Expression of the human c-fms proto-oncogene product (colony-stimulating factor-1 receptor) on peripheral blood mononuclear cells and choriocarcinoma cell lines.

The c-fms gene product is related, and possibly identical, to the receptor for the mononuclear phagocyte colony stimulating factor, CSF-1. Using antisera to a recombinant v-fms--coded polypeptide, glycoproteins encoded by the human c-fms locus were detected in mononuclear cells from normal peripheral blood and in promyelocytic HL-60 cells 24 h after induction of monocytic differentiation with phorbol ester. The 150-kD human c-fms--coded glycoprotein was expressed at the cell surface, was active as a tyrosine-specific protein kinase in vitro, and shared primary structural features with the product of the feline retroviral v-fms oncogene. A biochemically indistinguishable glycoprotein was detected in human choriocarcinoma cell lines. Like peripheral blood mononuclear cells and phorbol ester-treated HL-60 cells, the choriocarcinoma cells expressed high affinity binding sites for human CSF-1. In addition to serving as a lineage specific growth factor in hematopoiesis, CSF-1 may play a role in normal trophoblast development.

Phase I clinical trial of recombinant human tumor necrosis factor in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I study was undertaken to determine the toxicity and maximum-tolerated dose (MTD) of recombinant human tumor necrosis factor (rTNF) in children. PATIENTS AND METHODS: Twenty-seven patients with recurrent or refractory solid tumors were enrolled on the study. rTNF was administered daily for 5 days by 30-minute intravenous (IV) infusion, and doses were escalated in cohorts of three to six patients. Courses were repeated after a 9-day rest period, if toxicity was tolerable. Daily doses ranged from 100 to 350 micrograms/m2. RESULTS: Most courses were associated with grade I/II fever, rigors, nausea, or vomiting. Three patients experienced moderate dyspnea that responded to supplemental oxygen. All abnormalities resolved on discontinuation of the infusion. One patient had a cardiac arrest 90 minutes after receiving the first dose of rTNF and died 10 days later of related complications. In two other patients, rTNF was discontinued due to persistent grade IV hypotension. Toxicities were not consistently related to dose and no cumulative effects were noted. The dose-limiting toxicity was transient hepatic dysfunction, which occurred in three of six patients receiving 350 micrograms/m2; this toxicity was rapidly reversed on discontinuation of the rTNF. One patient, whose non-Hodgkin's lymphoma had recurred after bone marrow transplantation, had a partial response. Disease was stabilized in two patients. CONCLUSION: We recommend that phase II testing proceed at a dose of 300 micrograms/m2/d on the schedule described.

Escalating teniposide systemic exposure to increase dose intensity for pediatric cancer patients.

PURPOSE: The primary objective for this study was to determine whether controlling pharmacokinetic variability, by designing patient-specific dosage regimens for teniposide using a Bayesian estimation control strategy, would permit an increase in dose intensity without increased toxicity. PATIENTS AND METHODS: Twenty patients with relapsed acute lymphocytic leukemia were given teniposide as part of their induction and maintenance therapy. Before beginning reinduction therapy, an intensive pharmacokinetic study was performed based on 12 measured teniposide plasma concentrations. Doses were determined to achieve a targeted systemic exposure defined by an area under the plasma concentration time curve (AUC) beginning at an AUC consistent with that predicted for a patient with average pharmacokinetic parameters receiving the currently accepted maximal-tolerated dose. The targeted systemic exposure was then escalated in increments of 25% in cohorts of at least three patients until unacceptable toxicity occurred. In 36 follow-up studies, when teniposide was administered during maintenance therapy, a Bayesian strategy based on only three or five measured drug concentrations was evaluated for precision and bias for achieving the targeted systemic exposure against the full pharmacokinetic study. RESULTS: Teniposide clearance varied over a fivefold range (3.7 to 21.6 mL/min/m2). With the use of the patient-specific dosage regimens, the intensity of systemic exposure was increased 50% (1,656 mumol.h v 1,060 mumol/L.h) over that previously possible with standard fixed doses, with no increase in acute, nonhematologic toxicity. Teniposide concentrations (n = 265) were well predicted (R2 = .82) with as few as three measured values from the initial study. CONCLUSION: Targeting systemic exposure is clinically feasible, precise, and allows increased dose intensity for teniposide without increased risk of acute, nonhematologic toxicity, when compared with fixed-dose regimens.

