The management of cancer in the older adolescent.

Cancer in adolescents 15-19 years of age occurs at nearly twice the rate observed in 5- to 14-year-olds, but as of yet they have no explicit organisation for research and care, such as that structured for younger paediatric patients. Adolescents with cancer must be recognised as a subgroup of oncology patients with specific characteristics and needs requiring dedicated interest and management. The need is made most evident as outcome data indicates that adolescents are lagging behind in survival gains made in recent decades by both children and adults with cancer. Improvements in the overall survival, quality of care and quality of survival of adolescents with cancer will only occur by surmounting the challenges, discussed in this review, unique to this group of patients.

Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium.

Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened in April 2000, at Government Camp, Mount Hood, Oregon. This meeting, which was supported by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders, brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. Optimizing chemotherapy delivery to the CNS is crucial, particularly in view of recent progress identifying certain brain tumors as chemosensitive. The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. This report summarizes the discussions, future directions, and key questions regarding dose-intensive treatment of primary CNS lymphoma, CNS relapse of systemic non-Hodgkin's lymphoma, anaplastic oligodendroglioma, high-grade glioma, and metastatic cancer of the brain. The promising role of cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies for malignant gliomas are discussed.

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995.

Since 1968, the Children's Cancer Group (CCG) has treated more than 16,000 children with acute lymphoblastic leukemia (ALL). Herein, we report improvements obtained in CCG trials during two successive series of studies (1983-1988 and 1989-1995). Overall, 10-year EFS was 62% +/- 10% for the 1983-1988 series and 72% +/- 1% for the 1988-1995 series (P< 0.0001). Five-year cumulative rates of isolated CNS relapses were 5.9% and 4.4%. Therapy based on the Berlin-Frankfurt-Münster 76/79 study improved outcomes for intermediate and higher risk patients in the first series. For intermediate risk patients, delayed intensification (DI) was most crucial for improved outcome and cranial irradiation was safely replaced with maintenance intrathecal methotrexate, providing patients received intensified systemic therapy. In the second series, randomized trials showed better outcome with one vs no DI phase for lower risk patients, with two vs one DI phase for intermediate risk patients, and with the CCG 'augmented regimen' for higher risk patients with a slow day 7 marrow response. Cranial irradiation was safely replaced with additional intrathecal methotrexate for higher risk patients with a rapid day 7 marrow response. In a subsequent study, substitution of dexamethasone in place of prednisone in induction and maintenance improved outcome for standard risk patients. All patients received dexamethasone in DI. These successful treatment strategies form the basis for our current ALL trials.

Epidemiologic impact of children with brain tumors.

The impact of CNS tumors during childhood and adolescence has been steadily increasing. In many countries, brain and spinal cord tumors are now second in frequency only to leukemia as a cancer affecting children, and the most common cause of cancer mortality in the young. In the United States, brain tumors are now more common than acute lymphoblastic leukemia, and the proportion of cancer deaths due to CNS tumors has nearly doubled during the past 25 years. Worldwide, approximately 30,000-40,000 children develop CNS tumors each year, and the majority do not survive. Compared with most other malignancies that occur during childhood, CNS tumors have not been treated with comparable success in treatment outcome. Also, no specific risk factor, or set of risk factors, has been identified to explain a substantial proportion of CNS tumor occurrence. In many countries, CNS tumors are now the greatest challenge in pediatric oncology.

Oral cancer chemotherapy in paediatric patients: obstacles and potential for development and utilisation.

Although most cancer chemotherapy in children is administered parenterally, oral formulations are becoming increasingly available for use in patients as young as infants. Incentives for this approach include safety, flexibility, reduced financial cost, improved quality of life, and the potential for improved efficacy. The ability to deliver chemotherapy at home and apply schedules of administration that increase the agent's efficacy because patients do not require hospitalisation or visits to the clinic renders oral chemotherapy particularly attractive. Obstacles to oral chemotherapy in paediatric patients include restrictions in dose size and schedule, uncertain or low bioavailability, adverse effects of malabsorption, and adherence (noncompliance and refusal to take oral chemotherapy). Techniques to overcome most of these limitations are available or can be developed, and lack of an oral formulation can be solved in many instances by the pharmaceutical industry. Future developments in oral chemotherapy should not be limited to adult patient applications.

Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study.

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 micromol*h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 micromol*h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P =.007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P =.043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

Phase II trial of topotecan administered as 72-hour continuous infusion in children with refractory solid tumors: a collaborative Pediatric Branch, National Cancer Institute, and Children's Cancer Group Study.

