Old man river. The flow of pediatric oncology.

Progress in pediatric oncology has been made by gathering individual investigators and their work into even larger research groups. The authors liken this process to the way small waters coalesce to form large rivers. This pattern can be traced back for most of the entities included under the rubric pediatric oncology, but it is more convenient and informative to do so with respect to two specific entities: acute lymphoblastic leukemia and Wilms' tumor. These malignancies are used as surrogates for the liquid and solid tumors and are addressed in this article.

Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study.

PURPOSE: To investigate the antitumor activity and toxicity of topotecan, used alone and in combination with conventional therapy, in patients with metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Forty-eight patients younger than 21 years of age with newly diagnosed metastatic RMS received 2.0 to 2.4 mg/m(2) of topotecan intravenously daily for 5 days every 21 days before standard therapy. Two courses were given in the absence of progressive disease or excessive toxicity and response was assessed. Patients with at least a partial response (PR) to topotecan proceeded to therapy with alternating courses of vincristine 1.5 mg/m(2), dactinomycin 1.5 mg/m(2), and cyclophosphamide 2.2 g/m(2) (VAC) and vincristine 1.5 mg/m(2), topotecan 0.75 mg/m(2) daily x 5, and cyclophosphamide 250 mg/m(2) daily x 5. Patients who did not respond to topotecan received continuation therapy with VAC alone. RESULTS: The overall response rate to topotecan was 46% (complete response, 4%; partial response 42%). Unexpectedly, patients with alveolar RMS had a higher rate of response (65%) than those with embryonal RMS (28%; P: = .08). The most common grade 3 or 4 toxicities were neutropenia (67%), anemia (33%), thrombocytopenia (25%), and infection (21%). Two-year failure-free survival and survival estimates were 24% and 46%, respectively. Response to window therapy did not correlate with survival. CONCLUSION: The high response rate and acceptable toxicity profile of topotecan in children with advanced RMS support further evaluation of this agent in phase III trials. The superior responses in alveolar RMS are of interest.

Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation.

PURPOSE: To evaluate prospectively the effects on survival, relapse-free survival, and patterns of relapse of reduced-dose (23.4 Gy in 13 fractions) compared with standard-dose (36 Gy in 20 fractions) neuraxis irradiation in patients 3 to 21 years of age with low-stage medulloblastoma, minimal postoperative residual disease, and no evidence of neuraxis disease. PATIENTS AND METHODS: The Pediatric Oncology Group and Children's Cancer Group randomized 126 patients to the study. All patients received posterior fossa irradiation to a total dose of 54 Gy in addition to the neuraxis treatment. Patients were staged postoperatively with contrast-enhanced cranial computed tomography, myelography, and CSF cytology. Of the registered patients, 38 were ineligible. RESULTS: The planned interim analysis that resulted in closure of the protocol showed that patients randomized to the reduced neuraxis treatment had increased frequency of relapse. In the final analysis, eligible patients receiving standard-dose neuraxis irradiation had 67% event-free survival (EFS) at 5 years (SE = 7.4%), whereas eligible patients receiving reduced-dose neuraxis irradiation had 52% event-free survival at 5 years (SE = 7.7%) (P =.080). At 8 years, the respective EFS proportions were also 67% (SE = 8.8%) and 52% (SE = 11%) (P =.141). These data confirm the original one-sided conclusions but suggest that differences are less marked with time. CONCLUSION: Reduced-dose neuraxis irradiation (23.4 Gy) is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year EFS and overall survival than standard irradiation (36 Gy). The 5-year EFS for patients receiving standard-dose irradiation is suboptimal, and improved techniques and/or therapies are needed to improve ultimate outcome. Chemotherapy may contribute to this improvement.

Phase I and pharmacokinetic study of CI-980 in recurrent pediatric solid tumor cases: a Pediatric Oncology Group study.

To establish the maximum tolerated dosage (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetic parameters of CI-980, a novel tubulin binder, in children with solid tumors refractory to standard therapy. Patients 21 years of age or younger with adequate nutritional, hematopoietic, renal, and hepatic function were eligible. The patient must not have been pregnant. Patients with brain tumors were not eligible for any dosage level until it was demonstrated the level did not produce DLT in patients with extracranial solid tumors. The starting dosage level was 3.5 mg/m2/day, for 3 days, administered as a continuous intravenous infusion (80% of the adult MTD). If a dosage level was associated with dose-limiting myelotoxicity, growth factors were to be added. Thirty-three patients received CI-980. Twenty-four had solid tumor; 9 had brain tumor. The MTD achieved without granulocyte colony stimulating factor (G-CSF) was 3.5 mg/m2/day (DLT: neutropenia) and with G-CSF, it was as follows: patients with brain tumor, 4.2 mg/m2/day (DLT: myelosupression); and patients with solid tumor, 5 mg/m2/day (DLT: cortical toxicity). Several responses were seen, most notably prolonged stable disease in two of five patients with medulloblastoma. Pharmacokinetic data showed a mean steady state level of 1.74 ng/mL for two patients treated with the 5 mg/m2/day regimen, with rapid decay after the termination of the infusion. CI-980 showed preliminary evidence of activity in recurrent pediatric malignancies, with tolerable, reversible toxicities.

