The role of serum factors in the acceleration by Freund's complete adjuvant of the growth of transplanted murine leukemic cells.

Attempted nonspecific immunotherapy led to acceleration rather than retardation of tumor growth. Mice given injections of Freund's adjuvant were more susceptible to transplanted syngeneic Gross virus-induced leukemic cells when Freund's complete adjuvant was administered i.p. 0 to 7 days before or 1 day after tumor; thereafter, the adjuvant had no effect. Two serum-mediated phenomeana were demonstrated in vitro: (a) sera from mice immunized with Freund's complete adjuvant and tumor facilitated killing of tumor cells by peritoneal exudate cells from nonimmune mice; (b) sera from all mice with progressive tumor blocked the cytotoxicity of a xenogeneic tumor-specific serum. Certain sera produced both effects. However, sera that either blocked or facilitated tumor killing in vitro had no effect on the growth in vivo of transplanted tumor cells.

Pharmacology and phase I trial of high-dose oral leucovorin plus 5-fluorouracil in children with refractory cancer: a report from the Children's Cancer Study Group.

Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.

Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study.

To evaluate the effect of dactinomycin (AMD) dose and schedule on the frequency of severe hepatic toxicity in unirradiated National Wilms' Tumor Study-4 (NWTS-4) patients, we reviewed the records of 154 children randomized to single-dose AMD and 176 children randomized to divided-dose AMD administration. All the children also received vincristine in identical dose schedules for the first 10 weeks. The frequency of severe hepatic toxicity encountered in the early weeks of therapy was 14.3% (five of 35) among patients treated with 60 micrograms/kg of AMD, 3.7% (four of 108) among patients given 45 micrograms/kg, and 2.8% (five of 176) among patients treated with 15 micrograms/kg per dose times five doses (P = .025). The data suggest an increased frequency of severe hepatic toxicity with the higher, single-dose schedule of administration. However, the frequency of severe hepatic toxicity among the patients in the two remaining groups is markedly higher than the 0.4% observed among similar unirradiated patients in NWTS-3. The relationship of this toxicity to factors such as anesthetic agents, blood transfusions, intercurrent viral infection, or other presently unrecognized causes can be further evaluated only with a detailed investigation such as a case-control study.

The effect of initial management of hyperleukocytosis on early complications and outcome of children with acute lymphoblastic leukemia.

Data were collected from 124 patients with newly diagnosed acute lymphoblastic leukemia (ALL) and WBC greater than 200,000/microL seen at institutions affiliated with the Children's Cancer Study Group (CCSG) from April 1981 to May 1983. The presenting characteristics, initial management, early complications, and outcome were reviewed. All the children received vigorous intravenous (IV) hydration, alkalinization of the urine, and allopurinol. Thirty-two patients were started on full therapy with no additional measure. One or more special measures believed to reduce the complications of leukostasis and blast cell lysis were administered to 92 patients as follows: small initial doses of prednisone, 63; emergency cranial irradiation, 26; exchange transfusion, 21; and leukopheresis, 19. The incidence of CNS hemorrhage was only 3% (4/124). Seven patients expired during induction and four failed to achieve a remission by day 28. Nineteen patients (15%) had documented bacterial or fungal sepsis. Mild to moderate electrolyte abnormalities occurred in 29 patients: three patients required renal dialysis. Pretreatment with small doses of prednisone did not decrease the incidence of electrolyte abnormalities in those patients when compared with patients who received full chemotherapy. The event-free survival (EFS) for the 106 patients treated on one of the three intensive pilot studies is 55% at 36 months. On multivariate analysis the two significant adverse prognostic factors were massive splenomegaly (P = .02) and WBC count greater than 600,000/microL (P = .05). In conclusion, in patients with hyperleukocytosis the complications of blast cell lysis and leukostasis were manageable with acceptable morbidity and minimal mortality in a group of patients treated with vigorous hydration, allopurinol, and alkalinization of the urine before beginning chemotherapy. Selected patients with severe hyperuricemia and renal dysfunction may benefit from leukopheresis. No beneficial role was demonstrated for the use of small initial doses of prednisone or emergency cranial irradiation.

