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We describe the outcome of children with B-precursor acute lymphoblastic leukemia registered on Pediatric Oncology Group 8602 who switched to Erwinia asparaginase (ASP) due to an allergy to the Escherichia coli product. Between February 1986 and January 1991, children in complete remission after induction that included intramuscular E. coli ASP (6000 U/m2x6) were randomized for consolidation. One regimen included intensive weekly intramuscular E. coli ASP (25,000 U/m2/wkx24). In case of an allergic reaction to E. coli ASP, Erwinia ASP was substituted at the same dose and schedule. Of the 540 eligible patients, 408 switched to Erwinia ASP due to an allergic reaction. Allergic reactions were significantly associated with younger age, white race, and standard-risk acute lymphoblastic leukemia. Multivariate Cox analysis adjusting for these factors demonstrated no correlation between the switch per se or the timing of the switch and event-free survival.

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.

Background: Growth factor use has been shown to ameliorate chemotherapy-induced neutropenia, leading to shorter hospital stays and lower use of parenteral antibiotics, two costly areas of cancer treatment. Prior reports on pediatric patients have shown evidence of cost savings in some studies, but no such evidence in others. In this study a retrospective analysis compared the costs of inpatient supportive care for pediatric patients with T-cell leukemia and advanced lymphoblastic lymphoma enrolled in a Pediatric Oncology Group trial., Procedure: Patients 1-22 years of age were randomized to receive either granulocyte colony-stimulating factor (G-CSF; n = 45) or no G-CSF (n = 43) following induction and two cycles of maintenance therapy. There were no significant differences in neutropenia-related outcomes during the induction phase. During maintenance therapy, G-CSF patients had significantly fewer days to an ANC >500 cells/microl and a trend towards fewer days of hospitalization. Data on resource utilization were tabulated from case report forms. Costs were imputed from national data on hospitalization costs, average wholesale prices of pharmaceuticals, and patient billing information from a single institution., Results: Total median costs of supportive care were $34,190 for patients receiving G-CSF and $28,653 for patients not receiving G-CSF (P > 0. 05 for the cost difference). Sensitivity analyses demonstrated that the total cost difference was not statistically significant, even in scenarios that included reasonable variations in estimates of the range of the length of stay, antibiotic regimen, and dosage and cost of G-CSF., Conclusions: In the setting of pediatric leukemia, the cost of growth factor may offset potential savings from shorter hospital stays or lower antibiotic use, a finding consistent with that from the Children's Cancer Study Group., (Copyright 2000 Wiley-Liss, Inc.)

Purpose: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment., Methods: Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (<1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (> or =3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group., Results: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively., Conclusion: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.

Purpose: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL)., Patients and Methods: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C)., Results: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A., Conclusion: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).

Purpose: In childhood B-precursor acute lymphoblastic leukemia (ALL), possible interactions among sex, time, and widely used prognostic factors (age, WBC count, and DNA index) were investigated for the first 5 years after diagnosis., Patients and Methods: All eligible patients aged 1 to less than 22 years, registered between February 1986 and September 1994 in two B-precursor ALL studies from the Pediatric Oncology Group (POG), were included in the analysis. Cutpoints for age (3.0, 5.0, and 10.0 years), WBC count (10, 50, and 100 x 10(9)/L), and DNA index (DI; 1.16) were defined. Four time periods after diagnosis (years 1, 2, 3, and 4 and 5 combined) were selected for the study of prognostic significance over time. The cut-off date for analysis was April 1996., Results: A total of 3,717 children (2,010 boys and 1,707 girls) were included in the outcome analysis. No major differences between the sexes were observed in age, duration of symptoms before registration, WBC count, hemoglobin level, platelet count, ploidy, presence of CNS disease at diagnosis, or induction failure rate. Event-free survival (EFS) differences between sexes became significantly different from 2 years following diagnosis. At 5 years, in all subsets analyzed, boys fared worse than girls, although not all differences were statistically significant. Major sex differences in EFS were observed in older children (10 to 22 years), in patients with intermediate WBC counts (10 to 50 x 10(9)/ L), and in children who fit both of these subgroups, in whom the 2-year EFS was almost 20% higher in girls than in boys, reaching a 38% difference at 5 years., Conclusion: This study shows an outcome interaction among sex, time, and commonly used prognostic variables. The important sex difference observed at 2 and 5 years suggests that more intensive consolidation and/or maintenance therapy in some boys with B-precursor ALL should be investigated.