Acute lymphoblastic leukemia with the (8;14)(q24;q32) translocation and FAB L3 morphology associated with a B-precursor immunophenotype: the Pediatric Oncology Group experience.

Five pediatric patients are described with acute lymphoblastic leukemia (ALL) who at presentation had clinical findings suggestive of B cell ALL and lymphoblasts with FAB L3 morphology and the characteristic t(8;14)(q24;q32). However, the leukemia cells of all five patients failed to express surface immunoglobulin (sIg) and kappa or lambda light chains. Based on initial immunophenotyping results consistent with B-precursor ALL, four of these cases were initially treated with conventional ALL chemotherapy. These four patients were switched to B cell ALL treatment protocols once cytogenetic results became available revealing the 8;14 translocation. The fifth case was treated with B cell ALL therapy from the outset. Four of the five patients are in complete remission at 64, 36, 29 and 13 months from diagnosis. One patient relapsed and died 6 months after initial presentation. These five unusual cases with clinical B cell ALL, the t(8;14), and FAB L3 morphology, but negative sIg, demonstrate the importance of careful and multidisciplinary evaluation of leukemic cells with morphology, cytochemistry, immunophenotyping and cytogenetic analysis. Future identification of patients with this profile will allow us to expand our knowledge regarding prognostic significance and optimal treatment for this rare subgroup of patients.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

PURPOSE: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS: Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS: A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients. RESULTS: Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted. CONCLUSION: The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.

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.

Pediatric phase II cancer chemotherapy trials: a Pediatric Oncology Group study.

PURPOSE: This study reviewed the Pediatric Oncology Group experience with phase II clinical trials in children (< 21 years of age) with refractory tumors. PATIENTS AND METHODS: Patients registered in Pediatric Oncology Group phase II studies were evaluated. Patients had to be < 21 years of age with recurrent and refractory measurable disease. Tumor types and response rates were determined. Death on therapy from either drug toxicity, progressive disease, infection, or hemorrhage was measured. Tumor-specific, disease-free survival curves were calculated by Kaplan-Meier analysis. RESULTS: Between 1984 and 1994, 2,465 patient entries were made on 45 phase II trials. Malignancies registered included acute lymphocytic leukemia (ALL) (16.7%), acute myeloid leukemia (AML) (12.0%), osteogenic sarcoma (7.8%), neuroblastoma (7.2%), astrocytoma (7.2%), medulloblastoma (7.1%), glioma (6.7%), ependymoma (6.1%), and others (29.2%). The overall response rate was 19.6% (CR + PR) for children entered on phase II trials. Tumor-specific response rates ranged from 62.1% (23/37) for children with Hodgkin's disease to no responses (0/23) in patients with hepatoblastoma. When comparing single versus multiagent trials, a significantly better initial response rate was seen in the latter studies. However, 5-year survival was comparable. Progression-free survival for all tumor histologies were 12.9% and 9.2% at 2 and 5 years, respectively. Death on study was seen in 11.6% of the patients; however, only three deaths were directly related to drug toxicity. There were no significant gender differences in regards to response, progressive disease, or death on study. CONCLUSION: Phase II studies conducted in children offer a considerable likelihood of therapeutic benefit without exposing these patients to untoward toxicity.

Preservation of the bladder in patients with rhabdomyosarcoma.

