Prognostic variables in newly diagnosed children and adolescents with acute myeloid leukemia: Children's Cancer Group Study 213.

The objective of this study was to identify biologic parameters that were associated with either exceptionally good or poor outcome in childhood acute myeloid leukemia (AML). Among the children with AML who entered Children's Cancer Group trial 213, 498 patients without Down syndrome or acute promyelocytic leukemia (APL) comprise the basis for this report. Univariate comparisons of the proportion of patients attaining complete remission after induction (CR) indicate that, at diagnosis, male gender, low platelet count (< or =20 000/microl), hepatomegaly, myelodysplastic syndrome (MDS), French-American- British (FAB) category M5, high (>15%) bone marrow (BM) blasts on day 14 of the first course of induction, and +8 are associated with lower CR rates, while abnormal 16 is associated with a higher CR rate. Multivariate analysis suggests high platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 are independent prognostic factors associated with better CR. Univariate analysis demonstrated a significant favorable relationship between platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, low percentage of BM blasts (< or =15%), and abnormal 16 with overall survival. Absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 were determined to be independent prognostic factors associated with better survival.

Intraoperative high-dose-rate brachytherapy for the treatment of pediatric tumors: the Ohio State University experience.

PURPOSE: To determine whether intraoperative high-dose-rate brachytherapy (IO-HDRBT) can be used to decrease the dose of external beam radiotherapy (EBRT) in the treatment of children with soft-tissue sarcomas and, thereby, reduce morbidity without compromising local control. METHODS AND MATERIALS: From March 1992 through April 1999, 13 pediatric patients were treated with IO-HDRBT, low-dose EBRT, chemotherapy, and radical surgery at 21 sites that were not amenable to intraoperative electron beam therapy. The IO-HDRBT dose at 5 mm depth was 10 to 12.5 Gy for close margins/microscopic disease at 14 sites and 12.5 to 15 Gy for gross disease at 7 sites. The treatment volumes ranged from 4 to 96 cm(3) (mean 27). The EBRT dose was limited to 27-30 Gy in most cases to minimize growth retardation and preserve normal organ function. RESULTS: After a median follow-up of 47 months (range 12-97), 11 patients were alive and without evidence of disease (overall survival rate 85%, 4-year actuarial survival rate 77%). Of the 2 who died, 1 had Stage III pulmonary blastoma with a sacral recurrence; the other had Stage IV undifferentiated synovial sarcoma with a pulmonary recurrence. One local failure occurred in a patient with gross residual disease after incomplete resection for Stage IV pulmonary blastoma. The local control rate was 95%, and morbidity was observed in 3 patients (23%). One patient developed impaired orbital growth with mild ptosis. Another patient required orthopedic pinning of her femoral subcapital epiphysis and construction of a neobladder secondary to urethral obstruction. The third patient required reimplantation of her autotransplanted kidney secondary to chronic urinary tract infection and ureteral reflux. CONCLUSIONS: IO-HDRBT allowed for reduction in EBRT without compromising local control or disease-free survival in children with soft-tissue sarcomas. Tumor beds inaccessible to electron beam methods could be satisfactorily encompassed with IO-HDRBT techniques.

Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease.