TEL gene rearrangement is the most common genetic lesion in pediatric acute lymphoblastic leukemia (ALL), occurring in about 25% of B-lineage cases. We previously showed that, among patients treated on St Jude protocols, TEL rearrangement independently conferred an excellent prognosis. To extend these results to patients treated with antimetabolite-based therapy, we performed Southern blot analysis to determine the TEL gene status of 104 cases of B-lineage ALL treated on Pediatric Oncology Group 8602, matched on age, gender, and leukocyte count. There were 52 failures among the 77 patients with germline TEL, compared with only 8 failures among 27 patients in the rearranged group. Based on a two-sided logistic regression analysis, stratified for age (subdivided at 10 years), leukocyte count (subdivided at 50,000), and gender, the estimated odds of failing by 4 years in the germline TEL group is 5.4 times that of the rearranged TEL group, with 95% confidence from 1.9 to 15.6, two-sided P = .0009. Thus, the presence of a rearranged TEL gene is also associated with an improved survival among patients treated with antimetabolite-based therapy. Our results indicate that all newly diagnosed ALL patients should be screened for TEL gene rearrangements and suggest that these patients are candidates for less intensive therapy.

Since it is unclear whether methotrexate and cytarabine are synergistic or antagonistic in the treatment of acute lymphoblastic leukemia, the Pediatric Oncology Group studied the prognostic significance of a potential interaction between these agents. RBC methotrexate concentrations were compared from 140 patients at lower risk of relapse randomized to two treatment groups: one receiving six methotrexate infusions with overlapping cytarabine; the other, six methotrexate infusions alone. Samples from 248 patients from all risk groups were studied to determine whether patients with extremely low RBC methotrexate concentrations had inferior outcomes. Among low-risk patients studied 3 weeks after the sixth infusion, median RBC methotrexate concentrations were 0.13 nmol/ml RBCs (n = 71) for the methotrexate-only group and 0.02 nmol/ml RBCs (n = 69) for the methotrexate/cytarabine-treated low-risk patients, P < 0.001 by the two-sided Wilcoxon test. For low- and high-risk patients receiving methotrexate/cytarabine infusions, event-free survival at 1 and 3 years after RBC sampling was 97 +/- 2% and 90 +/- 3% for patients with concentrations greater than the median, and 88 +/- 3% and 78 +/- 4% for those with concentrations at or below the median. Log rank comparisons of event-free survival in the first year and overall yielded P = 0.005 and P = 0.04, respectively. Cytarabine altered methotrexate pharmacology when the drugs were infused together. Patients whose levels were extremely low had an adverse prognosis. Although this study could not assess efficacy of the methotrexate/cytarabine combination, it appears that concurrent administration is not optimal.

Purpose: To compare efficacy and toxicity of two schedules of intermediate-dose methotrexate (IDM) and cytarabine (Ara-C) in remission consolidation of childhood acute lymphoblastic leukemia (ALL)., Patients and Methods: In 1986, the Pediatric Oncology Group (POG) began a randomized trial to test two schedules of consolidation chemotherapy in children with newly diagnosed B-precursor cell ALL. MTX and Ara-C were given as overlapping 24-hour infusions. The dose and sequence of MTX and Ara-C administration were based on a preclinical model that had demonstrated synergism between these two agents. Two hundred fifteen patients in complete remission were randomized to front-loading consolidation therapy in which six MTX/Ara-C infusions were administered at 3-week intervals from the 7th through the 19th week of therapy. Two hundred thirteen patients in complete remission were randomized to receive standard consolidation therapy in which the six MTX/Ara-C infusions were given every 12 weeks from the 7th through the 67th week of therapy., Results: Both regimens produced similar rates of adverse side effects, except for a higher incidence of CNS toxicity in individuals randomized to the front-loading arm (32 of 215 v 12 of 213 patients, P = .002). Leukoencephalopathy occurred in three patients on the front-loading regimen and was permanent in one. By Kaplan-Meier analysis, the probability of continuing in complete remission for 5 years was 79% (SE = 5%) and 85% (SE = 5%) for good-risk patients, and 66% (SE = 6%) and 61% (SE = 7%) for poor-risk patients randomized to front-loading and standard regimens, respectively., Conclusion: Although differences in complete remission durations were not statistically significant by log-rank analysis (P = .62 for good-risk patients, .89 for poor-risk patients, and .99 overall), the results are comparable to those in previous studies using more toxic agents as components of remission consolidation therapy.