Treatment of children with stages II to IV anaplastic Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of the combination of vincristine, dactinomycin, and doxorubicin with (regimen J) or without (regimen DD-RT) cyclophosphamide on the relapse-free survival of children with stages II to IV Wilms' tumor and focal or diffuse anaplasia. PATIENTS AND METHODS: We reviewed the clinical courses of all randomized patients from National Wilms' Tumor Study (NWTS)-3 and NWTS-4 with stages II to IV anaplastic Wilms' tumor, and determined the 4-year relapse-free survival rate separately for those with focal or diffuse anaplasia. Anaplasia was evaluated using newly developed topographic definitions for focal and diffuse anaplasia. RESULTS: The 4-year relapse-free survival rate for five children with focal anaplasia who received regimen DD-RT was 80.0%, compared with 100.0% for eight children who received regimen J (P = .68). The 4-year relapse-free survival rate for 29 children with diffuse anaplasia treated with regimen DD-RT was 27.2%, compared with 54.8% for 30 children treated with regimen J (P = .02). CONCLUSION: We conclude that children with focal anaplasia have an excellent prognosis when treated with vincristine, doxorubicin, and dactinomycin. The addition of cyclophosphamide to the three-drug treatment regimen improved the 4-year relapse-free survival rate of children with stage II to IV diffuse anaplasia. This result suggests that further intensification of the treatment regimen for children with diffuse anaplasia may result in an additional improvement in prognosis.

Treatment of children with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of the sequential addition of doxorubicin (DOX) and cyclophosphamide (CTX) to the combination of vincristine (VCR) and dactinomycin (AMD) on the relapse-free survival of children with clear-cell sarcoma of the kidney (CCSK). PATIENTS AND METHODS: We determined the 6-year relapse-free survival rate for patients with CCSK treated on National Wilms' Tumor Study (NWTS)-1, NWTS-2, or NWTS-3 with the combination of VCR and AMD, with or without DOX, and for patients treated on NWTS-3 with the combination of VCR, AMD, and DOX with (regimen J) or without (regimen DD-RT) CTX. RESULTS: The 6-year relapse-free survival rate for the eight children with CCSK treated with VCR, AMD, and radiation therapy was 25.0%, compared with 63.5% for the 58 children treated with VCR, AMD, DOX, and radiation therapy (P = .09). The 6-year relapse-free survival rate for children with CCSK treated on regimen DD-RT was 64.6%, compared with 58.2% for those treated on regimen J (P = .79). CONCLUSION: We conclude that the addition of DOX to the combination of VCR plus AMD appeared to improve the 6-year relapse-free survival rate of children with CCSK. The addition of CTX in the dose and schedule used in NWTS-3 did not improve the 6-year relapse-free survival rate of children with CCSK. Because 30% of relapses occurred more than 2 years after diagnosis, prolonged follow-up evaluation of patients with CCSK is necessary.

Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of all-trans-retinoic acid (ATRA) administered on an intermittent oral schedule with interferon-alpha2a (IFN-alpha2a) in children with refractory cancer, and whether the marked reduction in plasma ATRA concentrations observed with chronic daily oral dosing could be circumvented with an intermittent dosing schedule. PATIENTS AND METHODS: Thirty-three children with refractory cancer (stratified by age, < or = 12 and > 12 years) were treated with ATRA 3 consecutive days per week and IFN-alpha2a 3 x 10(6) U/m2 5 consecutive days per week, both repeated weekly. The starting dose of ATRA was 60 mg/m2/d divided into three doses, with planned escalations to 90 and 120 mg/m2/d. Because severe headaches have been noted to occur on the initial day of ATRA administration, only two of three doses of ATRA were administered on day 1 of each week. RESULTS: Pseudotumor cerebri or dose-limiting headache was observed in two of five patients older than 12 years treated at the 120-mg/m2/d dose level and in one of six < or = 12 years at the 90-mg/m2/d level. Other non-dose-limiting toxicities of ATRA included reversible elevations in hepatic transaminases and triglycerides, dry skin, cheilitis, and nausea/vomiting. One child with recurrent neuroblastoma had an objective response of 6 months' duration, and one with recurrent Wilms' tumor had histologic maturation of multiple tumors. This intermittent schedule allowed for exposure to relatively high plasma concentrations of ATRA on a repetitive basis. Following 30-mg/m2 doses, the ATRA area under the concentration-time curve (AUC) decreased from 96 +/- 14 micromol/L/min on day 1 to 26 +/- 24 micromol/L/min by day 3 of drug administration, but on day 1 of the fourth consecutive week of therapy, the AUC averaged 110 +/- 16 micromol/L/min. The recommended pediatric phase II dose of ATRA administered on this schedule is 90 mg/m2/d. CONCLUSION: An intermittent schedule of ATRA administration appears to circumvent the low plasma drug exposure that is a result of the sustained upregulation of metabolism when this drug is administered on a chronic daily schedule. Based on the results of this trial, a phase II trial of ATRA/IFN-alpha2a in neuroblastoma and Wilms' tumor using this schedule is in progress.

A comparison of four staging systems for localized and regional neuroblastoma: a report from the Childrens Cancer Study Group.