PURPOSE: The study goal was to improve outcome in children with rhabdomyosarcoma by comparing risk-based regimens of surgery, radiotherapy (RT) and chemotherapy. PATIENTS AND METHODS: Eight hundred eighty-three previously untreated eligible patients with nonmetastatic rhabdomyosarcoma entered the Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) (1991 to 1997) after surgery and were randomized treatment by primary tumor site, group (1 to 3), and stage (I to III). Failure-free survival (FFS) rates and survival were the end points used in comparisons between randomized groups and between patient subgroups treated on IRS-III and IRS-IV. Most patients were randomized to receive vincristine and dactinomycin (VA) and cyclophosphamide (VAC, n = 235), or VA and ifosfamide (VAI, n = 222), or vincristine, ifosfamide, and etoposide (VIE, n = 236). Patients with group 3 tumors were randomized to receive conventional RT (C-RT) versus hyperfractionated RT (HF-RT). RESULTS: Overall 3-year FFS and survival were 77% and 86%, respectively. Three-year FFS rates with VAC, VAI, and VIE were 75%, 77%, and 77%, respectively (P =.42). No significant difference in outcome was noted with HF-RT versus C-RT (P =.85 and P =.90, respectively). Overall, patients with embryonal tumors benefited from intensive three-drug chemotherapy in IRS-IV (3-year FFS, 83%). The improvement was seen for patients with stage I or stage II/III, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage 2/3, group 3 disease had similar outcomes on IRS-III and IRS-IV. Three-year FFS for the nonrandomized patient subsets was 75% with renal abnormalities; 81% for paratesticular, group 1 cases; and 91% for group 1/2 orbit or eyelid tumors. Patients with paratesticular primaries had poorer outcomes if they were more than 10 years old (3-year FFS, 63% v 90%). Myelosuppression occurred in most patients, but toxic deaths occurred in less than 1%. CONCLUSION: VAC and VAI or VIE with surgery (with or without RT), are equally effective for patients with local or regional rhabdomyosarcoma and are more effective for embryonal tumors than therapies used previously. Younger patients with group 1 paratesticular embryonal tumors and all patients with group 1/2 orbit or eyelid tumors can usually be cured with VA chemotherapy along with postoperative RT for group 2 disease.

Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group.

PURPOSE: This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma. PATIENTS AND METHODS: One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival. RESULTS: Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P = 0.043; OS: 55% vs. 27%; P = 0.012). CONCLUSIONS: Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

Variables influencing end-of-life care in children and adolescents with cancer.

BACKGROUND: The purpose of this study was to describe the variables influencing end-of-life care in children and adolescents dying of cancer. MATERIALS AND METHODS: Records of 146 children with cancer who died at Children's Hospital were reviewed for demographics, diagnosis, location of death, withdrawal of life support, use of "do not resuscitate" (DNR) orders, and the length of time that those orders were in effect. RESULTS: Ninety-five patients were evaluated. Fifty-nine died of progressive disease and 36 deaths were therapy-related. Sixty-four percent of disease-related deaths occurred at home with support from home care or hospice. Only 10% of all patients died while receiving maximal aggressive support in the intensive care unit. Age, diagnosis (solid tumor vs. leukemia), cause of death, length of last hospital admission, and the duration of DNR orders had a significant correlation with the place of death and referral to and use of hospice. Thirty-five percent of all patients had hospice support. CONCLUSIONS: Most children who die of cancer die because of progressive disease at home with hospice support. Do not resuscitate orders were written for most patients who died. End-of-life decisions are influenced by patient diagnosis, cause of death, and age.

TEL/AML-1 fusion gene. its frequency and prognostic significance in childhood acute lymphoblastic leukemia.

TEL gene rearrangement due to the 12;21 chromosome translocation is believed to be the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL). A study was conducted to investigate the frequency and prognostic significance of TEL/AML-1 fusion gene resulting from a cryptic t(12;21)(p13;q22). Bone marrow samples from 86 patients diagnosed over the past 5 years at Columbus Children's Hospital were analyzed by fluorescence in situ hybridization (FISH) technique for TEL/AML-1 fusion gene, using LSI((R)) DNA probes. The positive cases were analyzed for clinical outcome. Patients in this study received treatment according to Children's Cancer Group (CCG) protocols. Fifteen of the 86 cases (17%) were positive for the fusion gene. All were B-cell lineage and except for one, all were CD10 positive. TEL/AML-1 was not found in any T-cell ALL. The mean overall survival (OS) following diagnosis for the TEL/AML-1-positive group was significantly longer than for the TEL/AML-1-negative group by log-rank = 7.84, P = 0.005. Similarly, the event-free survival (EFS) after remission for the positive group (median 94.5 months) was longer than the negative group (median 57 months) by log-rank = 7.19, P = 0.007. This study confirms that the TEL/AML-1 fusion gene may be the most common genetic event in childhood ALL, occurring in 17% of the patients. It appears restricted to the B-cell lineage. In this study, the presence of a TEL/AML-1 fusion gene was statistically significant in predicting both OS and EFS, indicating a favorable clinical outcome for these patients. Screening for TEL/AML-1 should become routine at diagnosis and a useful biological variable for risk stratification in future clinical trials.