This paper provides methods for storing and retrieving cytogenetics data, which must reside jointly in a reference laboratory and in a data co-ordinating center. The major piece of data is the character string that uses the International System for Human Cytogenetic Nomenclature. Simple and complex data retrieval, using Statistical Analysis System (SAS) functions INDEX and SUBSTR, are illustrated. Use of the methods of this paper can save considerable costs in setting up cytogenetic data systems compared with other proposed systems which have come to the authors' attention.

Purpose: Immunophenotypes and karyotypes of leukemic cells were analyzed in a large series of Down syndrome patients with acute lymphoblastic leukemia (ALL) to examine the frequency of adverse prognostic features in comparison with other patients with ALL., Patients and Methods: Presenting features and leukemic cell characteristics were compared for 76 patients with Down syndrome and 4,733 other patients with newly diagnosed ALL treated on protocols of the Pediatric Oncology Group (POG) and St Jude Children's Research Hospital (SJCRH). Treatment outcome was analyzed for the patients with non-T-cell disease enrolled on a single trial, for whom adequate follow-up data were available., Results: Down syndrome patients had lower platelet counts (P < .01) and were less likely to have an anterior mediastinal mass (P < .01) or CNS leukemia (P = .01). They were significantly more likely to have the pre-B immunophenotype (49% v 25.5%, P < .01) and less likely to have T-cell ALL (5.5% v 16%, P = .01). There was a notable absence among patients with Down syndrome of the t(4;11), t(1;19), and t(9;22), which are chromosomal translocations associated with an adverse prognosis in ALL. Treatment outcome did not differ significantly between patients with Down syndrome and the other children with non-T-cell ALL (P = .21); a third of the treatment failures in the former group resulted from treatment-related toxicities., Conclusion: Children with Down syndrome and ALL had a low frequency of adverse clinicobiologic features at diagnosis. However, these findings did not translate into a superior outcome, apparently because of treatment-related toxicity in this group. Future trials should focus on pharmacokinetics and other strategies to reduce toxicity in these compromised patients.

Structural rearrangements involving the short arm of chromosome 12 occur in 10% of cases of childhood acute lymphoid leukemia. The translocation t(12;17)(p13;q21), an uncommon 12p abnormality, was identified in five of 2620 cases (0.2%) successfully karyotyped by the Pediatric Oncology Group or St Jude Children's Research Hospital. All five cases were classified as early pre-B; however, CD10 (common acute lymphoblastic leukemia antigen) was expressed at lower levels than other markers of B-cell lineage. Two cases also expressed the myeloid-associated antigen CD33. Leukemic cells were pseudodiploid in four cases, with an extra chromosome 21 in the fifth case. All of these patients achieved complete remission. Two relapsed during subsequent therapy, and three remain in continuous remission for greater than or equal to 20 months.

Chromosome banding studies of 1,411 children with newly diagnosed acute lymphocytic leukemia (ALL) identified two patients with the t(2;14)(p13;q32) chromosome abnormality and a third patient with a complex three-way translocation involving the same breakpoints on chromosomes 2 and 14 but also involving chromosome 12 at band q11. The three cases demonstrated variability of immunophenotypes: one was a T-cell ALL, and two were early pre-B ALLs. All three patients achieved complete remissions and have remained in remission for 14-19 months.

Second malignant neoplasms (SMN) in late childhood or young adulthood in individuals who have been successfully treated for an initial malignancy have emerged as a late effect of therapy in survivors of childhood cancer. Although radiation therapy is frequently implicated, chemotherapy with alkylating agents and antimetabolites has also been associated with SMN. Soft tissue sarcomas are among the most frequent primary malignancies complicated by a SMN and account for a majority of nonhematolymphoid SMN. We present the clinical and pathologic findings in a patient who had a peripheral neuroepithelioma (primitive neuroectodermal tumor, PNET) of the soft tissues diagnosed at 17 years of age, was treated with high-dose irradiation and multidrug chemotherapy, and developed an angiosarcoma 14 years later. This case represents an uncommon combination of mesenchymal malignancies in a young patient with an unusually favorable clinical course following the diagnosis of PNET.

