Primate model for long-term study of intraventricularly or intrathecally administered drugs and intracranial pressure.

Meaningful pharmacokinetic investigations require animal systems which approximate the human situation. This report describes a primate model in which silicone catheters are placed into the fourth ventricle and the spinal subarachnoid space and connected to subcutaneous cerebrospinal fluid without tissue damage, prod, enables spinoventricular perfusion, and permits ventricular cerebrospinal fluid sampling over extended periods in unanethetized rhesus monkeys. This animal system may provide intraventricular pressure recordings and pharmacokinetic data similar to that obtained in man.

Pharmacokinetics of oral methotrexate in children.

The absorption and disposition kinetics of p.o. methotrexate were studied in 15 children. Serum levels and urinary excretion of methotrexate, as measured by the dihydrofolate reductase inhibition assay, were monitored following a routine p.o. dose (6.3 to 28.1 mg/sq m) administered after an overnight fast. Significant interindividual variability was noted in peak levels (range, 0.27 to 1.1 microM), time to peak (1 to 5 hr), area under the serum concentration-time curve (1.08 to 5.00 microM . hr), and the fraction of the dose absorbed (23 to 95%). Patients taking doses greater than 12 mg/sq m had a more prolonged absorptive phase and absorbed a smaller fraction of their dose, indicating that the mechanism of absorption may be saturable in some patients within the commonly administered dosage range. Urinary excretion was rapid, and the mean renal clearance of methotrexate was 1.6 times greater than was creatinine clearance, consistent with renal tubular secretion of the drug. While the marked degree of variability observed suggests a potential role for therapeutic drug monitoring in optimizing p.o. methotrexate therapy, the critical time points to monitor, the therapeutic and toxic ranges, and the intrapatient consistency of absorption must be defined before it will be practical and useful.

Enterohepatic circulation of methotrexate in rats in vivo.

The pharmacokinetics of the methotrexate enterohepatic cycle were studied in rats in vivo. For plasma levels of methotrexate between 10(-5) and 10(-8) M, biliary levels were directly proportional and concentrated 27-fold. When labeled methotrexate was administered in doses sufficient to achieve plasma levels of 10(-6) M, approximately 50% of methotrexate appeared in the bile in normal animals and up to 80% appeared in anephric animals. In spite of the high percentage of administered methotrexate which appeared in the bile, complete interruption of the enterohepatic cycle in otherwise normal animals did not affect the plasma decay curve of a bolus of methotrexate. The increased biliary excretion which occurred in animals with renal impairment was utilized with possible therapeutic implications. Bile drainage in these animals rapidly decreased plasma methotrexate levels compared to nondrained controls. This suggests that interruption of the methotrexate enterohepatic cycle may provide an alternative for the management of methotrexate toxicity associated with renal insufficiency.

Alteration of methotrexate uptake in human leukemia cells by other agents.

The uptake of methotrexate (MTX) and the effect of drugs known to either inhibit or enhance MTX transport in L1210 murine leukemia were studied in man using blast cells from patients with acute myelogenous leukemia in vitro. MTX uptake was found to proceed slowly, requiring at least 160 min for cells to reach a "steady state" when extracellular MTX concentrations were 1 muM. Efflux of MTX from preloaded cells required 80 to 120 min and the nonexchangeable or tightly bound fraction was 40% of the total intracellular drug. Utilizing doses that are estimates of achievable peak blood levels following single i.v. injection, cephalothin (21 mug/ml) and hydrocortisone (20 mug/ml) inhibited net MTX accumulation by 20 and 28%, respectively. Vincristine sulfate at 8.3 and 0.083 mug/ml enhanced MTX uptake by 54 and 33%, respectively, by inhibiting MTX efflux, thus increasing the level of intracellular drug in excess of the tightly bound fraction. The potential clinical implications of using MTX in combination with the aforementioned drugs for cancer chemotherapy are discussed.

Methotrexate levels in the interstitial space and seminiferous tubule of rat testis.