PURPOSE: To review the pathologic findings from children with gross residual rhabdomyosarcoma (RMS) of the bladder and compare the treatment outcome of those who underwent cystectomy with those who did not. PATIENTS AND METHODS: Primary and follow-up records and pathology specimens for 28 patients with gross residual disease entered onto the intergroup Rhabdomyosarcoma Study (IRS) III were reviewed. These patients were assigned to receive 20 weeks of multiagent induction chemotherapy and 4 weeks of radiotherapy. Future therapy decisions were based on clinical and histologic evaluation at 20 weeks. RESULTS: All patients had a clinical and histologic response. Thirteen patients underwent cystectomy at intervals that ranged from 1.5 to 38 months after the start of therapy. All but one patient are alive and well without recurrence. Reasons for cystectomy included presumed evidence of tumor growth from imaging studies, findings at cystoscopy, or histologic interpretation of biopsies. In 12 of 14 specimens from 15 patients who retained their bladder, no tumor cells were seen at first or second evaluation. In cystectomy specimens, tumor cellularity was markedly reduced and all tumor cells were in varying degrees of cellular maturation. Review of primary tumor specimens showed a greater degree of cellular maturation in patients with retained bladders than in those who underwent cystectomy. CONCLUSION: Bladder RMS is responsive to chemotherapy and radiotherapy. Twelve of 26 patients showed complete loss of tumor cells after induction therapy. Cystectomy specimens showed diminished tumor cells with varying degrees of cellular maturation. It is hypothesized that these tumors may have shown further maturation and ultimate loss of matured cells with continuing therapy.

Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: A phase I trial was conducted in children with refractory solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and pharmacodynamics for topotecan administered by a 30-min infusion for 5 consecutive days. PATIENTS AND METHODS: Forty children with a variety of recurrent solid tumors, including nine patients with neuroblastoma and 10 with brain tumors, were given topotecan as a 30-min infusion for 5 consecutive days, beginning with a dose of 1.4 mg/m2/day. The dose was escalated in 20% increments after establishing that DLT was not present at the prior dose. Drug toxicity was graded using standard criteria. Dose-limiting toxicity was defined as grade 3 or 4 nonhematopoietic toxicity or grade 4 hematopoietic toxicity lasting > 7 days. Pharmacokinetic studies were performed during the first infusion course. RESULTS: The DLT was hematopoietic and involved both platelets and neutrophils. Grade 4 hematopoietic toxicity of brief duration was seen at all dose levels. Over half of the patients received red blood cell transfusion support, and 19/40 received platelet transfusions. Hospital admissions for fever and neutropenia or for documented infections occurred in 32 of 169 courses of therapy. Gastrointestinal symptoms with nausea and vomiting or diarrhea were mild to moderate in 12 of the 40 patients. Antitumor responses were seen in three patients with neuroblastoma. An additional four patients (one with neuroblastoma, two with anaplastic astrocytomas, one with Ewing) had stable disease with continued therapy for > 6 months. Using a limited sampling model, pharmacokinetic studies were performed in 36 of the 40 patients. Topotecan lactone and total clearance were similar to those reported in other pediatric populations receiving topotecan by continuous infusion. A pharmacodynamic relation between systemic exposure to topotecan lactone and myclosuppression was observed. CONCLUSIONS: In heavily pretreated children, the MTD for topotecan given by intermittent 30-min infusion for 5 days is 1.4 mg/m2 without GCSF and 2.0 mg/m2/day with GCSF. The dose-limiting toxicity is hematopoietic. Data from this study provide the basis for further studies of topotecan in children with cancer.

Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3,600 cGy/20) with reduced neuraxis irradiation (2,340 cGy/13) in patients with low-stage medulloblastoma. A Combined Children's Cancer Group-Pediatric Oncology Group Study.

PURPOSE: To determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions in patients with newly diagnosed medulloblastoma between 3 and 21 years of age with low T stage (T1, T2 and T3A), minimal postoperative residual tumor, and no evidence of dissemination (M0). METHODS AND MATERIALS: Between June 1986 and November 1990, the Children's Cancer Group and the Pediatric Oncology Group randomized 126 patients in a two-arm study comparing the two different doses of neuraxis irradiation. In both arms, the posterior fossa received 5,400 cGy in 30 fractions. All patients were staged with myelography, postoperative lumbar cerebrospinal fluid cytology, and postoperative contrast-enhanced cranial computerized tomography to ensure no evidence of dissemination and no more than 1.5 cm3 residual tumor volume. Overall survival, progression-free survival, and patterns of recurrence were carefully monitored. Prospective endocrine and psychometric studies were performed to determine the benefit of decreasing the neuraxis radiation dose. RESULTS: Following an interim analysis at a median time on study of 16 months, the study was closed, since a statistically significant increase was observed in the number of all relapses as well as isolated neuraxis relapses in patients randomized to the lower dose of neuraxis radiation. CONCLUSIONS: In patients with newly diagnosed medulloblastoma considered to have a good prognosis on the basis of low T stage, minimal residual tumor after at least subtotal resection, and no evidence of dissemination after thorough evaluation, there is an increased risk of early relapse associated with lowering the dose of neuraxis radiation from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions.

The importance of phase I/II trials in pediatric oncology.