The antitumor activity of topotecan administered as a 72-h continuous i.v. infusion was evaluated in children with refractory neuroblastoma and sarcomas of soft tissue and bone. We also attempted to increase the dose intensity of topotecan by including an intrapatient dose escalation in the trial design. Ninety-three children (85 eligible and evaluable for response) with recurrent or refractory neuroblastoma, osteosarcoma, Ewing's sarcoma/peripheral neuroectodermal tumor, rhabdomyosarcoma, or other soft-tissue sarcomas received topotecan administered as a 72-h i.v. infusion every 21 days. The initial dose was 1.0 mg/m2/day, with subsequent intrapatient dose escalation to 1.3 mg/m2/day for those patients who did not experience dose-limiting toxicity after their first cycle of topotecan. There was one complete response in a patient with neuroblastoma (n = 26) and one partial response in a patient with Ewing's sarcoma/peripheral neuroectodermal tumor (n = 25). No complete or partial responses were observed in 17 patients with osteosarcoma, 15 patients with rhabdomyosarcoma, or 2 patients with other soft-tissue sarcomas; however, 8 patients had prolonged (15-48 weeks) stable disease while receiving topotecan. Topotecan was well tolerated. The most commonly observed toxicities were myelosuppression (dose-limiting) and nausea and vomiting. Intrapatient dose escalations were performed in 68% of the patients who received more than one cycle of topotecan, and 1.3 mg/m2/day was tolerated by 79% of the patients who received the higher dose and were evaluable for hematological toxicity. In conclusion, topotecan administered as a 72-h continuous infusion every 21 days is inactive (objective response rate, < 20%) in children with refractory or recurrent neuroblastoma and sarcomas of soft tissue or bone.

Neuroblastoma screening in the United States: results of the Texas Outreach Program for neuroblastoma screening.

BACKGROUND: Mass screening of infants for neuroblastoma began in Japan after studies suggested that survival rates could be improved by early detection. This study was initiated in 1991 to test the methodology and feasibility of screening for neuroblastoma within the U. S. health care system. METHODS: Infants ages 5-10 months (mean age, 9 months, 25 days) who were born in Texas were screened for neuroblastoma. An enzyme-linked immunoadsorbent assay (ELISA) for homovanillic acid (HVA) and vanillylmandelic acid (VMA) used to quantify the HVA and VMA was performed on urine extracted from specimens dried on filter paper. Infants were recruited to participate in the study by several methods, and the effectiveness of each method was determined by calculating compliance rates. RESULTS: Between February 1991 and June 1994 a total of 14,046 infants were recruited to participate in neuroblastoma screening. Neuroblastoma was detected in 2 children for an incidence rate of 1 in 7023. A total of 291,158 screening kits were distributed to the parents of these infants, resulting in an overall compliance rate of only 4.8%. Compliance rates varied by method of distribution of the test kits: Houston Women, Infants, and Children (WIC) clinic (53%), volunteers (31%), Rio Grande Valley WIC clinics (14.5%), the patient's private physician (9.9%), and by mail (4.7%). CONCLUSIONS: Early detection of neuroblastoma in infants ages 5-10 months was achieved using ELISA. Compliance rates were poor, but clinics with a preventive health focus, such as the WIC clinics, achieved higher compliance rates than did private physicians.

Conduct of phase I trials in children with cancer.

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.

Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group.

BACKGROUND: Children with acute lymphoblastic leukemia with multiple poor prognostic factors and who have a lymphomatous mass at diagnosis, whether of T- or non-T-immunophenotype, are at increased risk of short term remission and extramedullary recurrence, and are in need of better therapies. METHODS: Six hundred and ninety-four eligible patients ranging in age from 1-20 years were entered on the study. Sixty-five percent of the patients had T-cell immunophenotype. Of these, 678 were randomized to one of four regimens: Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D: the New York (NY) regimen. RESULTS: Complete remission was induced in 97% of patients. The overall event free survival (EFS) +/- the standard deviation was 60 +/- 4% 6 years after diagnosis, in contrast to 36 +/- 6% in a comparable historic group. The EFS of the 371 T-cell patients was 62 +/- 7%. EFS was best on the NY (67 +/- 7%) and the BFM (67 +/- 6%) arms. These were significantly better than the EFS on the 2 LSA-L2 regimens, with an EFS of 53 +/- 8% (Regimen B) and 42 +/- 11% (Regimen C) (P = 0.03 and 0.0003 for NY vs. Regimen B and NY vs. Regimen C; P = 0.01 and 0.0001 for BFM vs. Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central nervous system (CNS) recurrence rate than the identical chemotherapy Regimen B (16 +/- 5% vs. 6 +/- 4%; P = 0.02), although the difference in overall EFS did not reach the required level for significance. Testicular recurrence varied from 2-8% in comparison with 20% in the historic group. EFS was not influenced by age, gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition to treatment regimen and early response rate, initial leukocyte count, hemoglobin level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal mass had univariate prognostic influence on EFS. In multivariate analysis, only the kinetics of response, leukocyte count (unfavorably, P < 0.0001), and mediastinal mass status (favorably, P = 0.01) were prognostic. CONCLUSIONS: The adverse prognostic implications of lymphomatous ALL can be minimized by the NY and BFM regimens. Cranial irradiation resulted in better CNS disease control when added to the LSA2-L2 regimen, but did not improve the overall disease free survival. With improved systemic chemotherapy, there was no excess of lymph node, testicular, or other local recurrence without prophylactic irradiation to sites of initial bulk disease or to the testes.

