Ian Toogood

Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction

Methods to detect and quantify minimal residual disease (MRD) after chemotherapy for acute lymphoblastic leukaemia (ALL) could improve treatment by identifying patients who need more or less intensive therapy. We have used a clone-specific polymerase chain reaction to detect rearranged immunoglobulin heavy-chain gene from the leukaemic clone, and quantified the clone by limiting dilution analysis. MRD was successfully quantified, by extracting DNA from marrow slides, from 88 of 181 children with ALL, who had total leucocyte counts below 100 x 10(9)/L at presentation and were enrolled in two clinical trials, in 1980-84 and 1985-89. Leukaemia was detected in the first remission marrow of 38 patients, in amounts between 6.7 x 10(-2) and 9.9 x 10(-7) cells; 26 of these patients relapsed. Of 50 patients with no MRD detected, despite study of 522-496,000 genomes, only 6 relapsed. The association between MRD detection and outcome was significant for patients in each trial. In the first trial, patients relapsed at all levels of detected MRD, whereas in the later trial, in which treatment was more intensive and results were better, the extent of MRD was closely related to the probability of relapse (5 of 5 patients with > 10(-3) MRD, 4 of 10 with 10(-3) to 2 x 10(-5), 0 of 3 with levels below 2 x 10(-5), and 2 of 26 with no MRD detected). Early quantification of leukaemic cells after chemotherapy may be a successful strategy for predicting outcome and hence individualizing treatment in childhood ALL, because the results indicate both in-vivo drug sensitivity of the leukaemia and the number of leukaemic cells that remain to be killed by post-induction therapy.

Childhood cancer: a 4-year prospective study of the psychological adjustment of children and parents.

PURPOSE The objective of this 4-year prospective study was to assess the psychological adjustment of children treated for cancer and their parents. PATIENTS AND METHODS Children aged 2 to 12 years with cancer diagnosed and their parents and families (n = 39) were assessed immediately after their diagnosis and then annually for the next 4 years. At each assessment, the psychological adjustment of the children and their families was compared with the adjustment of a cohort of children and families in the general community (n = 49). RESULTS Immediately after the diagnosis of cancer in the children, the children and their parents had significantly more psychological problems than children and parents in the community. However, at subsequent assessments, there was no difference in the number of psychological problems experienced by children and parents in the two groups. CONCLUSIONS In the longer term, the prevalence of psychological problems experienced by children treated for cancer and their parents does not differ from that found in children and parents in the general community. Future research should give greater attention to other aspects of the lives of children treated for cancer and their parents, including their broader health-related quality of life.

Childhood cancer : A two-year prospective study of the psychological adjustment of children and parents

OBJECTIVE To follow prospectively the psychological adjustment of young children, parents, and families during the first 2 years after the childrens diagnosis of cancer. METHOD Children aged 2 to 5 years with cancer diagnoses and their parents and families (n = 38) were assessed immediately after diagnosis, 1 year after diagnosis, and 2 years after diagnosis. At each assessment, the psychological adjustment of the children and their families was compared with the adjustment of a cohort of children and families in the general community (n = 39). RESULTS Children with cancer and their parents experienced significantly more emotional distress than children and parents in the community during the period immediately after diagnosis. However, the number of problems experienced by the children with cancer and their parents declined during the first year after the childrens diagnosis and stabilized at a level comparable with that found among children and parents in the general community. CONCLUSION Although the results are consistent with reports that suggest that in the longer term the prevalence of psychological problems among children with cancer is similar to that found among children in the general community, they also highlight the considerable distress experienced by children and parents during the period immediately after the childrens diagnosis.

Excessive spinal cord toxicity from intensive central nervous system- directed therapies

Background. Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty‐three cases of myelopathy that occurred in patients who received intensive CNS‐directed therapy were evaluated to identify the determinants of this severe CNS toxicity.

Psychological adjustment of families of children and adolescents treated for leukemia.

This report describes a follow-up study in which the prevalence of emotional and behavioral problems in a group of 42 children and adolescents treated for leukemia is compared with the prevalence of problems in a matched control group selected from the general population. The prevalence of problems among the siblings of the two groups, and the adjustment of the two groups of families, are also examined. The Achenbach Child Behavior Checklist, for completion by parents, and the Achenbach Child Behavior Checklist and Rutter B2 Behavioural Scale, for completion by teachers, are used to identify both social competence and behavioral problems. In addition, the Family Concept Inventory is used to evaluate the adjustment of families. The leukemic children and adolescents were found to have significantly more problems and less social competence, particularly in school-related activities, than either the control group or their own siblings. There was no difference in the prevalence of problems between the two groups of siblings, nor between the two groups of families. It is suggested that careful prospective studies are needed to identify the cause of the problems experienced by the leukemic children and adolescents so that programs may be developed to prevent their emergence.

A 3-year follow-up of the intellectual and academic functioning of children receiving central nervous system prophylactic chemotherapy for leukemia

This prospective study compared the intellectual and academic functioning of two groups of children treated for cancer over the 3 years after their diagnosis. One group consisted of children who received central nervous system (CNS) prophylactic chemotherapy, and the other group consisted of children with cancer who did not receive CNS chemotherapy. The results suggest that the children who received CNS chemotherapy experienced more adverse effects from their treatment in the area of academic functioning than the children who did not receive CNS chemotherapy. Although there were no differences in the academic, functioning of the two groups of children immediately after their diagnosis, 3 years postdiagnosis, the CNS-treated children scored more poorly on academic tests of reading, spelling, and arithmetic than the non-CNS-treated children. The results suggest that CNS chemotherapy prophylaxis may impede academic achievement.

