 years of age who were expected to have been diagnosed to have cancer, but only 21% of the cancer patients in the 15-19-year age group. CONCLUSIONS The national pediatric cancer cooperative groups allow the majority of American children < 15 years of age and their families equal opportunity to access clinical cancer trials, regardless of race or ethnicity. Among patients 15-19 years of age, however, > 75% are not being enrolled by any cooperative group sponsored by the National Cancer Institute. Thus, older adolescents are disadvantaged with respect to access to the national clinical trials, regardless of their race or ethnicity.

Racial Differences in the Survival of Childhood B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study

PURPOSE We conducted a historic cohort study to test the hypothesis that, after adjustment for biologic factors, African-American (AA) children and Spanish surname (SS) children with newly diagnosed B-precursor acute lymphoblastic leukemia had lower survival than did comparable white children. PATIENTS AND METHODS From 1981 to 1994, 4,061 white, 518 AA, and 507 SS children aged 1 to 20 years were treated on three successive Pediatric Oncology Group multicenter randomized clinical trials. RESULTS AA and SS patients were more likely to have adverse prognostic features at diagnosis and lower survival than were white patients. The 5-year cumulative survival rates were (probability +/- SE) 81.9% +/- 0.6%, 68.6% +/- 2.1%, and 74.9% +/- 2.0% for white, AA, and SS children, respectively. Adjusting for age, leukocyte count, sex, era of treatment, and leukemia blast cell ploidy, we found that AA children had a 42% excess mortality rate compared with white children (proportional hazards ratio [PHR] = 1.42; 95% confidence interval [CI], 1.12 to 1. 80), and SS children had a 33% excess mortality rate compared with white children (PHR = 1.33; 95% CI, 1.19 to 1.49). CONCLUSION Clinical presentation, tumor biology, and deviations from prescribed therapy did not explain the differences in survival and event-free survival that we observed, although differences seem to be diminishing over time with improvements in therapy. The disparity in outcome for AA and SS children is most likely related to variations in chemotherapeutic response to therapy and not to compliance. Further improvements in outcome may require individualized dosing based on specific pharmacogenetic profiles, especially for AA and SS children.

Results of little or no treatment for lymphocyte-predominant Hodgkin disease in children and adolescents

Purpose The nodular lymphocyte-predominant form of Hodgkin disease (LPHD) is a distinct clinicopathologic entity with a favorable prognosis. To see if children and adolescents could be spared the adverse sequelae of treatment, the authors adopted a policy of little or no treatment of localized LPHD in 1989. Patients and Methods Presentation, pathology, and outcomes were reviewed for 15 consecutive children and adolescents with LPHD seen at a single institution since 1989. One patient was lost to follow-up and two patients were seen only once in consultation and treated elsewhere. These three cases were excluded, leaving twelve: nine males and three females, ranging in age at diagnosis from 2 to 17 years (median 11). Eleven of the 12 had stage I disease, and 1 had stage II. Six received no treatment following excisional biopsy, while five received a brief treatment with chemotherapy only. One was initially treated with involved field radiotherapy (IFRT) due to an initially imprecise histologic diagnosis of classic Hodgkin disease. Results All patients are alive, without evidence of disease, for periods ranging from 2 to 13+ years after diagnosis (median 6 years). One patient recurred locally with LPHD 6 years after initial brief chemotherapy and was then treated with IFRT, achieving a prolonged second remission. Conclusion Children and adolescents with localized LPHD have an excellent prognosis and may be safely approached either with a wait-and-see attitude of no initial therapy after initial adenectomy or with less aggressive treatments.

Non-anaplastic peripheral T-cell lymphoma in childhood and adolescence: A Children’s Oncology Group Study

Peripheral T‐cell lymphomas (PTCL) other than anaplastic large cell lymphoma (ALCL) are rare in young patients. While a high proportion of adults with PTCL have poor risk disease, pediatric PTCL is not well characterized. This study examines the outcome of localized and advanced PTCL in pediatric patients treated in standardized fashion.