Recurrent or induction therapy-resistant ANLL carries a grave prognosis. The combination of AMSA at 100 mg/M2 daily for 5 days and etoposide at 200 mg/M2 daily for the first 3 days of therapy was given to 40 patients with refractory ANLL. An additional 17 patients received those two agents plus azacitidine at a dosage of 250 mg/M2 on days 4 and 5. All three drugs were given as one-hour infusions. All patients had normal electrolyte determinations daily and were on cardiac monitors during the period of drug administration. No arrhythmias were detected in 522 doses of AMSA. Toxicities observed were primarily related to myelosuppression. Forty-nine of the 57 patients required hospitalization for suspected or proven infection. Nausea/vomiting and mucositis were the next most commonly occurring toxicities. Responses were seen in 22 patients.

One hundred six children with newly diagnosed non-T-, non-B-cell acute lymphoblastic leukemia (ALL) were treated in a Pediatric Oncology Group (POG) pilot study in which six courses of intermediate-dose methotrexate (MTX) and cytosine arabinoside (Ara-C) (1 g/m2 each) were added to a "backbone" of standard continuation therapy. The dose and sequence of MTX/Ara-C administration were based on a preclinical model that demonstrated synergism between MTX and Ara-C. Poor-risk patients (n = 49) were assigned to "up-front" therapy, in which the MTX/Ara-C courses were administered during the initial 15 weeks of remission. Standard-risk patients (n = 57) were assigned to "spread-out" therapy, in which the MTX/Ara-C courses were interspersed at 12-week intervals within continuation treatment. Toxicity after intermediate-dose MTX/Ara-C, principally neutropenia and fever, was judged significant but manageable. Unexpectedly, the incidence of fever and neutropenia less than 500/mm3 was greater after "spread-out" therapy (38%) than after "up-front" therapy (6%). At 4 years, the Kaplan-Meier estimate of event-free survival (EFS) is 71% (+/- 7%) for standard-risk patients and 53% (+/- 8%) for poor-risk patients. The results of this pilot study support the use of intermediate-dose MTX/Ara-C in additional studies.

Between January 1979 and April 1983, 113 children undergoing their first relapse of acute lymphoid leukemia (ALL) at any site were registered in Pediatric Oncology Group study 7834; 98 were eligible and evaluable. In addition to radiotherapy administered to sites of local relapse, induction consisted of vincristine, doxorubicin, and prednisone (VAP) chemotherapy. Continuation therapy consisted of triple-drug intrathecal therapy and regimens of 6-thioguanine and cytarabine alternating with vincristine, prednisone, cyclophosphamide, and cytarabine. Randomization in continuation was between VAP pulses or no pulse, regardless of the site of relapse. This report provides long-term follow-up of these patients. Thirty-two of 39 children with bone marrow involvement achieved a complete response (CR). Only one of these is alive in an unmaintained remission, a child who did not have an initial CR. Thirty-four of 36 evaluable children with central nervous system involvement as the site of relapse achieved CR. Of these ten are alive; eight are in continuing CR. Nineteen of 20 boys with testicular relapse achieved CR. Of these, 14 are still alive and not receiving therapy, although only one half received treatment in compliance with the protocol described. These results illustrate the possibility of cure of patients who have relapsed with ALL when it is (1) confined to a meningeal or gonadal site and (2) treated vigorously with radiotherapy and a new regimen of systemic chemotherapy. The results reconfirm the need to prevent an initial relapse at any site.

We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.

