Function and quality-of-life of survivors of pelvic and lower extremity osteosarcoma and Ewing's sarcoma: the Childhood Cancer Survivor Study.

Limb-sparing surgeries have been performed more frequently than amputation based on the belief that limb-sparing surgeries provide improved function and quality-of-life (QOL). However, this has not been extensively studied in the paediatric population, which has unique characteristics that have implications for function and QOL. Using the Childhood Cancer Survivor Study, 528 adult long-term survivors of pediatric lower extremity bone tumours, diagnosed between 1970 and 1986, were contacted and completed questionnaries assessing function and QOL. Survivors were an average of 21 years from diagnosis with an average age of 35 years. Overall they reported excellent function and QOL. Compared to those who had a limb-sparing procedure, amputees were not more likely to have lower function and QOL scores and self-perception of disability included general health status, lower educational attainment, older age and female gender. Findings from this study suggest that, over time, amputees do as well as those who underwent limb-sparing surgeries between 1970 and 1986. However, female gender, lower educational attainment and older current age appear to influence function, QOL and disability.

Hb H hydrops foetalis syndrome: a case report and review of literature.

Haemoglobin H (Hb H) disease is caused by deletion or inactivation of three alpha-globin genes, leaving only one intact and active alpha-globin gene. People with Hb H disease usually have moderate anaemia, but are generally thought to be asymptomatic. Some Hb H disease patients require transfusions, and there are reports of fetuses with Hb H disease who have severe anaemia in utero resulting in fatal hydrops foetalis syndrome. We now report a case of Hb H hydrops foetalis syndrome, caused by the inheritance of a hitherto novel alpha-globin gene point mutation (codon 35 TCC-->CCC or Serine-->Proline) and an alpha-thalassaemia deletion of the Filipino type removing all zeta-alpha-globin genes on the other chromosome 16. The infant was delivered prematurely because of pericardial effusion and fetal distress, and was found to have severe anaemia and congenital anomalies. A review of the relevant literature on this syndrome is presented, and serves to underscore the phenotypic variations of Hb H disease and the need for surveillance for this condition among newborns and genetic counselling in communities with a high proportion of at-risk populations.

Using research to change practice: enteral feedings for pediatric oncology patients.

This report details a study whose purpose was to show the safety of and describe the clinical and financial outcomes of nasogastric (NG) and nasojejeunal (NJ) tube feedings for nutritional support during and after intensive treatment for cancer. During a 17-month period, NG or NJ tubes were inserted in 25 patients who experienced, or were anticipated to experience, suboptimal nutrition during or after their chemotherapy (n = 14), radiation therapy (n = 2), or chemotherapy plus radiation (n = 5), after bone marrow transplant (n = 2), and as a result of neurological impairment (n = 2). Patient ages ranged from 1 month to 14 years. NG/NJ tubes were used for a total of 1415 patient days (median 40 days). Of those, 756 days occurred in the hospital (median, 18 days) and 659 were outpatient days (median = 12 days). Total parenteral nutrition (TPN) was used during 104 patient days (range, 1 to 35 days), and combination NG/NJ feedings were given with TPN for a total of 101 days. A comparable number of days of TPN therapy for the NG-fed patients would have cost $177,390 (average $135/day), compared with $65,700 (average, $50/day) for enteral feedings, for a savings of $111,690. Ten patients experienced grade 2 to 3 diarrhea and/or vomiting during the study. No untoward outcomes were identified. Enteral feedings were found to be a safe and cost-effective method for providing nutrition to these children with cancer.

A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis.

Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC(0-96)). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC(0-96) was 128 +/- 70 mg/dL.hour for the rasburicase group and 329 +/- 129 mg/dL.hour for the allopurinol group (P <.0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P <.0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy.

Transient monosomy 7: a case series in children and review of the literature.

BACKGROUND: Monosomy 7 and deletions of the long arm of chromosome 7 [del (7q)] are recurrent, nonrandom chromosomal abnormalities associated with both de novo and therapy-related myelodysplastic syndromes (MDS). The overall prognosis for children and adults with these chromosomal abnormalities is poor. In the current report, the authors present five children with MDS associated with monosomy 7/del(7q) who achieved spontaneous hematologic disease remission as well as a review of the literature. METHODS: Five children with either de novo or treatment-related MDS who achieved spontaneous hematologic disease remission are presented. Relevant clinical, cytogenetic, and fluorescent in situ hybridization data are included. RESULTS: All patients were boys. Three had de novo MDS whereas two others previously had received chemotherapy for another malignancy. Four patients achieved spontaneous and durable hematologic disease remission that was associated with cytogenetic disease remission in all three patients tested. The fifth patient developed a disease recurrence and died with evidence of clonal evolution after a long interval of hematologic and cytogenetic remission. CONCLUSIONS: A subset of children who develop MDS associated with monosomy 7 or del(7q) achieve spontaneous hematologic and cytogenetic improvement. Although this appears to be uncommon, further data are needed to determine the percentage of patients who improve without therapy and to define clinical characteristics that may predict this clinical outcome. These findings suggest that monosomy 7/del(7q) is insufficient to produce full leukemic transformation.

Iron chelation with deferoxamine: comparing the results of a critical pathway to a national survey.