Primary lymphoma of bone in children.

Primary lymphoma of bone (PLB) occurs infrequently in children. Between January 1962 and November 1988, 395 children with non-Hodgkin's lymphoma (NHL) were treated at St. Jude Children's Research Hospital. Eleven of these patients (2.8%) presented with a bone primary, usually in the femur (eight of 11 patients). The median age of these seven boys and four girls at presentation was 13 years (range, 5.5 to 19 years). Seven patients had one or more additional bones involved. All patients had high-grade lymphomas based on the National Institutes of Health (NIH) Working Formulation. The histologic subtypes included six large-cell lymphomas, three lymphoblastic lymphomas, one small-noncleaved, non-Burkitt's lymphoma, and one unclassifiable lymphoma. Treatment consisted of multiagent chemotherapy combined with local radiation therapy in seven of 11 patients. Six of 10 children who received chemotherapy as a component of their initial therapy, including all who presented with localized tumor, are alive with no evidence of disease 2+ to 85+ months (median, 42.5 months) after cessation of treatment; one patient has just completed chemotherapy. Each of the four patients who died showed leukemic conversion 5 to 11 months after diagnosis, and three died of progressive disease. One patient died of sepsis during chemotherapy-induced neutropenia with no evidence of disease at necropsy. We conclude that optimal therapy for PLB, as with all other forms of NHL, should focus on the histologic subtype and stage of disease.

Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia.

PURPOSE: To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia. PATIENTS AND METHODS: Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course. RESULTS: Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted. CONCLUSION: The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.

CNS involvement in children with newly diagnosed non-Hodgkin's lymphoma.

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.

Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy.

Twenty-five children with refractory solid tumors were given recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in escalated doses of 60 to 1,500 micrograms/m2 as 2-hour intravenous infusions, beginning 24 hours after myelosuppressive treatment with cisplatin and etoposide. Tolerance to rhGM-CSF was exceptional even at dose levels that exceeded the maximum-tolerated dosage (MTD) reported for adults. The agent produced dose-related increases in platelet and neutrophil counts, resulting in significantly shorter durations of severe neutropenia and thrombocytopenia (P less than .01 for each analysis). At the higher dosages (greater than or equal to 750 micrograms/m2), treatment with rhGM-CSF reduced the median number of days of antibiotic therapy for fever and neutropenia by approximately one half. We conclude that rhGM-CSF is well tolerated by leukopenic children in doses as high as 1,500 micrograms/m2. An MTD was not reached in this study. The ability of the growth factor to reduce severe neutropenia and thrombocytopenia suggests it will have an important role in the management of childhood solid tumors.

Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962 to 1988.

To gauge the impact of intensified therapy on the survival of infants (younger than 1 year, n = 129) and children (greater than or equal to 1 year of age, n = 275) with neuroblastoma, we analyzed the results of eight successive clinical trials comparing various combinations of antineoplastic drugs, surgery, and radiotherapy. Changes in treatment did not affect the survival of children with involved noncontiguous lymph nodes or distant metastatic disease until the combination of cisplatin and teniposide (CDDP/VM26) was added to a basic regimen of cyclophosphamide and doxorubicin (CTX/DOX). The resulting 4-year survival was 28% +/- 5% (SE) compared with 7% +/- 2% for previous treatments (P less than .001 by the log-rank test). The 4-year survival of infants with metastatic disease was improved by administering CTX/DOX to all patients, reserving CDDP/VM26 for those whose disease was resistant to the former combination: 82% +/- 6% versus 45% +/- 8% in earlier studies; P less than .001. In the subset of infants whose tumors had disseminated to bone or bone marrow at diagnosis, this therapeutic approach increased the probability of long-term survival from 48% +/- 10% to 85% +/- 9% (P = .01). The small group of children over 1 year of age with localized unresectable tumors also fared significantly better with the switch to CTX/DOX chemotherapy (4-year survival, 93% +/- 7% v 42% +/- 13%; P = .02). Multivariate analysis indicated that young age, limited-disease stage, nonadrenal primary site, and intensified treatment were independent predictors of a more favorable outcome. We conclude that substantial advances in the treatment of neuroblastoma have occurred over the past 25 years at this institution. The current overall 4-year survival probability of 57% +/- 4% compares favorably with estimates for most other common solid tumors of childhood.