Eighty-seven children with central nervous system (CNS) leukemia were randomized to receive either induction intrathecal chemotherapy (ITC) and cranial irradiation (CRT) plus maintenance ITC, or induction ITC and craniospinal irradiation (CSpRT) with no maintenance ITC. ITC consisted of six weekly injections of methotrexate, hydrocortisone, and arabinosylcytosine. Also, intensification of systemic induction and maintenance chemotherapy was given. CRT + ITC was given as CRT, 2400 rad in 12 fractions followed by ITC maintenance bimonthly for 2 years. Craniospinal irradiation consisted of CRT + 1400 rad in ten fractions to the spine. Randomization was stratified according to whether CNS leukemia occurred at initial diagnosis of acute lymphocytic leukemia (ALL) (Stratum I, 15 patients), during first bone marrow (BM) remission (Stratum II, 49 patients), simultaneous with first BM relapse (Stratum III, 12 patients), or during second BM remission (Stratum IV, 11 patients). The median follow-up for patients who remain at risk is 15 + months. Eight children (seven on CRT + ITC, one on CSpRT) developed presumed therapy related encephalopathy. In Stratum II, 16 of 29 (55%) patients receiving CRT + ITC experienced adverse events: 3 deaths during continuous complete remission (CCR) and 13 relapses (2 CNS, 1 CNS + BM, 1 BM + testes, and 2 testes) as compared with only 5 relapses in 20 (25%) patients on CSpRT (1 CNS, 1 CNS + BM, 1 BM, and 2 testes). The children on both regimens were comparable for sex, race, age at initial ALL diagnosis, time from ALL diagnosis to first episode of CNS leukemia, systemic therapy both before and after CNS relapse, and number of blasts in the spinal fluid at diagnosis of CNS leukemia. The conclusion is that children with isolated CNS leukemia can achieve prolonged survival with aggressive therapy, and that CSpRT is possibly less toxic and more likely than is CRT + ITC to prevent subsequent BM and testicular relapse (P less than 0.02), but not subsequent CNS relapse (P = 0.7). A possible systemic therapy effect of spinal irradiation is postulated to explain the superiority of CSpRT.

Eleven patients with osteogenic sarcoma (9), Hodgkin disease (1), and mesenchymal sarcoma (1), were treated with 5-fluorouracil (5-FU) and cisplatin (DDP). Myelosuppression and vomiting of variable degrees occurred in all. No responses were seen.

Seventy-three patients under 18 years of age with a recurrent central nervous system tumor were randomized to receive combination chemotherapy with MOPP or OPP. Patients were stratified according to the tumor type into four major disease categories: (1) medulloblastoma, (2) astrocytoma and other glioma, (3) ependymoma, and (4) miscellaneous tumors to provide equal distribution of patients for each treatment within each disease category. Evaluation of response was based on computerized brain scan findings. Thirty-five patients received MOPP and 38 received OPP treatment. There were three complete and six partial remissions among patients receiving MOPP and one complete and five partial remissions among patients receiving OPP. In addition, six patients on MOPP had stable disease for seven to 21 months. Only two patients on OPP had stable disease(6 and 36 months). Most of responses in both treatment regimens occurred in patients with medulloblastoma and astrocytoma. Median duration of remission was nine months for the MOPP and 11 months for the OPP. Two patients on MOPP regimen had fatal myelosuppression. Although the more toxic MOPP regimen produced more responses than OPP in children, differences in the duration of response or survival were not statistically significant (P = .79 and P = .84, respectively).

One hundred four children with advanced leukemia in relapse (74 with acute lymphocytic leukemia [ALL] and 30 with acute nonlymphocytic leukemia [ANLL]) received AMSA (4'-(9-Acridinylamino) methanesulfon -m-anisidide) at a dose of 120 mg/m2/day for 5 days (Regimen I) or 60 mg/m2/day for 10 days (Regimen II). Children with ALL were randomized between Regimens I and II (31 and 36 evaluable patients, respectively). All 29 evaluable patients with ANLL were treated on Regimen I. Eighty-eight percent of evaluable patients experienced severe or life-threatening toxicity, with no statistical differences between Regimens I and II. Bacterial or fungal infections (considered life-threatening or fatal) occurred in 17 children with ALL and in 7 with ANLL. Fatal cardiac toxicity occurred in one patient. Complete or partial response occurred in 25.0% (SE = 8.8%), 28.1% (SE = 8.0%), and 25.9% (SE = 8.4%) of evaluable patients on ALL Regimen I, ALL Regimen II, and ANLL, respectively. However, responses were of short duration (16-91 days). There was no significant difference in the duration of survival from treatment start for the two ALL regimens (P = 0.46). The median duration of survival for ANLL patients was significantly longer (P = 0.004) than that of ALL patients treated on Regimens I and II combined. Eighty-two percent of the complete or partial responses (18 of 22) occurred after the first course of AMSA. At the dose schedules investigated, and in a heavily pretreated patient population, AMSA had activity in childhood leukemia. However, the high incidence of severe, life-threatening, or fatal infections meant that the quality and quantity of responses and survival was not commensurate with the toxicity, and that it would be difficult to incorporate this drug into combination chemotherapy with other myelosuppressive agents.