Progress in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas.

Advances in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas continue in the Intergroup Rhabdomyosarcoma Study Group (IRSG) and European cooperative groups. The use of molecular biology techniques in soft tissue sarcomas are redefining the classic pathology of these small blue cell tumors. Improvements in imaging, radiotherapy, and surgery, in part, deserve credit for the better survival seen in all cooperative trials. These advances confound the interpretation of consecutively run chemotherapy trials using historical comparisons. The IRSG has reported improvement in the prognosis of both nonmetastatic and metastatic embryonal rhabdomyosarcoma as attributable to three, three-drug regimens that use cyclophosphamide at 2.2 g/m2 in either maintenance or induction and maintenance therapy. Patients of any age with metastatic, nonembryonal, and those over 10 years of age with metastatic embryonal rhabdomyosarcoma continue to have a poor prognosis, which even megatherapy has failed to change. The doublet of ifosfamide and etoposide in combination with vincristine, actinomycin D, and cyclophosphamide at 2.2 g/m2 achieved a remarkable 3-year survival of 58% in patients with metastatic rhabdomyosarcoma and undifferentiated soft tissue sarcoma. The topoisomerase I inhibitor, topotecan, has recently been found by the IRSG to have a 57% overall response rate in patients with metastatic alveolar rhabdomyosarcoma. Topotecan has completed testing with cyclophosphamide in a phase II window study in newly diagnosed patients with metastatic disease and has been incorporated into a randomized trial in intermediate risk patients in IRSG-V. Molecular studies in IRSG-V will be applied in the detection of occult bone marrow metastases and the evaluation of resection margins at initial and second-look surgery. Long-term follow-up will be required in patients with gross residual sarcoma randomized to conventional and hyperfractionated radiotherapy in IRSG-IV to assess late effects. Although older patients with unfavorable histology and metastatic disease continue to have a poor prognosis, the overall 5-year survival of children and adolescents with nonmetastatic and metastatic rhabdomyosarcoma is approaching 80%. As molecular discoveries advance the diagnosis and detection of rhabdomyosarcoma, it is hoped that the futuristic molecular based treatment strategies in development and early testing will further improve survival in high-risk patients with metastatic soft tissue sarcoma.

Use of brachytherapy to preserve function in children with soft-tissue sarcomas.

Pediatric soft-tissue sarcomas are managed with a multimodality treatment program that includes surgery, chemotherapy, and external-beam radiotherapy (teletherapy). The use of teletherapy in young children can result in significant long-term toxicities (especially growth retardation of bones and organs). Brachytherapy, if feasible, is an attractive alternative for the treatment of pediatric soft-tissue sarcomas, since it irradiates small volumes and, thus, may potentially minimize complications. Aggressive chemotherapy is used to achieve systemic control and tumor shrinkage, thereby facilitating conservative surgery and brachytherapy. The brachytherapy techniques used in children are similar to those employed in adults. Low-dose-rate (LDR) brachytherapy with manually afterloaded removable iridium-192 is commonly used, although it is associated with some radiation exposure hazards. Low-energy radionuclides (e.g., iodine-125) and remote afterloading technology have been used to reduce radiation exposure hazards. Brachytherapy, in conjunction with chemotherapy and surgery but without supplementary teletherapy, has produced good local control with acceptable late complications in selected patients with localized tumors. Brachytherapy can also be used as a boost to moderate dose external-beam radiotherapy for more extensive tumors. The use of newer modalities, such as high-dose-rate, pulsed-dose-rate, and intraoperative brachytherapy, has allowed brachytherapy to be given to younger children and infants, but the long-term morbidities of these modalities need to be established.

Neurofibromatosis-Noonan syndrome and acute lymphoblastic leukemia: a report of two cases.

Two boys with neurofibromatosis-Noonan syndrome in whom acute lymphoblastic leukemia (ALL) developed are described. Both patients demonstrated B-lineage leukemias with normal cytogenetics. They were treated with combination chemotherapy and remain in remission off therapy. Patients with neurofibromatosis-Noonan syndrome may be at increased risk for ALL.

Feasibility of intraoperative high-dose rate brachytherapy to boost low dose external beam radiation therapy to treat pediatric soft tissue sarcomas.