PURPOSE: The clinical outcomes of an institution's critical pathway that uses a comprehensive approach to serum ferritin management are reported. The results of this center are compared with the results of a national survey of deferoxamine (DFO) use and serum ferritin level outcomes. METHODS: Current DFO dosing and serum ferritin levels of 38 patients at this center were summarized. A questionnaire was then sent to 98 centers throughout the United States requesting information on criteria for beginning treatment with DFO, administration methods, dose modifications, and serum ferritin levels. RESULTS: The application of a critical pathway in this program resulted in 29 of 38 patients maintaining serum ferritin levels <2,000 ng/mL. Of the 42 institutions that responded to the survey, 10 attained this ferritin level in > or =50% of their patients. Ferritin levels ranged from 500 ng/mL to >20,000 ng/mL, and wide variations were reported in all study parameters. CONCLUSIONS: Iron overload can be effectively managed with alteration of DFO doses and routes using a consistent approach. Modification of administration methods, including administration of DFO during red blood cell transfusions, are indicated to attain ferritin levels of <2,000 ng/mL.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The effect of chemotherapy dose intensity on the hematological toxicity of the treatment for Wilms' tumor. A report from the National Wilms' Tumor Study.

PURPOSE: To determine the relationship between hematological toxicity and actual dose intensity of treatment of patients randomized to therapy during the first 28 months of the National Wilms' Tumor Study-4. METHODS: The mean minimum white blood cell count (WBC), platelet count (PLT), hemoglobin, and absolute neutrophil count (ANC) during the first two courses of chemotherapy and the mean number of days of hospitalization for toxicity were compared between standard and "pulse-intensive" regimens for all randomized patients entered on National Wilms' Tumor Study-4 between August 6, 1986 and December 31, 1988. The mean dose intensity of dactinomycin, vincristine, and doxorubicin received during the first two courses and the entire course of treatment was compared between standard and "pulse-intensive" regimens. RESULTS: The mean minimum WBC, PLT, and ANC were all significantly lower during the first two courses of chemotherapy for stage I patients treated with the standard regimen, compared with the "pulse-intensive" regimen. The mean dose intensity of dactinomycin and doxorubicin was significantly higher for patients treated with the "pulse-intensive" regimens, compared with the appropriate standard regimen. CONCLUSIONS: The "pulse-intensive" administration schedule for the treatment of children with Wilms' tumor permits administration of chemotherapy at a higher dose intensity without an increase in hematological toxicity.

Uterus didelphys and unilateral lower limb amelia in a discordant monozygotic twin. A case report.

Uterus didelphys and unilateral lower limb amelia were diagnosed in a discordant identical twin. The discordant occurrence of these anomalies in monozygotic twins suggests a possible coincidence.

Treatment of overt isolated testicular relapse in children on therapy for acute lymphoblastic leukemia. A report from the Childrens Cancer Group.

BACKGROUND: Fifty-seven children with acute lymphoblastic leukemia (ALL) receiving therapy who experienced overt isolated testicular relapse while in bone marrow remission were entered into a study that featured an intensive retreatment regimen. METHODS: The objective was to determine whether a change in chemotherapy and local irradiation would prevent subsequent marrow relapse and increase the survival rate. The regimens used (modified Berlin-Frankfurt-Munster or modified New York) delivered acceptable therapy based on analyses of toxicity data. RESULTS: Overall survival at 5 years from the time of testicular relapse was 47%, with an event-free survival of 43%. Events have been documented in 28 of 55 evaluable children. Analysis of these patients revealed that 23 children had bone marrow relapse, 4 children had central nervous system relapse, and 1 child had testicular relapse. In addition, two patients were removed from the study for toxicity, one child for infection (mucormycosis), and five children had a bone marrow transplantation while in remission and became ineligible to continue in the study. Two children were removed at the request of their parents, and nine children were lost to follow-up. CONCLUSION: Because of their high risk of developing systemic relapse, boys with ALL who experience isolated overt testicular relapse during active therapy should be retreated with intensive treatment.

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.

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

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

Measured resting energy expenditure in children.

The majority of equations used to predict values for basal metabolic rates (BMRs) are the result of indirect calorimetry measurements performed in the 1930s and 1950s. To assess the reliability of these equations in predicting the resting energy expenditure (REE) of the children in our community, indirect calorimetry was performed on 92 male and 107 female healthy children 2-3 h postprandial. Each individual was measured for a duration of 15-20 min. The data for analysis were obtained from 5-15 min steady-state periods. Subjects ranged in age from 5 to 16 years. The results were compared with BMRs calculated from the Harris-Benedict equation (Harris J, Benedict F. A biometric study of basal metabolism in man. Washington, DC: Carnegie Institute of Washington, publication no. 279, 1919.), the Food and Agriculture Organization/World Health Organization/United Nations University (FAO/WHO/UNU) equations, and the equations proposed by Schofield for use by the 1985 FAO/WHO/UNU Nutrition Committee. The values predicted by the FAO/WHO/UNU and Schofield equations were consistent with the measured resting values for all the children in the study population. Ninety-two children weighed between 90-110% of their ideal body weight. When the measured REE and estimated BMR were compared by gender and age in these children, the Schofield equations provided the best estimates. Ninety-four of the study subjects weighed > 110% of their ideal body weight. The predicted estimates by all equations were consistent with the measured values in this subgroup of the population. We conclude that the FAO/WHO/UNU and Schofield equations are reliable estimates of metabolic rate in healthy children when measurement of REE is not possible.