Fractionated cyclophosphamide and back to back high dose methotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (Snccl) : A randomized trial of the Pediatric Oncology Group

BACKGROUND The Pediatric Oncology Group (POG) conducted a two-arm, randomized study for the treatment of children and adolescents with stage III small, non-cleaved cell lymphoma (SNCCL). Regimen A, based on the groups previous best treatment for this group of patients, included cyclophosphamide (CTX) and high-dose methotrexate (MTX), as well as vincristine (VCR), prednisone (PRED), and intrathecal (IT) chemoprophylaxis. Regimen B, based on a single institution pilot study (Total B therapy), consisted of two rapidly alternating chemotherapy combinations (CTX, VCR, doxorubicin; MTX, and cytarabine (Ara-C) plus coordinated IT chemotherapy. PROCEDURE One hundred thirty-four consecutive patients were entered on this study. Seventy patients were randomized to Regimen A, and 64 patients to Regimen B. One hundred and twenty-two patients are eligible for response. RESULTS Complete remission (CR) was achieved by 81% (52/64) of patients on Regimen A, and 95% (55/58) of patients on Regimen B (p=0.014 one-sided). The two-year event-free survival (EFS) is 64% (SE=6%) on Regimen A, and 79% (SE=6%) on Regimen B (p=0.027 by one-sided logrank test). No patient has relapsed on either regimen after a year from diagnosis, although one patient had a second malignancy at day 371. Severe, but manageable, hematologic toxicity was seen in the majority of patients on both regimens, but was more frequent on Regimen B. CONCLUSIONS We conclude that the cure rate in stage III SNCCL is significantly improved with the use of a short, six-month chemotherapy regimen of fractionated CTX alternated with coordinated MTX and Ara-C. Results suggest that drug schedule, not simple drug selection, influences outcome.

Equal participation of minority patients in U.S. national pediatric cancer clinical trials

Purpose To determine the ethnic/racial distribution of patients entered in national pediatric cancer clinical trials relative to the patient population served. Methods: The ethnic/racial distribution of 29,134 patients <20 years of age entered in clinical trials conducted by the Childrens Cancer Group (CCG) and Pediatric Oncology Group (POG) between January 1, 1991 and June 30, 1994 were compared with the expected distribution of patients of the same age in the United States. The latter was predicted from the 1989 to 1991 crude incidence data of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program applied to the 1990 United States census. Results: Of the patients on CCG and POG trials, 11.6% were reported to be Hispanic, 10.4% were African-American, and 4.7% were other racial groups. The expected values were 9.1%, 10.7%, and 4.3%, respectively. Representation of minority patients was equal or greater than expected for 24 of 27 subgroups analyzed. Conclusions: In the United States, minority children with cancer are proportionately represented on clinical trials of the two national pediatric cancer cooperative groups. They and their families are provided with an equal opportunity to access clinical cancer trials and the potential benefits of cancer research.

Molecular and virologic characteristics of lymphoid malignancies in children with AIDS.

Purpose: To characterize AIDS‐associated lymphoid malignancies in children. Patients and Methods: We studied lymphomas and B‐cell leukemias from 25 children with AIDS for immunoglobulin heavy chain gene clonality, c‐myc oncogene abnormalities, and presence of HIV and Epstein‐Barr virus. Results: Monoclonal immunoglobulin gene rearrangements were identified in 22 of 23 cases tested, the single exception being one of mucosa‐associated lymphoid tissue. Immunoglobulin gene/c‐myc translocations were found in 3 of 4 cases of B (surface immunoglobulin‐positive)‐acute lymphoblastic leukemia, 8 of 11 small noncleaved cell lymphomas, and 1 of 5 large cell lymphomas. Mutations of c‐myc were found in 2 of 13 small noncleaved cell lymphomas, 1 of 2 Epstein‐Barr virus‐positive mucosa‐associated lymphoid tissue neoplasms, and 1 of 4 Epstein‐Barr virus‐negative B‐acute lymphoblastic leukemia. Six small noncleaved cell lymphomas, both mucosa‐associated lymphoid tissue neoplasms and one of large cell lymphoma had high levels of Epstein‐Barr virus in tumor tissue. Hodgkins disease tissue and B‐acute lymphoblastic leukemia tumors were negative for EBV. Proviral HIV‐1 was not detected in any tumor. Conclusions: AIDS‐associated lymphoid malignancies in children appear to have a different distribution of histologic subtypes than adult HIV‐infected individuals, fewer large cell lymphomas occur in children. The small noncleaved cell lymphomas exhibit a lower frequency as well as different locations of c‐myc mutations than AIDSassociated small noncleaved cell lymphomas in adults.