PURPOSE: To determine if a single intraoperative high-dose-rate brachytherapy (IOHDR) dose can be used in conjunction with low dose external beam radiation therapy (EBRT) to treat soft tissue malignancies in children with reduced morbidity. METHODS: From March 1992 to February 1995, six pediatric patients (4 boys, 2 girls; ages ranging from 4-13 years; median 10.5 years) were treated with IOHDR in conjunction with EBRT, chemotherapy, and radical surgery at nine sites not treatable by standard intraoperative electron beam radiation therapy techniques. The IOHDR dose was 10 Gy (at 7 sites with microscopic residual disease) or 12.5 Gy (at 2 sites with minimal gross residual disease) prescribed at 0.5 cm depth. The treatment volume varied from 9-96 cc (mean 30.3 cc). IOHDR was used in these patients because the tumor locations prevented positioning and insertion of conventional intraoperative electron beam applicators. The EBRT dose was limited to 27-30.6 Gy (median dose 27.4 Gy) postoperatively in all patients to minimize growth retardation or altered organ function. The median initial EBRT field size was 211 cm2 (range 25-483), with a median of two fields per patient (range 1-2). RESULTS: After a median follow-up of 40 months (range 22-62 months), all the patients were alive, five of them without evidence of disease. The other patient, with stage IV undifferentiated synovial sarcoma developed regrowth of pulmonary metastases at 14 months and local failure at 34 months. Toxicity was seen in two patients. One patient developed recurrent urinary infections and ureteral stenosis after 6 months and required a left nephrectomy. Another developed mild to moderate loss of visual acuity and impaired orbital growth after 6 months. CONCLUSIONS: Use of IOHDR in conjunction with low dose EBRT to obtain local control and long-term disease-free survival in pediatric soft tissue sarcomas is feasible with acceptable toxicity. Tumor beds not treatable with standard electron beam intraoperative radiation therapy could be satisfactorily encompassed with IOHDR.

Mobilization of peripheral blood stem cells in children using G-CSF after carboplatin containing myelosuppressive chemotherapy.

PURPOSE: Peripheral blood stem cell (PBSC) apheresis provides an alternative to autologous marrow harvest as a source of hematologic stem cells for transplantation in children with solid tumors. PATIENTS AND METHODS: Eight children with metastatic or recurrent solid tumors underwent 27 apheresis procedures. Recovery from myelosuppressive chemotherapy occurred without continuous daily growth factor support prior to mobilization. Granulocyte colony stimulating factor (G-CSF) at 16 microgs/kg/day was used to increase stem cells in the peripheral circulation. CD 34 positive cells, mononuclear cells (MNC), and CFU-GM were measured in the apheresis products. Prior chemotherapy was examined as a clinical factor that affected PBSC yield. RESULTS: A significant correlation was found between CD 34+/kg and CFU-GM/kg of the products (r = 0.758, P < 0.001). Patients receiving cumulative doses of carboplatin over 1,600 mg/m2 produced adequate MNC (1 x 10(8)/kg) but yielded significantly less CD 34+ cells or CFU-GM than those patients receiving less carboplatin. Prior doses of etoposide and ifosfamide did not effect PBSC yield. CONCLUSIONS: The mobilization technique was well tolerated, and the products obtained produced trilineage engraftment in the patients that underwent peripheral blood stem cell transplantation. Peripheral blood stem cell apheresis in children can be optimized by selection of appropriate candidates and mobilization with G-CSF after an absence of hematopoietic growth factor support.

The National Cancer Data Base report on patterns of childhood cancers in the United States.