Clinical trials in pediatric oncology over the past 30 years have led to the situation today where most children with newly diagnosed cancer can be treated effectively, and many are cured. Despite this dramatic improvement in outcome for many children diagnosed with cancer, about 30-40% of children will die of their disease [1]. Although some attempts have been made to improve outcome by increasing the dose intensity of existing therapies, intolerable side effects and marginal increases in cancer cell kill limit this approach. Clearly, effective new anti-cancer agents are necessary to significantly improve the survival and quality of life in children with cancer. Well-organized pediatric Phase I trials to establish the maximum tolerated dose (MTD), and Phase II trials to establish efficacy, are critical to the identification of new anti-cancer agents.

Cyclophosphamide dose escalation in combination with vincristine and actinomycin-D (VAC) in gross residual sarcoma. A pilot study without hematopoietic growth factor support evaluating toxicity and response.

PURPOSE: The Intergroup Rhabdomyosarcoma Study (IRS) initiated an escalating-dose cyclophosphamide (Cyc) pilot without hematopoietic growth factor (HGF) support in combination with vincristine (Vcr) and actinomycin-D (Amd), known as VAC, to establish a Cyc dose with myelotoxicity comparable to an ifosfamide (Ifos), Vcr, and Amd combination regimen (VAI). A Cyc dose equivalent to Ifos was to be determined when comparable myelotoxicity was achieved. PATIENTS AND METHODS: Patients with either rhabdomyosarcoma or undifferentiated soft-tissue sarcoma and gross residual (clinical group III) disease were eligible for the VAC pilot. Feasibility and toxicity were evaluated in the VAC pilot at each Cyc level before escalating the dose. Starting at CYC 1.2 g/m2 dose escalation was planned at increments of 20-25% in cohorts of 8-10 patients until myelotoxicity at a severe or worse grade was seen in > 90% of the patients. RESULTS: One hundred nineteen eligible patients were evaluated for toxicity and response at four Cyc levels: 1.2, 1.5, 1.8, and 2.2 g/m2. Eight of 87 (9%) evaluable at 2.2 g/m2 had a toxic death. Six of these were attributable to myelotoxicity. Patients age 1-3 years were most vulnerable. The overall complete response (CR) rate of 68% was poorly predicted by the weeks 8 and 20 CR rates of 20 and 40%, respectively. During the first year and overall, myelotoxicity at 2.2 g/m2'1 with VAC was comparable to Ifos 1.8 g/m2'5. Cyc was relatively more myelotoxic than Ifos in the second year of the VAC pilot. Based on actual amount of drug given, a standardized Ifos dose of 9.0 g/m2 was equivalent to 2.1 g/m2 of Cyc, giving an Ifos/Cyc ratio of 4.3. CONCLUSION: Myelotoxicity using 2.2 g Cyc/m2 in a single intravenous infusion was dose limiting in this VAC pilot without HGF. In the first year and overall, myelotoxicity is comparable to that with VAI using Ifos at 9.0 g/m2. An ongoing IRS-IV randomized trial of VAC and VAI should provide a comparison of the efficacy of Ifos and Cyc in children and adolescents with embryonal or alveolar rhabdomyosarcoma and undifferentiated soft-tissue sarcomas.

Cyclophosphamide/doxorubicin vs. cisplatin/teniposide in the treatment of children older than 12 months of age with disseminated neuroblastoma: a Pediatric Oncology Group Randomized Phase II study.

This prospective study was designed to estimate the response rates and to compare two drug pairs, cyclophosphamide/doxorubicin (Cy/A) and cisplatin/teniposide (P1/VM) in previously untreated patients with disseminated neuroblastoma > 12 months of age at diagnosis. Estimated complete clinical response rates after five courses of therapy were 13% (70 patients) and 22% (64 patients) for Cy/A and P1/VM, respectively (P = 0.17). After surgical removal of residual tumors in patients with partial response, the complete response rates were 27% and 34% (P = 0.50), respectively. The overall CR/PR rates after induction and surgery were 59% and 73% (P = 0.077). There was no significant difference in event free survival (P = 0.48) or survival (P = 0.40). Five year survival on the two arms were 14% (SE = 5%) and 12% (SE = 4%), respectively. Toxicity was significant but manageable. The Cy/A arm had significantly higher hematopoietic toxicity but significantly lower GI toxicity. Significant allergic reactions were seen with the P1/VM arm, none in the Cy/A arm. Given the activity of these two regimens, further therapy with a combination of these regimens is suggested.

A phase I study of acivicin in refractory pediatric solid tumors. A Pediatric Oncology Group study.