Twenty-six children greater than 1 year of age with previously untreated stage IV neuroblastoma were randomized to receive either a five-drug regimen (prednisone, cyclophosphamide, actinomycin D, vincristine, and daunorubicin) or a two-drug regimen (cyclophosphamide and vincristine). Complete response rates were 6% and 9% for the five-drug and the two-drug regimens respectively. Partial response rates were 13% and 27% for the five-drug and the two-drug regimens respectively. The mean duration of the seven responses was 9 months, and all 26 patients had died within 2 years. Neither regimen was effective for long-term disease control in these children with neuroblastoma.

The "late" relapse patterns of childhood acute leukemia were studied in 83 children in their first continuous complete remission for more than three years prior to randomization for stopping therapy (40 patients) or continuing therapy (43 patients) for a total of six years. Twenty of 83 (22.9%) have relapsed: Ten in the bone marrow, one in the central nervous system, and nine in the testes. The testes relapse rate of 41.1% (7/17) in males discontinuing therapy at three years was much higher than that of 8.7% (2/23) in males continuing therapy. This difference is significant at P = 0.01 (Wilcoxon test).

Between 1949 and 1978, 119 children with the diagnosis of neuroblastoma or ganglioneuroblastoma were treated at the Washington University Medical Center. Of these, 50 (41%) were alive and disease-free 3 or more years after diagnosis. Important prognostic variables included stage of tumor (Evans staging), histology, age at diagnosis, and site of primary tumor. A stepwise logistic regression analysis of these data has shown that, in order of significance, stage, histology and age at diagnosis are independent prognostic variables. Sex of the patient and nodal status at diagnosis (where known) were not significant prognostic variables. No effects of individual treatment modalities could be detected. This study confirms the overwhelming influence of factors unrelated to treatment in determining the prognosis of neuroblastoma.

Plasmapheresis has been shown to reduce total and free bilirubin levels in acute exacerbations of Crigler-Najjar syndrome, type I (CNS-TI), but its effectiveness in long-term management has not been reported. An 18-year-old (yo) male with CNS-TI, who required prolonged daily high-intensity phototherapy to prevent cerebral nervous system symptoms, developed increasingly frequent bouts of confusion, nausea, and vomiting associated with free bilirubin concentrations (fbcs) greater than 10-15 nmol/L. Pending consideration of orthotopic liver transplantation, plasma exchange (approximately 3 liters per procedure) was begun in 12/84 using the IBM/COBE 2997 with 5% albumin as replacement fluid. Frequency of treatments was guided by twice weekly fbcs, with plasma exchange for fbc greater than 10-15 nmol/L. Pre-exchange and postexchange fbcs ranged from 27.5 to 11 nmol/L and 9.2 to 2 nmol/L, respectively. Seventy-two exchanges were performed over a 28 month period. Irreversible CNS damage did not occur, and the patient underwent successful liver transplantation in April of 1987, with complete correction of his metabolic disorder. He remains well 18 months following transplantation.

Members of Childrens Cancer Study Group and the Pediatric Division of the Southwest Oncology Group conducted a study of chemotherapy for children with malignant liver tumors. All patients received vincristine, cyclophosphamide, Adriamycin and 5-fluorouracil in 6 weekly cycles for one year. Surgical resection and irradiation were employed when indicated. Between January 1976 and August 1978, 62 patients were entered on study; one was rejected for a protocol error, and ten had inadequate trials of chemotherapy, dying within one month of entry. The median time on study for all patients was 12 months. Twenty-four patients had no measurable disease following surgical treatment and chemotherapy was employed as adjuvant treatment; 20/24 (83%) remain relapse-free from 8-42+ months, (median, 30 months). In 27 patients, residual measurable disease was available to determine the response to chemotherapy. The response rate was 12/27 (44%), lasting 3-45 months (median, 18 months). The median follow-up of all survivors is 30 months. Hematologic toxicity was significant, particularly during the initial courses of chemotherapy; 28/57 patients developed severe toxicity which was fatal in three. The results from the current study were compared to those from a previous one initiated in 1972, in which actinomycin D, vincristine, and cyclophosphamide were given in sequence, one during each month for one year. Although the population of the two studies was not identical, there was a difference in the response rates (P = 0.02), relapse-free interval (P = 0.008), and survival (P = 0.003). The most striking improvement was seen in the patients with Group I disease, there were 7/11 relapses in the first study and 1/16 in the current one.