BACKGROUND: Patterns of and progress against childhood cancer have been reported on multi-institution, regional, national, and international bases by several sources in the past. These sources have included clinical cooperative group trials and population-based registries. In general, the population-based surveys have excluded brain tumors of either benign or uncertain behavior. The authors of this article investigated the patterns of data reported for the period 1985-1993, motivated by their interest in assessing the potential of National Cancer Data Base (NCDB) data to 1) facilitate individual institution review and 2) cover institutions that are not members of the Pediatric Oncology Group or the Children's Cancer Group, which are both national clinical cooperative groups. METHODS: Six annual calls for data, starting with a call for 1985 and 1988 cases, were issued to approximately 2100 hospitals with cancer programs (1340 programs approved by the Commission on Cancer of the American College of Surgeons and 760 other programs). The baseline data items of the NCDB included patient demography, tumor characteristics, initial treatment, and follow-up. The data for each patient were coded in the traditional manner by trained cancer registrars before being transmitted to the NCDB in standard format. RESULTS: In the most recent year for which data were reported, the NCDB included 42% of all estimated U.S. childhood cancers. The cases were reported by institutions that were members of the Pediatric Oncology Group and the Children's Cancer Group as well as nonmember institutions. The distribution of diagnostic groups reported to the NCDB was generally similar to that reported to SEER, except for lymphomas and brain cancer (the NCDB series included benign as well as malignant brain tumors). The distribution of diagnostic groups reported to the NCDB did not change over the 9-year reporting period (1985-1993). With regard to ethnicity, the most varied distribution of diagnostic groups was found among African American patients. For many types of cancer, the survival of those patients reported to the NCDB was similar to that of patients included in the SEER population-based series. These cancers included Wilms' tumor (NCDB 89% vs. SEER 88%), non-Hodgkin's lymphoma (NCDB 74% vs. SEER 70%), soft tissue sarcomas (NCDB rhabdomyosarcomas 70% and sarcomas 79% vs. SEER soft tissue sarcomas 71%), and neuroblastoma (NCDB 58% vs. SEER 57%). CONCLUSIONS: The authors concluded that the number of brain tumors of benign and uncertain behavior being diagnosed were significant enough in number that they should be included in regional and national cancer registries that report data for clinical purposes. They further concluded that for reasons of data inclusion and institutional coverage, the NCDB will be an important data base for pediatric cancers that will warrant increased use by pediatric investigators.

Undifferentiated sarcomas of children: pathology and clinical behavior--an Intergroup Rhabdomyosarcoma study.

Undifferentiated soft tissue sarcoma (UND-STS) is the most poorly defined tumor eligible for intergroup Rhabdomyosarcoma Studies (IRS). Recent IRS UND-STS experience was reviewed to assess the histologic characteristics and clinical behavior of undifferentiated sarcomas. Of the 1,527 patients entered on IRS-III and IRS pilot-IV, 96 had tumors classified by the IRS Pathology Committee as UND-STS. Of these, 52 had adequate histologic material for this study. After application of immunohistochemistry, 18 tumors were reclassified, mostly as embryonal rhabdomyosarcomas (RMS), primitive neuroectodermal tumors, and intraabdominal desmoplastic small found cell tumors. The remaining 34 UND-STS had a diffuse hypercellular histologic pattern made up of sheets of medium-sized cells. The tumor cells had a minimal to moderate amount of cytoplasm and a variable nuclear morphology, predominately vesicular with finely granular chromatin. Except for reactivity with antibodies against vimentin, most tumors had a negative immunohistochemical profile. The 5 year Kaplan-Meier survival estimate for patients with non-metastatic disease was 72%, a significant improvement when contrasted with patients diagnosed to have UND-STS in IRS-I and IRS-II.

Behavioral adjustment and social functioning of long-term survivors of childhood leukemia: parent and teacher reports.

Obtained parent and teacher reports of behavior and social competence for children who were survivors of acute lymphoblastic leukemia (ALL). At follow-up, children were 5-18 years of age, 48 months postdiagnosis, in first continuous remission, and off chemotherapy. Each child had been randomized to receive either 1,800 cGy whole brain radiation therapy (WBRT) plus intrathecal methotrexate (IT MTX), or IT MTX alone as central nervous system prophylaxis, and one of four chemotherapy regimens that varied in treatment intensity. Scores on standardized measures (CBCL-P/T and PIC) were generally similar to instrument norms. Parents, but not teachers, reported heightened child somatic concerns. There was no effect of WBRT or chemotherapy regimen on ratings of behavioral adjustment. Results indicate minimal psychosocial morbidity among long-term survivors of ALL and suggest that the stressful life events associated with cancer and its treatment do not cause significant behavioral or emotional difficulties.

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.

Successful treatment of disseminated central nervous system malignant rhabdoid tumor.