11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia.

PURPOSE: Leukemic cell characteristics were analyzed in infants less than 1 year of age with acute lymphoblastic leukemia (ALL) to determine adverse prognostic factors that might explain the poor prognosis of this group. PATIENTS AND METHODS: Treatment outcomes were analyzed according to the presenting clinical and laboratory features of 30 infants treated between May 1979 and April 1993. A stepwise multivariate regression model was used to identify the most important prognostic indicator with respect to event-free survival. RESULTS: Infant ALL cases were characterized by high presenting leukocyte count (median, 87 x 10(9)/L), increased frequency of CNS leukemia (50%), and blast cells with a CD10- phenotype (67%), myeloid-associated antigen expression (48%), and 11q23/MLL rearrangement (68%). The 11q23/MLL involvement was correlated with age less than 6 months, CD10- phenotype, myeloid-associated antigen expression, and high leukocyte count. Although 11q23/MLL involvement, age less than 6 months, myeloid-associated antigen expression, and female sex were each significantly associated with an inferior treatment outcome, only rearranged 11q23/MLL emerged as an independent predictor of prognosis in multivariate analysis (P = .01). Infants with this genetic abnormality had a 4.7-fold (95% confidence interval, 1.3- to 17.0-fold) increased risk in adverse events compared to other infants. CONCLUSION: The 11q23/MLL involvement of blast cells identifies a major subgroup of infant ALL cases that require an innovative treatment approach. Infants who lack this genetic abnormality have an intermediate prognosis and could be treated accordingly on risk-directed protocols.

Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children.

PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.

Recombinant human TNF-alpha stimulates the secretion of granulocyte colony-stimulating factor in vivo.

Tumor necrosis factor (TNF) is a macrophage-derived cytokine that causes hemorrhagic necrosis of several human tumors in vitro. It has a wide range of biologic effects including stimulation of secretion of both granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) by normal adult lung fibroblasts in culture. No in vivo data are available on the effect of exogenously administered TNF on cytokine production. In the studies reported here, we show that G-CSF accumulates in the serum in vivo in response to recombinant TNF (rTNF) administration. At the peak of the response circulating levels of 2-6 ng/ml of biologically active G-CSF are detectable. Surprisingly, circulating levels of GM-CSF, interleukin-3 as well as a number of other cytokines were not detectable within the limits of the assays. The results indicate that the levels of GM-CSF or interleukin-3 are minimally 100-fold lower than the peak levels of G-CSF. These data illustrate the complex interplay that cytokines have in vivo. Understanding these interactions in humans is crucial to the correct use of this new class of agents in the clinic.

Clinical significance of CD10 expression in childhood acute lymphoblastic leukemia.