A 14-year-old boy survived for 7 years after the initial diagnosis and treatment of acute lymphocytic leukemia. Neurologic deterioration occured repeatedly throughout his complicated clinical course but it was most severe and only partially reversible following orally administered pyrimethamine. The neuropathologic lesions were distinctive and included a diffuse reactive astrocytosis, axonal degeneration, status spongiosis, circumscribed foci of demyelination and coagulative necrosis, and mural thickening with luminal narrowing of microcirculatory vessels. This collection of findings represents the leukoencephalopathy of childhood leukemia that we and others believe results in large part from the combined effects of cranial irradiation and chemotherapy. The role of folic acid antagonists, namely methotrexate and pyrimethamine, are particularly noteworthy in this regard.

To determine optimal dosage, Dihydroxyanthracenedione (DHAD) was given once daily for 3 days at dosage levels of 6, 7, 8, and 10 mg/m2 in combination with a 7-day continuous infusion of cytosine arabinoside (Ara-C). Nineteen of 20 children with leukemia who received these agents developed fever requiring hospitalization. There were 4 deaths-2 due to proven infection. One patient developed nonfatal cardiotoxicity. No other significant toxicity was noted. Responses were seen in 7 of 20 patients. The recommended DHAD dosage was 8 mg/m2/day when given in combination with Ara-C.

Between June 1977 and December 1978, occult testicular leukemia (OTL) was discovered at three years of continual complete remission (CCR) from the time of diagnosis of acute lymphoblastic leukemia (ALL) in 5 of 59 (8.5%) of males undergoing bilateral wedge testicular biopsy at 1 of 15 participating Southwest Oncology Group (SWOG) institutions. Forty-six of the 54 males with normal biopsies (78% of the total group of 59) have remained free of recurrent ALL at a median of 18 months (range 13 to 23 months) since the biopsy procedure, whereas eight have relapsed for the first time--five bone marrow (BM), one sclera, one simultaneous BM and testes, and one testes--at a median of 12.5 months (range 4 to 22 months) after the normal testicular biopsy. With aggressive therapy after biopsy in the five boys with OTL, one has died 19 months after biopsy (after two BM relapses), one is alive 21 months after biopsy (after two BM relapses), and three are alive and free of recurrent ALL 13, 16, and 19 months, respectively, since the diagnosis of OTL.

Complete remission (CR), 5-year remission duration (RD), and overall 5-year survival rates are 74%, 28% and 25%, respectively, for previously untreated children with acute nonlymphocytic leukemia diagnosed between 1977 and 1981, following induction therapy with vincristine, doxorubicin and prednisone (VAP), consolidation therapy with 6-thioguanine, cytosine arabinoside (TA) and cyclophosphamide/vincristine/cytosine arabinoside/prednisone (COAP), and maintenance therapy of alternating TA and COAP with or without VAP pulses. Approximately 20% are free of their disease for more than 5 years. High white blood cell counts (WBC) at diagnosis and M3 and M6 morphology were associated with lower CR rates, while M5 morphology was associated with higher CR rates. Patients with M1 morphology had shorter remission duration as compared to those with M4 or M5 morphology. Low WBC and age between 2 and 10 years at diagnosis were associated with longer remission durations and survival. Patients with M4 morphology also survived longer. The observed CR rates are comparable to other studies initiated at the same time as this study but survival is less than those reported more recently. Low WBC at diagnosis and M4/M5 morphology may identify relatively favorable prognostic groups.

Forty-five children with acute nonlymphoblastic leukemia in relapse received a total of 56 courses of L-asparaginase combined with vincristine and prednisone. The complete remission rate of 40% (12 of 30 trials) in patients resistant to vincristine and prednisone was almost identical to that in children still sensitive to vincristine and prednisone (42%, 11 of 26 trials). The complete remission rate of 38% (14 of 37 exposures) in those children who had not received L-asparaginase previously compared favorably with the complete remission rate in those children who had received prior L-asparaginase (47%, 9 of 19 exposures). Forty-seven of the 56 induction trials were in children with 1 or more remissions and 14 of these were in children with 3 or more prior remissions. Toxicity was minimal.