The ability of methotrexate (MTX) to pass from the blood into the interstitial space and seminiferous tubule of the rat was investigated using testicular micropuncture. MTX was administered to anesthetized adult Wister rats via a femoral vein cannula. Constant plasma levels of MTX were achieved by giving a priming dose followed by a constant infusion of 1, 10, or 100 mg/kg/hr with 6 to 27 rats studied at each dose. Blood (via a jugular vein cannula), testicular interstitial fluid, and seminiferous tubule fluid (via direct micropuncture) were periodically sampled during the 4 hr of drug infusion. Under steady-state conditions, when compared to corresponding plasma values, MTX levels were 2- to 4-fold lower in the testicular interstitial fluid and 18- to 50-fold lower in the seminiferous tubule. These results indicate that, in the rat, a significant blood-testis barrier to MTX exists at the tubular but probably not at the capillary-interstitial level. If these results can be extrapolated to humans, they do not provide a pharmacological explantation for the frequent occurrence of leukemic relapse in the interstitium of the testes in boys with acute lymphocytic leukemia.

A primate model for study of methotrexate pharmacokinetics in the central nervous system.

A new technique enabling repetitive sampling of cerebrospinal fluid (CSF) in unanesthetized rhesus monkeys was developed to study the pharmacokinetics of methotrexate (MTX) in the CSF. CSF and plasma MTX levels were monitored following intraventricular and intravenous MTX administration. CSF and plasma MTX disappearance curves in the monkey were virtually identical to curves generated in humans, suggesting that the mechanisms of transport between the CSF and plasma compartments are similar in both species. These observations validate this experimental primate model and indicate its potential application to the pharmacological study of CNS chemotherapeutic agents in man.

Active transport of methotrexate from cerebrospinal fluid in humans.

The cerebrospinal fluid (CSF) efflux kinetics of methotrexate (MTX) were studied in three patients with indwelling Ommaya reservoirs. A small dose of MTX was injected intraventricularly several hr after the start of a high-dose continuous i.v. infusion of MTX. In all patients, the CSF antifolate concentration returned to the preinjection level before the end of the i.v. infusion. This result indicated that the efflux of MTX from CSF in humans is independent of plasma drug concentrations. Efflux kinetics were further characterized in one patient. Serially obtained CSF samples after intraventricular injections demonstrated a biphasic disappearance curve with alpha- and beta-phase half-disappearance times of 1.7 and 6.6 hr, respectively. Prolongation of the beta-phase half-time was associated with oral acetazolamide medication and with increased intracranial pressure, indicating that inhibition of CSF production slows MTX clearance. CSF MTX concentration, however, declined more rapidly than that of simultaneously administered diethylenetriaminepentaacetic acid, an extracellular marker substance excreted by bulk flow, indicating that bulk flow excretion alone is insufficient to account for MTX efflux from human CSF. Evidence that there is an active transport component was provided by probenecid pretreatment which also prolonged the CSF MTX half-life. These findings suggest that both passive and active mechanisms govern MTX efflux from the CSF in humans and that they can be inhibited by acetazolamide and probenecid, respectively.

Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule.

Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every 12 h for 5 consecutive days, with courses repeated every 21 days. Dose reduction, initially to 200 mg/m2/day and subsequently to 140 mg/m2/day, was required because dose limiting myelosuppression and mucositis were encountered at the 290- and 200-mg/m2/day dose levels. Non-dose limiting toxicities included transient elevations in liver function tests, mild nausea, and skin rashes. The maximum tolerated dose was 140 mg/m2/day for 5 days. Pharmacokinetic monitoring was performed at steady state during the first course. For the 140-, 200-, and 290-mg/m2/day dose groups, the mean +/- SE peak plasma concentrations were 5.3 +/- 0.84, 9.3 +/- 1.7, and 10.2 +/- 2.3 microM, respectively, and occurred at a median of 1.5 h following the p.o. dose. The mean area under the plasma concentration-time curves were 18.1 +/- 2.3, 45.4 +/- 8.9, and 56.9 +/- 16.3 microM.h, respectively. Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively. Dose limiting toxicities were observed in 9 of 10 patients with 12-h trough piritrexim concentrations greater than 0.5 microM, whereas only 2 of 7 patients with trough concentrations less than 0.5 microM experienced dose limiting toxicities. A limited pharmacokinetic sampling strategy that allowed the area under the plasma concentration-time curve to be accurately predicted from the 3- and 6-h plasma drug concentration was developed. The recommended dose for future phase II trials is 140 mg/m2/day administered p.o. every 12 h for 5 consecutive days. Pharmacokinetic monitoring at 3, 6, and 12 h postdose may be useful for estimating bioavailability and for predicting which patients are at greatest risk for developing toxicity.