The independent significance of CD10 expression in childhood acute lymphoblastic leukemia (ALL) is uncertain because most studies have not adjusted for other risk features, such as age and immunophenotype, or for treatment effects. We reassessed the clinical importance of CD10 expression in patients who received highly effective contemporary treatment. CD10 antigen was detected in blast cells from 384 of 408 patients (94%) with B-lineage ALL and 36 of 90 (40%) with T-cell ALL. In the B-lineage subgroup, CD10 expression was associated with favorable presenting features: age > or = 1 year, lower leukocyte count (< 50 x 10(9)/l), and leukemic cell DNA index > or = 1.16 or hyperdiploidy > 50 chromosomes. One-half of the patients with CD10- B-lineage ALL had 11q23 chromosomal abnormalities. Separate analysis of the marker in T-cell ALL revealed no differences between CD10+ and CD10- cases in clinical features or karyotypic patterns, with the exception of a lower frequency of central nervous system leukemia and a higher frequency of 9p abnormalities in the former subgroup. CD10+ T-cell cases were also significantly more likely than CD10- cases to coexpress CD21, CD1, CD4, or CD8. Lack of CD10 expression was independently associated with an adverse prognosis in T-cell ALL (p = 0.02). However, for the larger subgroup of patients with B-lineage ALL, CD10 expression has no independent prognostic significance.

Pharmacokinetics of irinotecan and its metabolites SN-38 and APC in children with recurrent solid tumors after protracted low-dose irinotecan.

Irinotecan (IRN), a topoisomerase I interactive agent, has significant antitumor activity in early Phase I studies in children with recurrent solid tumors. However, the disposition of IRN and its metabolites, SN-38 and APC, in children has not been reported. Children with solid tumors refractory to conventional therapy received IRN by a 1-h i.v. infusion at either 20, 24, or 29 mg/m2 daily for 5 consecutive days for 2 weeks. Serial blood samples were collected after doses 1 and 10 of the first course. IRN, SN-38, and APC lactone concentrations were determined by an isocratic high-performance liquid chromatography assay. A linear four-compartment model was fit simultaneously to the IRN, SN-38, and APC plasma concentration versus time data. Systemic clearance rate for IRN was 58.7 +/- 18.8 liters/h/m2 (mean +/- SD). The mean +/- SD ng/ml x h single-day lactone SN-38 area under the concentration-time curve (AUC(0-->6) was 90.9 +/- 96.4, 103.7 +/- 62.4, and 95.3 +/- 63.9 at IRN doses of 20, 24, and 29 mg/m2, respectively. The relative extent of IRN conversion to SN-38 and metabolism to APC measured after dose 1 were 0.49 +/- 0.33 and 0.29 +/- 0.17 (mean +/- SD). No statistically significant intrapatient difference was noted for SN-38 area under the concentration-time curve. Large interpatient variability in IRN and metabolite disposition was observed. The relative extent of conversion and the SN-38 systemic exposure achieved with this protracted schedule of administration were much greater than reported in adults or children receiving larger intermittent doses.

Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy.

UNLABELLED: A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. PURPOSE: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. METHODS: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 microg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). RESULTS: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 microg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77 1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1-20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were < 1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. CONCLUSIONS: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.

Extending principles learned in model systems to clinical trials design.

Clinical results with irinotecan (CPT-11 [Camptosar]) and other camptothecin derivatives in various cancers, although encouraging, have fallen short of the expectations predicted by preclinical models. One proposed explanation for this is that preclinical xenograft models do not predict for the sensitivity of human cancer. In this article, we describe the results of several studies suggesting that this explanation is incorrect. Instead, our results indicate that the discrepancy between clinical response rates and findings in preclinical models may be due to a failure to incorporate the principles learned from preclinical studies into the design of clinical trials. Our analysis suggests that if differences in host tolerance are taken into account, the xenograft models are quite accurate predictors of clinical response. Moreover, application of the principles derived from preclinical models to the design of clinical trials may significantly enhance clinical response rates. Thus, the camptothecin analogs provide a paradigm for better integrated, pharmacokinetically driven, preclinical and clinical development of new drugs.

Haemopoietic growth factors in paediatric oncology: a review of the literature.