Combination chemotherapy with adriamycin and DTIC was used in 102 evaluable patients under 15 years of age who had previously treated metastatic solid tumors. Responses, defined as 50% or more reduction in all tumor masses, occurred in 10 out of 27 patients with neuroblastoma, 3 out of 8 patients with Wilms tumor, 7 out 15 patients with Ewing sarcoma, 2 out of 6 patients with osteosarcoma, 5 out of 13 patients with rhabdomyosarcoma, and 15 out of 33 patients with miscellaneous tumors which included a patient who had a complete regression of an extensive juvenile angiofibroma. Response rate to combination chemotherapy with adriamycin and DTIC in patients with Ewing sarcoma was significantly superior to the response rate obtained with adriamycin alone in another Southwest Oncology Group Study. Major toxicity included nausea, vomiting, myelosuppression, high incidence of pneumocystis carinii pneumonia (5 patients) and congestive heart failure (4 patients). There was 7 drug-associated deaths due to sepsis (1), pneumocystis carinii pneumonia (4), and congestive heart failure (2).

Twenty-six out of a total of 49 patients who were treated for Wilms' tumor at the Mallinckrodt Institute of Radiology between January 1960 and December 1975 have survived at least five years. The median follow-up time is 153 months (12 years, 9 months). One girl, who received pelvic irradiation, has not reached puberty at age 14, but the other 25 patients are currently in good health and have no major complaints or functional impairments at present. Twenty-one patients have, however, developed some complication at some time since treatment. Serious side-effects requiring hospitalization included one case of pericarditis and one of esophageal varices secondary to portal hypertension. Both these patients, however, had advanced tumors requiring aggressive treatment and their complications should be seen in perspective. There has also been one case of temporary low grade renal failure and one of transient hypertension. More common complications were 14 instances of scoliosis (only three have had any symptoms, however), five of osseous hypoplasia, three of soft tissue hypoplasia, three of liver damage and three of lung damage. There was one case of osteochondroma within a radiotherapy field. The factors pertaining to these complications and the anticancer therapy which preceded them are discussed in detail. We conclude that, whereas structural changes following modern radiotherapy for Wilms' tumor are very common, severe dysfunctions are infrequent. Even more extended periods of observation will be required before the total number of abnormalities is ascertained. However, the striking observation from this study is the lack of late functional effects.

A remission-induction regimen for childhood leukemia using cyclophosphamide, asparaginase, vincristine, and prednisone (CAVP) was compared to standard vincristine-prednisone (VP) induction. The more intensive regimen was associated with a lower complete remission rate (81% vs 93%) and a higher early death rate from infection (15% vs 5%) for acute lymphocytic leukemia. In contrast, complete remission was achieved in 58% of children with acute nonlymphocytic leukemia treated with CAVP compared to 18% for VP. Early death rates were similar (27% vs 25%). These observations corroborate previous studies in childhood nonlymphocytic leukemia showing activity for asparaginase. Preliminary analysis of remission duration and survival for responders shows no advantage for those who survived the more intensive induction.

To determine how many children with acute lymphoblastic leukemia were initially referred to a pediatric hematologist because of isolated significant thrombocytopenia ([platelet count less than 50,000/mm3] and an otherwise normal complete blood cell count and physical findings), a retrospective review of the Pediatric Oncology Group's charts was undertaken. Review of the records of 2239 children enrolled in the past two acute lymphoblastic leukemia protocols showed that none of these children had significant thrombocytopenia with no other hematologic or physical manifestations of acute lymphoblastic leukemia when they were first seen by the hematologist. The results suggest that routine bone marrow aspiration in the child with isolated thrombocytopenia may be unnecessary to rule out acute lymphocytic leukemia.

ICRF-159 is active in several animal tumor model systems and human adult malignancies. In this phase II study, ICRF-159 was given on a weekly schedule, 3000 mg/m2/day, orally in three divided doses at 6-hour intervals to 78 children with a variety of malignant neoplasms. Fifty-three patients were evaluable for tumor response. Toxicity was primarily hematopoietic and gastrointestinal. There were no responses in any of the eight patients with osteogenic sarcoma, four with lymphoma, five with Ewing's sarcoma, ten with neuroblastoma, or six with rhabdomyosarcoma. There was a transient partial response in one of four children with Wilms' tumor. Further trials with this drug using this schedule are not indicated for the common childhood solid tumors.