Eight drugs in one day chemotherapy in children with brain tumors: a critical toxicity appraisal.

The toxicity of a new chemotherapeutic regimen for CNS tumors using eight anticancer agents administered in a 12-hour period was evaluated in 34 children with newly diagnosed and recurrent tumors treated at the Children's Hospital and Medical Center in Seattle. The chemotherapy included methylprednisolone, vincristine, lomustine (CCNU), procarbazine, hydroxyurea, cisplatin (CDDP), and either cyclophosphamide or imidazole carboximide (DTIC). The first five patients additionally received high-dose methotrexate (HDMTX), but because of excessive toxicity this was replaced by cytarabine. Of 125 courses administered without HDMTX, red cell transfusions were required in 15% of the courses and platelet transfusions were required in 8%. Hospitalization for empiric treatment of fever associated with neutropenia occurred in 6% of courses. Three episodes of documented sepsis occurred. Virtually all hematologic toxicity occurred in patients with recurrent disease. Renal toxicity occurred in 14% of patient courses. One patient died of renal failure and sepsis following therapy. Neurologic and hepatic complications were infrequent. High-frequency hearing loss above the voice range was common, but clinically significant hearing loss occurred in only three patients. Severe nausea and vomiting were infrequent. Overall, the toxicity of "eight in one" chemotherapy in newly diagnosed patients was minimal; toxicity was greater in patients with recurrent disease.

Acute lymphoblastic leukemia in infants less than one year of age: a cumulative experience of the Children's Cancer Study Group.

A retrospective review of all 115 infants less than 1 year of age with acute lymphoblastic leukemia (ALL) entered on a consecutive series of recent Children's Cancer Study Group (CCSG) leukemia protocols was undertaken to examine in detail the outcome and clinical course of a large group of similarly treated infants. In comparison to the 4,392 children older than 1 year, entered on the same studies, infants had a significantly (P = .0001) increased incidence of leukocytosis, hepatosplenomegaly, meningeal leukemia at presentation, hypogammaglobulinemia, and failure to achieve complete remission (CR) status by day 14 of induction therapy. In contrast, lymphadenopathy, non-L1 French-American-British (FAB) morphology, mediastinal mass, and T cell leukemia were not more frequently observed. Ninety percent of these infants successfully completed the induction phase of therapy. With a median follow-up of 35 months, life table estimate of disease-free survival is only 23% at 4 years. Identical disease-free survival rates for infants were observed in each of the individual studies reviewed. Excessive toxicity resulting in limitation of therapy delivered was not a causative factor for the disappointing outcome of these patients. Rather, early disease recurrence, characterized by bone marrow relapse (55%) and CNS (22%) relapse, was the major factor responsible for the extremely poor prognosis of this patient group. Identical CNS relapse rates were observed in those patients who received cranial irradiation as part of CNS prophylaxis (21.8%) and in those patients who did not receive cranial radiotherapy (24%). Results of salvage therapy for patients who experienced systemic or extramedullary relapse were dismal. Debilitating neuropsychologic sequellae, presumably related to CNS irradiation, have been observed in 50% of the small number of long-term survivors. Infants less than 1 year of age with ALL present with a constellation of features which predict a poor outcome and constitute the group of children with ALL at greatest risk for treatment failure.

Remission induction of meningeal leukemia with high-dose intravenous methotrexate.

Twenty children with acute lymphoblastic leukemia who developed meningeal disease were treated with a high-dose intravenous methotrexate regimen that was designed to achieve and maintain CSF methotrexate concentrations of 10(-5) mol/L without the need for concomitant intrathecal dosing. The methotrexate was administered as a loading dose of 6,000 mg/m2 for a period of one hour followed by an infusion of 1,200 mg/m2/h for 23 hours. Leucovorin rescue was initiated 12 hours after the end of the infusion with a loading dose of 200 mg/m2 followed by 12 mg/m2 every three hours for six doses and then every six hours until the plasma methotrexate level decreased to less than 1 X 10(-7) mol/L. The mean steady-state plasma and CSF methotrexate concentrations achieved were 1.1 X 10(-3) mol/L and 3.6 X 10(-5) mol/L, respectively. All 20 patients responded to this regimen, 16/20 (80%) achieved a complete remission, and 20% obtained a partial remission. The most common toxicities encountered were transient serum transaminase and bilirubin elevations, neutropenia, and mucositis. One patient had focal seizures and transient hemiparesis but recovered completely. High-dose intravenous methotrexate is an effective treatment for the induction of remission after meningeal relapse in acute lymphoblastic leukemia.