A prospective study of the psychological adjustment of parents and families of children with cancer

This study compared the psychological adjustment of parents and families of children with cancer, with the adjustment of parents and families in the community. In the weeks after their childrens diagnoses, the mothers of children with cancer reported significantly more anxiety and insomnia, somatic symptoms and social dysfunction than mothers in the community. These problems had declined by the time of a 1 year follow‐up assessment However, at the follow‐up assessment the mothers of children with cancer reported significantly more symptoms of depression and somatic symptoms than mothers in the community. A similar pattern of findings was evident among the fathers although the fathers generally reported less distress than was reported by the mothers. The results also suggest that a year after the childrens diagnoses, the families in which there was a child with cancer were functioning less effectively than the families in the community.

Monitoring minimal residual disease in peripheral blood in B-lineage acute lymphoblastic leukaemia

The use of peripheral blood rather than marrow has potential advantages for monitoring minimal residual disease during the treatment of leukaemia. To determine the feasibility of using blood, we used a sensitive polymerase chain reaction method to quantify leukaemia in the blood and marrow in 35 paired samples from 15 children during induction treatment. Leukaemic cells in the blood ranged from 1.1 × 10−2 to < 9.4 × 10−7 leukaemic cells/total cells, corresponding to 1.3 × 107 to < 2 × 103 leukaemic cells/l. In 15 paired samples, leukaemia could be quantified in both tissues and in 20 paired samples, leukaemia was not detected in one or both tissues so that only upper level limits could be set. In the former 15 pairs, the level of leukaemia in peripheral blood was directly proportional to that in marrow but was a mean of 11.7‐fold lower. Leukaemia in blood was detected in 10/12 pairs in which the level in marrow was > 10−4, but in only two of 13 pairs in which the level in marrow was < 10−5. Patients studied at multiple time‐points showed parallel declines in the number of leukaemic cells in both tissues. The results showed that leukaemia could be monitored in peripheral blood during induction therapy, and quantitative considerations based on the results suggest that monitoring of blood during post‐induction therapy may be of value in detecting molecular relapse.

Postoperative Chemotherapy in Children Less Than 4 Years of Age with Malignant Brain Tumors: Promising Initial Response to a Vetopec-based Regimen A Study of the Australian and New Zealand Children's Cancer Study Group (anzccsg)

Purpose: Postoperative chemotherapy with indefinite postponement of radiation therapy in children <4 years old with brain tumors was investigated in a multi-institutional study. Patients and Methods: From 1991 to 1995. 42 patients aged 3 to 47 months (median 20) with brain tumors were enrolled in a 2-phase chemotherapy protocol: 16 patients had medulloblastoma (MB); 8 had supratentorial primitive neuroectodermal tumor (PNET); 14 had ependymoma; and 4 had other tumors. The initial phase was comprised of 4 courses of the 3-drug regimen: vineristine (VCR), etoposide (VP-16). and intensive cyclophosphamide (CPA) in a previously reported schedule (VFTOPEC). The continuation phase was comprised of 2-drug courses: A. CPA + VCR: B. cisplatin + VP-16; and C. carbopfatin + VP-16, for a total duration of 64 weeks. Results: Response to VETOPFC was evaluable in 28 patients with postresection residual (25) and/or metastatic (1 M2, 6 M3) tumor. There were 9 complete responses (CR) and 9 partial responses (PR) with a combined CR + PR of 64% (95% confidence interval [CI] 44 to 81). In 12 evaluable patients with MB, CR + PR was 82% (48 to 98); in 6 patients with PNET. 50% (12 to 88); and, in 8 patients with ependymoma. 86% (42 to 99). Of 40 patients eligible for further analysis, 6 remain progressionfree at a median of 30 months, 14 are alive at a median of 38 months. 29 have progressed at a median of 7 months (range. 2 to 37 months), and 26 have died. The progression-free and overall survival rates at 36 months are estimated to be 11% (95% CI 1 to 22) and 34% (18 to 50). respectively. Conclusions: The initial response to the VETOPEC regimen is encouraging and warrants study of further dose escalation. Survival remains poor with current strategies in this high-risk population.

Longitudinal follow-up of the intellectual and academic functioning of children receiving central nervous system-prophylactic chemotherapy for leukemia: a four-year final report.

This longitudinal investigation extends our prospective study of the intellectual and academic functioning of children treated for cancer to 4 years after diagnosis. In the longer term, the children who received central nervous system (CNS) chemotherapy experienced greater neurocognitive deficits, particularly in the area of academic achievement, than did the children who did not receive CNS chemotherapy. Specifically, the CNS chemotherapy-treated children scored lower on academic tests of reading at 3 and 4 years after diagnosis. The results suggest that CNS chemotherapy prophylaxis may adversely effect the development of higher-order mental abilities and cognitive skills during the late-effects period and may also impair academic achievement.