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 Children's 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.

Infant cancer in the U.S.: histology-specific incidence and trends, 1973 to 1992.

BACKGROUND: Many cancers in infants demonstrate unique epidemiologic, clinical, and genetic characteristics compared with cancers in older children. Few epidemiologic reports, however, have focused on this important age group. METHODS: Population-based data from the Surveillance, Epidemiology, and End Results (SEER) program were used to estimate relative frequency, incidence rates, and average annual percentage change of rates among children in their first year of life (infants) who were diagnosed with a malignant neoplasm from 1973 to 1992 (N = 1461). RESULTS: The greatest proportion of cases (12%) was diagnosed during the first month of life, with extracranial neuroblastoma accounting for 35% of this total. Overall, the average annual incidence rate was 223/1,000,000 infants. Extracranial neuroblastoma was the most common infant malignancy (58/1,000,000 infants per year), followed by leukemias (37/1,000,000), brain and central nervous system (CNS) tumors (34/1,000,000), and retinoblastoma (27/1,000,000). White infants had a 32% higher incidence rate than black infants. The average annual percentage increase in rates for all cancer from 1973 to 1992 was 2.9% (95% CI: 1.9%, 3.8%). For neoplasms with at least 100 cases, increasing trends were greatest for retinoblastoma (4.6%), CNS (4.1%), and extracranial neuroblastoma (3.4%). CONCLUSIONS: Incidence rates increased notably over the study period. Future studies should consider the unique presentation of infants with cancer when developing new hypotheses related to cancer etiology and gene-environment interactions.

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 Children's 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.

The U.S. pediatric cancer clinical trials programmes: international implications and the way forward.

The four national paediatric cancer clinical trials organisations in the United States--the Children's Cancer Group, the National Wilms' Tumor Study Group, the Intergroup Rhabdomyosarcoma Study Group and the Pediatric Oncology Group--were formed in 1955, 1969, 1972 and 1979, respectively. Together, the Children's Cancer Group and Pediatric Oncology Group serve as a national registry of nearly all childhood cancers in the United States, provide a national network of communication for researchers, care providers and families of paediatric patients with malignant disease and conduct laboratory investigations and clinical trials of new treatments of cancers in infants, children, adolescents and young adults. Nearly 95% of patients with cancer in the United States who are below 15 years of age are registered by the Children's Cancer Group and the Pediatric Oncology Group and more than half of American children with cancer are entered into at least one trial by a paediatric group. Improved survival of children receiving treatment according to well-defined protocols in specialised children's centres, in contrast to children who received treatment outside of these centres, has been shown for those with acute lymphoblastic leukaemia, lymphoma, Wilms' tumour, medulloblastoma, rhabdomyosarcoma and Ewing's sarcoma. By the year 2000, the overall cure rate for United States children and adolescents with cancer should exceed 85%. To reach this goal, the way forward will depend on international collaboration, implementation of global harmonisation, prevention of the erosion of biomedical research and clinical trials by the managed health care industry, increased public and private financial support and continued recruitment into paediatric oncology of brilliant and dedicated young investigators. The specific challenges ahead include: (1) transferring the knowledge, methodologies and technologies to countries that are less fortunate; (2) conducting multinational clinical trials in conjunction with paediatric cooperative groups in other countries; (3) accessing older adolescent patients who currently do not participate in cooperative group trials; (4) merging clinical trials by adult collaborative groups that overlap with the paediatric groups, as in acute lymphoblastic leukaemia, acute myelogenous leukaemia, Hodgkin's disease, osteosarcoma and germ cell tumours; (5) establishing a stable source of funding for national and international cooperative paediatric cancer clinical trials; (6) creating an informatics system that can link paediatric cooperative group operation centres around the world, and the institutions within each collaborative group; and (7) securing the support of the insurance industry and government in covering clinical trials.

Accidental intramuscular vincristine: lack of untoward effects and recommendations for management.

Vincristine was inadvertently injected into a thigh of three children. In each case the accident occurred as a result of the mixing of a syringe containing vincristine with a syringe of L-asparaginase which the patient was scheduled to receive on the same day. Within minutes, each patient was treated topically with cold compresses and the area was infiltrated with a solution of 8.4% sodium bicarbonate. Only one patient had discomfort of the thigh after the injection, none of the patients have had any sequelae, either acute or delayed. Measures to avoid mistaken injection of vincristine for asparaginase are readily achievable and have prevented recurrences of intramuscular vincristine administration at the institutions where they have been implemented. Nonetheless, other instances of intramuscular vincristine injection are anticipated and should be rapidly recognized and quickly managed with local applications of cold and sodium bicarbonate.