Leydig cell function in boys following treatment for testicular relapse of acute lymphoblastic leukemia.

Current practice for achieving local control of testicular relapse in males with acute lymphoblastic leukemia (ALL) includes the use of 2,400-rad testicular radiation. Although this therapy is known to cause germ cell depletion, it has been assumed that it does not alter testicular secretion of testosterone. To test this assumption, we measured gonadotropin and testosterone levels in seven boys with ALL who had been treated with radiation for clinically apparent testicular relapse. In four of seven boys, testicular relapse was bilateral with overt involvement of one testicle and microscopic involvement of the other. Three of these four boys demonstrated delayed sexual maturation, and in addition to elevated follicle-stimulating hormone (FSH) concentrations, testosterone levels were low and luteinizing hormone levels were elevated compared with controls. These data indicate that boys with overt testicular leukemia who are treated with 2,400-rad testicular radiation are at risk for Leydig cell dysfunction. However, the relative contributions of radiation, prior chemotherapy, and leukemic infiltration to this dysfunction remain to be clarified.

Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) CCG-160 protocol series was designed to evaluate prognostic factors in acute lymphoblastic leukemia (ALL). Patients were assigned to one of three prognostic groups based upon initial WBC count and age. To determine the optimal duration of therapy, CCG-160 patients completing 2 years of treatment in continuous remission were randomized ("late randomization") to discontinue therapy or receive another year of maintenance therapy. The prognostic significance of early response to induction therapy, as measured by the percentage of lymphoblasts in the day-14 bone marrow (d14 BM) aspirate, was evaluated in 2,516 children. For 1,490 patients with complete data, the status of the d 14 BM was a highly significant predictor of disease-free survival (DFS) by univariate and multivariate analysis (P less than .0001). The observed/expected (O/E) failure rate in patients with d14 M1 (less than 5% blasts), M2 (4% to 25% blasts), or M3 (greater than 25% blasts) BM rating who were subsequently M1 on day 28 or day 42, was .87, 1.59, and 2.30, respectively (P less than .0001). Patients with M2 or M3 d14 BM were more likely to have L2 ALL (modified French-American-British [FAB] morphologic classification), P less than .001. The significance of the d14 BM rating persisted after correction was made for WBC count and clinical prognostic groups using current CCSG criteria, except in infants less than 12 months of age. The d14 BM was also the most significant predictor of DFS in 975 patients after late randomization at 2 years following diagnosis. The O/E failure rate in patients with d14 M1, M2, or M3 BM was .88, 1.78, and 2.02, respectively (P = .0002, trend). Other significant predictors of late relapse were prognostic groups (P = .0003, trend) and initial WBC count (P = .004, trend). Predictive for both early and late relapse of ALL, early response should be monitored closely and alternative treatment regimens should be considered for slow responders.

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.

Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen.

During the period 1976-1981, 3241 children were enrolled on three major studies of acute lymphoblastic leukemia by participating institutions of the Children's Cancer Study Group. Each study included a different method of central nervous system (CNS) prophylaxis: (1) standard therapy with cranial irradiation, 2400 rads, and intrathecal methotrexate at 12 mg/m2 six times during consolidation (CCG-141); (2) a modification of CCG-141 in which the intrathecal methotrexate was initiated during induction (CCG-141A); and (3) a reduced cranial irradiation dose of 1800 rads with intrathecal methotrexate given at the same frequency as a CCG-141A, with or without maintenance intrathecal methotrexate, but with a dosage regimen derived from CNS volume considerations rather than based on body surface area (CCG-160 series). Strategy 3, a change in the intrathecal methotrexate dosage, has resulted in the lowest incidence of CNS leukemia to date (p less than 0.007). The cumulative 3-yr CNS relapse rate has decreased from 8%-10% to 2%-5% in average-risk patients (p less than 0.02; life table estimate) and from 23%-27% to 6% in high-risk patients (p less than 0.0002; life table estimate), despite a reduction in the cranial irradiation dose from 2400 to 1800 rads. Maintenance intrathecal chemotherapy has had a marginal effect among patients randomized to receive this additional therapy (p = 0.06). The overall outcome has been an increase in the continuous complete remission rate (p = 0.04) but not in the estimated 3-yr continuous hematologic remission or survival rates.