Forty-two patients with progressive solid tumors and brain tumors were entered in this Phase I study of the glutamine antagonist acivicin given intravenously over thirty minutes daily for five days. The major toxicities encountered were myelosuppression and central nervous system toxicity (nightmares and somnolence). The maximum tolerated dosage on this schedule was 26 mg/M2 daily for five days. Six patients including three patients with brain tumor had stable disease.

Prognostic features of Ewing's sarcoma on radionuclide bone scan after initial treatment.

OBJECTIVE: To study short-term changes in the radiopharmaceutical bone scan (BS) appearance of Ewing's sarcoma for indicators of decreased survival or future disease progression. METHODS: One-hundred and four patients with non-metastatic Ewing's sarcoma were evaluated at three time points: time of diagnosis (pre-biopsy), after induction chemotherapy (13 weeks) and after radiation therapy (20 weeks). Radiographs, computed tomograms (CTs) and BSs were obtained at each interval. Primary lesion activity and size on BS were evaluated and compared to radiographic and CT findings. RESULTS: No significant relationship was found at any time point between absolute radiopharmaceutical activity within the primary lesion and either disease progression or patient survival. Relative changes in BS activity between time points were also not significantly related to disease progression or survival despite a significant decrease in activity among the three time points. The size of the BS abnormality compared to the CT abnormality at the primary lesion site was related to both survival and disease progression at the post-induction chemotherapy time point (P = 0.025 and P = 0.014, respectively) with larger BS abnormalities indicating worse prognosis and survival. This relationship lost its significance at the post-radiation time point. No other significant relationship between the relative size of the BS abnormality and the size of the plain radiographic or CT abnormality was detected. CONCLUSION: Our data suggest that BS imaging of the primary lesion of Ewing's sarcoma provides little information in terms of predicting long-term survival or disease progression in patients with non-metastatic Ewing's sarcoma.

Acute myeloid leukemia in patients treated for rhabdomyosarcoma with cyclophosphamide and low-dose etoposide on Intergroup Rhabdomyosarcoma Study III: an interim report.

The early occurrence of five cases of acute myeloid leukemia (AML) in children treated for primary rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Study III (IRS III) has prompted this report. These patients received cyclophosphamide and four received etoposide in addition to other agents. There were 1,062 eligible patients entered on IRS III between 1984 and 1991. Following surgery, treatment consisted of multiagent chemotherapy and radiotherapy in select clinical groups. Median follow-up time is 3.7 years (range 0-7.4 years). Incidence densities and odds ratios for AML were calculated for various treatment groups. Five cases of secondary AML have been reported through August 1992. A single case of osteogenic sarcoma was reported in the same period and a patient with myelodysplastic syndrome has occurred since that time. Median time to development of AML was 39 months. Incidence density of AML for patients receiving neither cyclophosphamide nor etoposide was 0, for those receiving cyclophosphamide but no etoposide it was 7.6, and when both agents were given, it was 51.6. The odds ratios of AML for the latter two groups indicated a risk of AML which was seven times higher in the patients who received both agents. A history of breast cancer was present in all five families of patients with AML and several other cancers had occurred in three families. Preliminary analysis suggests a possible causal role for low-dose etoposide in addition to that assumed for cyclophosphamide in the early development of AML among pediatric patients treated for rhabdomyosarcoma.

Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study.

PURPOSE: A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed. PATIENTS AND METHODS: Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation. RESULTS: A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%. CONCLUSION: Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.

Prognostic features of Ewing sarcoma on plain radiograph and computed tomography scan after initial treatment. A Pediatric Oncology Group study (8346)

BACKGROUND: The authors studied the short-term changes in the plain radiographic and computed tomography (CT) appearance of Ewing sarcoma for indicators of decreased survival or future disease progression. METHODS: The authors evaluated CT scans and plain radiographs of the primary tumor site from 105 patients with Ewing sarcoma at diagnosis (prebiopsy), after induction chemotherapy (13 weeks), and after radiation therapy (20 weeks). RESULTS: Data suggest an association between postinduction CT findings of medullary involvement, cortical destruction, lysis, permeation, and unhealed pathologic fracture and decreased survival. On the postradiation scans, only medullary involvement was associated with worsened survival. No plain radiographic features were significant at any time. Absolute greatest tumor dimension was not significantly related to survival or tumor progression. The Cox model suggested that fractional change in greatest tumor dimension on CT at the time points studied relative to the prebiopsy CT was correlated to survival. Log-rank testing did not corroborate this finding. All significant associations appeared to result from adverse outcomes in small subgroups. CONCLUSIONS: Our data suggest that CT obtained immediately after induction chemotherapy and radiation may have some limited use in predicting the long-term prognosis of patients with Ewing sarcoma.