PURPOSE: Malignant rhabdoid tumor (MRT) of the central nervous system (CNS) is pathologically identical to MRT of the kidney. CNS MRTs have the clinicopathological behavior of a high-grade intracranial sarcoma, and the children have a very poor prognosis. We report on three cases of primary CNS MRT with a review and summary of the pediatric literature with respect to demographic features and multidisciplinary management. PATIENTS AND METHODS: The 18 cases reviewed had a male to female ratio of 1.0 and an extremely young median age of 32 months. Our three cases of CNS MRT were treated with surgery, chemotherapy, radiotherapy, and triple intrathecal (TIT) chemotherapy similar to the Intergroup Rhabdomyosarcoma Study III guidelines for parameningeal primary tumors with intracranial extension. RESULTS: The three patients described in this report are surviving with no evidence of disease at 5 years, 2 years, and 9 months from diagnosis. Before these three cases, only four of 16 reported patients were known to have survived. One unique case in our report involved disease in the cerebral cortex, sinuses, and orbit with metastases to the subarachnoid space. This metastatic MRT responded to treatment with TIT, multiagent chemotherapy and cranial-spinal radiation after partial resection of only the cortical portion of the MRT. CONCLUSIONS: Disseminated CNS MRTs can be treated using multidisciplinary management with an approach similar to that used to treat rhabdomyosarcoma.

Association of childhood rhabdomyosarcoma with neurofibromatosis type I and birth defects.

Rhabdomyosarcoma (RMS) is an uncommon malignant soft tissue sarcoma whose cause is largely unknown. Reported risk factors include genetic alterations (e.g., p53 mutations, a defective gene at 11p15.5, or specific chromosomal translocation of t(2:13)), and parents' use of drugs around the time of conception. We present results from a national, case-control study of 249 RMS cases (170 males and 79 females) and 302 controls (196 males and 106 females). The cases, aged 0-20 years at diagnosis, were identified via the Intergroup RMS Study-III during 1982-1988. Controls were selected by random digit telephone dialing. As a supplement to the original study, information on genetic diseases and birth defects (BD) was collected from the subjects' parents by telephone interview. Fifty-six (22.5%) cases and 55 (18.2%) controls were reported to have genetic diseases or BD (odds ratio [OR] = 1.30,95% confidence interval [CI] = 0.85-2.02, P = .21). The case group had a significantly higher frequency of neurofibromatosis type I (NF1) than did the control group, i.e., five cases (2.0%) had NF1 vs. zero controls (P = .02). The case group also had a higher frequency of major BDs than did the control group (6.0% vs. 2.6%, OR = 2.36, 95% CI = 0.92-6.52, P = .05). However, this excess was only observed in males (7.6% vs. 2.6%, OR = 3.16, 95% CI = 1.02-10.41, P = .02). Among the 15 cases having both RMS and major BDs, six (40.0%) had both conditions in the same regional anatomic site: Two (13.3%) had both in the extremities, two (13.3%) in the genitourinary system, and two in the head and neck. These findings suggest that common genetic mechanisms or in utero exposures may be involved in the development of many childhood tumors and congenital abnormalities.

Cytosine arabinoside and mitoxantrone induction chemotherapy followed by bone marrow transplantation or chemotherapy for relapsed or refractory pediatric acute myeloid leukemia.

The purpose of this study was to determine the induction rate, duration of response and toxicity of cytosine arabinoside (1.0 gm/m2 i.v. over 2 h q 12 h x 8 doses days 1 through 4) and mitoxantrone (12 mg/m2 over 1 h daily x 4 doses days 3 through 6) in pediatric patients with acute myeloid leukemia (AML). Patients achieving a complete remission received either bone marrow transplantation or further chemotherapy. Twenty-seven of 37 evaluable patients (73% (95% confidence interval 59-87%)) achieved a complete remission. For all responding patients, the projected median time to relapse is 12 months. The projected 1 and 2 year disease-free survival is 47% (28-66) and 41% (21-61) with a range of follow-up of 0 to 48+ months. The major toxicity was bone marrow suppression and infection. This therapy is very active in pediatric AML and has acceptable toxicity. Some patients treated achieve prolonged survival.