Recombinant haemopoietic growth factors (HGFs) are an attractive adjunct to reduce morbidity from chemotherapy regimens and their use has become widespread in paediatric oncology. Although patients receiving HGFs often have faster haematological recovery after intensive chemotherapy, this does not always translate into meaningful clinical benefits. This article reviews the clinical effectiveness of HGFs in a variety of different contexts. Most published studies have used granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) as prophylaxis to ameliorate the subsequent neutropenia following intensive chemotherapy. These 2 agents have also been used to mobilise peripheral blood stem cells for autologous transplantation. HGFs specific for anaemia and thrombocytopenia are currently in paediatric clinical trials and it is hoped that the proper context and administration strategy can be found to make their use clinically effective. This article also reviews data on toxicity, specifically focusing on differences between various formulations of growth factors. HGFs are expensive, and cost-benefit analyses reviewed in this article give an important perspective on the financial aspects of paediatric cancer care. Because HGFs do not benefit every child receiving chemotherapy and overuse increases costs and may result in unnecessary adverse effects, evidence-based guidelines for their rational use in paediatric oncology are proposed.

Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in children after intravenous and subcutaneous administration.

Despite its widespread use, only limited pharmacokinetic data exist for recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), especially in children. We evaluated the pharmacokinetics of rhGM-CSF in children who had undergone intensive multiagent chemotherapy: 11 children with refractory solid tumors received 500-1500 micrograms/m2 of rhGM-CSF (sargramostim) as a daily 2-h intravenous (iv) infusion, and seven children received subcutaneous (sc) rhGM-CSF at 1500-2000 micrograms/m2/d in two daily injections for 2 weeks. Serum samples obtained before and after rhGM-CSF administration were analyzed for granulocyte-macrophage colony-stimulating factor (GM-CSF) by a bioassay and by ELISA. Concentrations measured by the two methods were highly correlated (r2 = 0.89, p < 0.001). Following 2-h iv infusions, the concentration-time data were best described by a two-compartment, first-order elimination model. The median (range) for rhGM-CSF systemic clearance (CI) was 49 mL/min/m2 (range, 15-118 mL/min/m2), terminal half-life (t1/2) was 1.6 h (range, 0.9-2.5 h), and the time the GM-CSF concentration was > 1 ng/mL was 9 h (range, 6-13 h). The CI was not dose dependent or related to patient age. The absolute neutrophil count day 14 of GM-CSF was significantly related to GM-CSF dosage and platelet count on day 1. There was a weak correlation between AUC and duration of neutropenia (p = 0.05). The sc concentration-time data were best described by a one-compartment model with first-order absorption and elimination. Median apparent clearance was 72 mL/min/m2 (range, 27-231 mL/min/m2) and t1/2 was 2.3 h (range 0.7-3.8 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor.

Although infants (age less than 1 year) with neuroblastoma have a favorable overall prognosis, metastatic disease is associated with poorer treatment outcome. To assess the role of surgery in these patients, the authors reviewed survival data for 151 infants treated for neuroblastoma, focusing on patient and tumor characteristics, biological markers, and surgical management among the 99 patients with metastatic disease. Patients were divided into early (1961 to 1978) and contemporary (1979 to 1993) treatment eras. Potential prognostic factors were statistically tested to determine their significance in affecting survival. Five-year survival by Pediatric Oncology Group stage was: A, 100% (+/- 0%); B, 94% (+/- 6%); DS, 77% (+/- 9%); C, 73% (+/- 9%); and D, 61% (+/- 8%). Survival for infants with metastatic disease (stages C, D, and DS) was affected significantly by treatment era (P = .0001). Analyses restricted to patients treated during the contemporary era showed prognostic significance for DNA index (P = .02), N-myc copy number (P = .007), serum lactate dehydrogenase level (P = .001), and extent of resection (P = .01). A > or = 95% resection of the primary tumor was found to be associated with improved survival. Significantly more surgical complications were associated with resections performed at the time of diagnosis (P = .007), and delaying surgery until after several courses of chemotherapy did not decrease survival. In conclusion, multiple factors affect the outcome of treatment for infants with metastatic neuroblastoma, and whenever feasible, a > or = 95% resection of the primary tumor should be performed in this patient subgroup.