Four major staging systems have been used to estimate the prognosis for children with local and regional neuroblastoma (NBL). Data obtained at diagnosis for 251 neuroblastoma patients from two Childrens Cancer Study Group (CCSG) studies were analyzed according to staging systems of the CCSG, St Jude Children's Research Hospital, the Pediatric Oncology Group (POG), and the Union Internationale Contre le Cancer (UICC) tumor-nodes-metastasis (TNM) system. The most significant variables were found to be age, tumor stage, extent of tumor removal, transgression of the midline by tumor infiltration, and site of primary tumor. Involvement of lymph nodes per se was not a bad prognostic sign unless associated with extension beyond the midline, the latter being the single most important prognostic variable. All four staging systems had value for prognostication and all identified with accuracy the low stage patient (stage I, stage A) who fares well (greater than or equal to 87% survival). The CCSG definition of stages II and III disease discriminated prognostic groups best among the remaining patients, and was able to identify the child with local-regional NBL with poor survival. The estimated 5-year survival rates for children with regional tumor (stage III, IIIA[N]), according to the four systems were 44%, 74%, 74%, and 74% for the CCSG, St Jude, POG, and UICC methods, respectively. We conclude that all four staging systems effectively define good-prognosis patients with localized disease but that the CCSG staging system most accurately identifies patients with regional tumor who have a poor outcome.

Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group.

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106.

PURPOSE: On past Childrens Cancer Group (CCG) trials, children with acute lymphoblastic leukemia and unfavorable presenting features had obtained an event-free survival (EFS) rate of no better than 50%. Following promising pilot experience, this study was conducted to determine the benefit and morbidity of two intensive experimental regimens, Reg A, based on the Berlin-Frankfurt-Münster (BFM) 1976 regimen, and Reg B, the New York regimen. PATIENTS AND METHODS: Between February 1983 and November 1984, 217 eligible children with acute lymphoblastic leukemia and unfavorable presenting features were entered and randomly assigned to receive Reg A, Reg B, or Reg C, the control regimen. Assignment to Reg C was halted in November 1984 after interim analyses showed an inferior outcome. Subsequently, between November 1984 and March 1987, an additional 328 patients were randomly allocated to receive Reg A or Reg B. RESULTS: The 7-year EFS rate was 63% (+/- 6%, 1 SD) for Reg A, 61% (+/- 6%) for Reg B, and 40% (+/- 6%) for Reg C (P < .006). The difference between Reg A or Reg B and Reg C remained greater than 20 percentage points for EFS at 7 years and 15 percentage points for survival. Relative to Reg C, patients on Reg A accrued 16.3 additional days of hospitalization on average and, on Reg B, 20.2 days. EFS and survival were similar on Reg A and Reg B, but Reg B required more days of parenteral therapy and greater exposure to anthracyclines and alkylating agents. CONCLUSION: Both Reg A and Reg B provided a better outcome than Reg C for children with acute lymphoblastic leukemia and unfavorable presenting features. Outcomes on Reg A and Reg B were similar. Use of the more effective but more toxic regimens resulted in 78 additional hospital days per relapse prevented on Reg A and 101 days on Reg B. The current CCG trial for this population builds on Reg A.

Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of the administration of different regimens for the treatment of Wilms' tumor (WT). PATIENTS AND METHODS: Between August 6, 1986 and September 1, 1994, 905 previously untreated children aged younger than 16 years with stage II favorable histology (FH) WT (low-risk [LR]), stages III to IV FH WT, or stages I to IV clear-cell sarcoma of the kidney (high-risk[HR]) were randomized after the completion of 6 months of chemotherapy to discontinue (short) or continue for 9 additional months (long) treatment with chemotherapy regimens that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either divided-dose (STD) courses (3 days) or single-dose (PI) treatment with doxorubicin. RESULTS: The 4-year relapse-free survival (RFS) rates after the second randomization for LR patients were 83.7% for the 190 patients treated with short and 88.2% for the 187 patients treated with long chemotherapy (P = .11). The 4-year RFS rates after the second randomization for HR FH patients were 89.7% for the 256 patients treated with short and 88.8% for the 246 patients treated with long chemotherapy (P = .87). The charge for treatment with the short PI treatment regimens for all children with stages I through IV FH WT was approximately one half of that with the long STD treatment regimens. CONCLUSION: The short administration schedule for the treatment of children with WT is no less effective than the long administration schedule and can be administered at a substantially lower total treatment cost.

Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: The National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of administration of different regimens for the treatment of Wilms' tumor (WT). PATIENTS AND METHODS: Between August 6, 1986 and September 1, 1994, 1,687 previously untreated children less than 16 years of age with stages I to II/favorable histology (FH) or stage I/anaplastic histology WT (low-risk [LR] group) or stages III to IV/FH WT or stages I to IV/clear cell sarcoma of the kidney (high-risk [HR] group) were randomized to treatment that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either STD courses (3 days) or PI treatment with doxorubicin. RESULTS: The 2-year relapse-free survival (RFS) rates for LR patients were 91.3% for 544 randomized to treatment with PI and 91.4% for 556 randomized to treatment with STD chemotherapy (P = .988). The 2-year RFS rates for HR patients were 87.3% for 299 randomized to treatment with PI and 90.0% for 288 randomized to treatment with STD chemotherapy (P = .865). CONCLUSION: We conclude that patients treated with PI combination chemotherapy for LR or HR WT or clear cell sarcoma of the kidney have equivalent 2-year RFS to those treated with STD regimens. PI drug administration is recommended as the new standard based on demonstrated efficacy, greater administered dose-intensity, less severe hematologic toxicity, and the requirement for fewer physician and hospital encounters.

Relationship between dose schedule and charges for treatment on National Wilms' Tumor Study-4. A report from the National Wilms' Tumor Study Group.

National Wilms' Tumor Study-4 was designed to evaluate the efficacy, toxicity, and cost of administration of different regimens for the treatment of Wilms' tumor. The charges for treatment with dactinomycin and doxorubicin administered by two different schedules were calculated using current charges in Buffalo, N.Y. An annual savings of approximately $779,259 could be achieved by the use of the short, pulse-intensive (i.e., single-dose) treatment regimens for all children with Wilms' tumor of stages I-IV/favorable histology. The pulse-intensive administration schedule for the treatment of children with Wilms' tumor permits administration of chemotherapy at a substantially lower total treatment cost.

Emergency medical services and the pediatric patient: are the needs being met?

Emergency medical systems are being developed throughout the United States primarily to deal with myocardial infarction and trauma. These programs often fail to recognize the special needs of the critically ill child. Data collected in Los Angeles County from the LA County Trauma Surveys, Mobile Intensive Care Unit Rescue Reports, and Base Station Hospitals demonstrate that children represent approximately 10% of the paramedic calls. The calls are for medical problems as well as trauma. These data suggest that children have a higher death rate in the field than adults, and deaths occur more commonly in areas where there are no pediatric centers. Children are often secondarily transferred from emergency departments to other centers for definitive care. This study suggests that the needs of children in the prehospital setting are not being met.

t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors?

We report an apparently balanced t(4;19)(q35;q13.1) as the sole cytogenetic change in a highly malignant extraskeletal sarcoma in a 12-year-old-boy. Tumor cells were negative for all immunocytochemical markers except vimentin and neuron-specific enolase. Electron microscopy indicated chondroblastic differentiation. The tumor was categorized as a malignant sarcoma with differentiation toward extraskeletal mesenchymal chondrosarcoma. Reports of a similar translocation in an embryonal rhabdomyosarcoma (RMS) and in a dedifferentiated sarcoma with both rhabdomyosarcomatous and osteosarcomatous elements suggest that this translocation can arise in a primitive mesenchymal stem cell that can differentiate along at least these three pathways.

Neuroblastoma: the challenge and frustration.

Neuroblastoma occurs in 500 children yearly in the United States. Recent findings in tumor biology and the evaluation of biochemical markers have been helpful in predicting outcome, but clinicians have not been able to exploit these findings to develop successful therapy. Staging is important, but it will be necessary to standardize staging at various centers to compare results of therapy. The role for autologous bone marrow transplantation in the management of neuroblastoma remains to be determined, and search for effective therapy continues. This disease has challenged cell biologists, it has served as a basis for intense scientific inquiry, and it has defied the therapeutic attempts of pediatric oncologists. It is hoped that current enquiry will inspire newer therapies and fulfill the goal of offering all children with this tumor an opportunity to be cured.

Diastolic hypertension in Wilms' tumor survivors: a late effect of treatment? A report from the National Wilms' Tumor Study Group.

Following treatment by the National Wilms' Tumor Study Group (NWTS) 2,243 children with Stages I-IV Wilms' tumor, have remained relapse-free for 5 or more years. Of these, 1,528 children had at least one blood pressure measurement recorded during follow-up. Using standards developed by the Second Task Force on Blood Pressure Control in Children, it appears that 5 or more years following diagnosis the general distribution of blood pressures for NWTS survivors may be above that for the national population, especially at the younger ages.

Remaining problems in the treatment of patients with Wilms' tumor.

Major advances have been made in the treatment of children with Wilms' tumor. Remaining areas of investigation include the role of adriamycin and the treatment of children with stage III and IV disease and the role of whole lung radiation therapy in the treatment of children with pulmonary metastases. Long-term follow up of successfully treated patients will provide valuable insight into the importance of genetic factors in the cause of Wilms' tumor.