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.

Cytoreduction and prognosis in acute lymphoblastic leukemia--the importance of early marrow response: report from the Childrens Cancer Group.

PURPOSE: To quantify the residual marrow lymphoblast fraction that best defines patients at high risk for relapse, and the optimal time for assessment during remission induction. PATIENTS AND METHODS: The residual lymphoblast percentage was evaluated on day 7 (n = 220) and day 14 (n = 205) during a four- or five-drug induction in patients with poor prognostic factors. The rate of cytoreduction was related to event-free survival (EFS) and other factors. RESULTS: On the New York (NY) regimen, 68%, 14%, and 18%, and on the Berlin-Frankfurt-Munster (BFM) regimen, 56%, 15%, and 29% of patients had M1 (< 5% blasts), M2 (5-25%), or M3 (> 25%) responses on day 7 (P = .075). On day 14, the corresponding values were 87%, 6%, 7% on NY and 84%, 8%, 8% on BFM. For patients who achieved remission by day 28 and a day-7 marrow rating of M1, M2, or M3, the 6-year EFS rate was 78%, 61%, and 49% (P < .001). The day-14 ratings predicted for a 72%, 32%, or 40% EFS (P < .001). Patients with 5% to 10% blasts day 7 had three times as many events as those with less than 5% and had no better EFS than those with 11% to 25% blasts. Patients with a WBC count more than 200,000/microL at diagnosis and an M1 day 7 marrow had an EFS rate of 69%, while for those with M2 or M3, the EFS rate was 41%. Day-7 marrow had greater prognostic significance than the day-14 evaluation. For slow responders on day 7, the day-14 marrow provided additional information. EFS for patients who achieved M1 by day 14 was 65%. EFS decreased to 20% for those still M2 or M3 on day 14. Day-7 and -14 evaluations had significance for patients of all ages and WBC levels. CONCLUSION: Marrow aspiration on day 7 of therapy provided more useful information than that on day 14. However, day-14 marrow provided additional information for patients with a poor day-7 response. The rate of cytoreduction is a powerful, independent prognostic factor that can identify patients with a slow early response who are at risk for a short remission duration.

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.

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.

Eight drugs in one day chemotherapy for brain tumors: experience in 107 children and rationale for preradiation chemotherapy.

The development of a new multidrug chemotherapy regimen for primary brain tumors was based upon the cellular heterogeneity within individual tumors, the Goldie-Coldman and Price-Goldie-Hill hypotheses, and known agonistic effects of certain drug combinations and sequences. Eight drugs (vincristine [VCR], hydroxyurea, procarbazine, CCNU, cisplatin, cytosine arabinoside [Ara-C] high-dose methylprednisolone, and either cyclophosphamide or dacarbazine) were administered within 12 hours in an attempt to minimize myelosuppression. Courses were repeated at 2- to 4-week intervals. The regimen was devised to include lipid and water soluble drugs, polar and nonpolar agents, phase-specific and cell-cycle independent agents, and antineoplastics with different mechanisms of action. More than 330 courses of the regimen were administered to 107 children with brain tumors whose tumor had recurred or had been incompletely resected at diagnosis. Tumor response according to protocol-specified criteria and independent review was evaluable in 78% of the patients. After just two cycles of chemotherapy and within a 4- to 6-week interval, 50% had an objective tumor response including 15.5% who had a complete response (CR). Nephrotoxicity and high-frequency hearing losses were noted after three to five courses of therapy in approximately half of the patients. Transfusions with red cells or platelets and use of antibiotics for fever and neutropenia were required in 10% to 25% of patients. The regimen appears satisfactory for preradiation chemotherapy in newly diagnosed patients with residual tumor after surgery, but it must be compared with standard therapeutic approaches in prospective controlled trials before its relative value can be established.