In-111 pentetreotide scintigraphy in patients with neuroblastoma. Comparison with I-131 MIBG, N-Myc oncogene amplification, and patient outcome.

OBJECTIVE: 1. To evaluate the relative efficacy of In-111 pentetreotide and 1-131 radioiodinated meta-idobenzyl guanidine (MIBG) for detection of primary and metastatic neuroblastoma. 2. To assess the prognostic value of In-111 pentetreotide uptake. METHODS AND MATERIALS: Seven In-111 pentetreotide and seven I-131 MIBG scans were obtained in six patients with stage IV neuroblastoma and 1 with stage III ganglioneuroblastoma. Three scans were obtained at initial staging and four were obtained during therapy. Correlation was made with concomitant computed tomography scans, bone scans, N-myc oncogene amplification, and clinical outcome. RESULTS: Primary tumor was present in six patients and had been resected in 1. In-111 pentetreotide uptake was seen in two of six primary tumors, I-131 MIBG scan was positive in five of six. In-111 pentetreotide scan was positive in two of four patients with bone metastases, I-131 MIBG scan was positive in three of four. Both showed liver metastases in one patient and did not show bone marrow metastases in another. Overall sensitivity for primary or metastatic disease was 57% (four of seven) for In-111 pentetreotide and 86% (six of seven) for MIBG. Correlation between N-myc oncogene and In-111 pentetreotide uptake was seen in four of seven patients. In-111 pentetreotide uptake correlated with the clinical outcome in six patients with more than 1 year follow-up. Two patients with negative In-111 pentetreotide scans had unfavorable outcome. One patient died, and the other had local recurrence 15 months after diagnosis. Four patients with a positive scan are alive without disease on follow-up at 13-31 months after diagnosis. CONCLUSION: In-111 pentetreotide scintigraphy is less sensitive than I-131 MIBG for detecting active neuroblastoma. In-111 pentetreotide uptake on scintigraphy may correlate with the prognosis. However, a larger series of patients is needed for further evaluation.

The role of 131 iodine-metaiodobenzylguanidine scanning in the correlative imaging of patients with neuroblastoma.

OBJECTIVE: Metaiodobenzylguanidine (MIBG) scans were studied to determine the impact of the scan results on the clinical treatment of pediatric patients with neural crest tumors. METHODS: Serial scans were reviewed retrospectively for 27 patients with neural crest tumors: 25 with initial diagnoses of neuroblastoma (NB), 1 with ganglioneuroblastoma, and 1 with ganglioneuroma (GN). Results were compared with bone scans and computed tomography scans, as well as surgical pathologic findings. RESULTS: At initial diagnosis, when compared with bone and computed tomographic scans, MIBG imaging did not identify any unsuspected lesions that resulted in a change in staging. Thirteen patients with NB who had initially positive MIBG scan results had serial studies that normalized during therapy. However, after completion of therapy, 8 of 13 had relapses of the disease. Although areas of active disease were well delineated by other standard imaging modalities for all 8, only 4 (50%) had MIBG study results that were positive in sites of relapse. There were 4 cases of GN (1 at diagnosis and 3 after therapy for NB) demonstrating an uptake of MIBG that was similar in appearance to that in NB. CONCLUSIONS: MIBG imaging did not change the staging or alter treatment during therapy for any patient. Normalization of positive study results was an unreliable indicator of outcome for children with NB. Furthermore, when relapse occurred, MIBG scans identified only 50% of those with active NB. The uptake of MIBG in GN was indistinguishable from that in NB. In this series, the results of serial MIBG studies did not have a significant impact on patient treatment.

Complete surgical resection combined with aggressive adjuvant chemotherapy and bone marrow transplantation prolongs survival in children with advanced neuroblastoma.

BACKGROUND: A multi-modality approach combining surgery with aggressive chemotherapy and radiation is used to treat advanced neuroblastoma. Despite this treatment, children with advanced disease have a 20% 2-year survival rate. Controversy has developed regarding the efficacy of combining aggressive chemotherapy with repeated surgical intervention aimed at providing a complete surgical resection (CSR) of the primary tumor and metastatic sites. Several prospective and retrospective studies have provided conflicting reports regarding the benefit of this approach on overall survival. Therefore, we evaluated the efficacy of CSR versus partial surgical resection (PSR) using a strategy combining surgery with aggressive chemotherapy, radiation, and bone marrow transplantation (BMT) for stage IV neuroblastoma. METHODS: A retrospective study was performed with review of the medical records of 52 consecutive children with neuroblastoma treated between 1985 and 1993. Twenty-eight of these 52 children presented with advanced disease, 24 of which had sufficient data to allow for analysis. All children were managed with protocols designed by the Children's Cancer Group (CCG). Statistical analysis was performed using Student's t test, chi 2 test, and Kaplan-Meier survival curves. RESULTS: Mean survival (35.1 months) and progression-free survival (29.1 months) for the CSR children was statistically superior to that of the PSR children (20.36 and 16.5 months, p = 0.04 and 0.04, respectively). Similar significance was demonstrated using life table analysis of mean and progression-free survival of these two groups (p = 0.05 and < 0.01, respectively). One-, 2-, and 3-year survival rates for the CSR versus the PSR group were 100%, 80%, and 40% versus 77%, 38%, and 15%, respectively. An analysis of the BMT group compared with those children treated with aggressive conventional therapy showed improvement in mean and progression-free survival. CONCLUSIONS: Aggressive surgical resection aimed at removing all gross disease is warranted for stage IV neuroblastoma. CSR is associated with prolonged mean and progression-free survival. BMT prolongs mean and progression-free survival in children with stage IV disease. These results suggest that CSR and BMT offer increased potential for long-term remission in children with advanced neuroblastoma.

Phase I/II study of bisantrene in childhood cancer: a report from the Childrens Cancer Study Group.

A phase I/II study of bisantrene using a 3-week schedule was undertaken in 171 children with refractory leukemias and solid tumors. The doses ranged from 190 to 430 mg/m2. The maximum tolerated dose for children with solid tumors and acute leukemias was 280 mg/m2 and 360 mg/m2 every 3 weeks, respectively. The dose limiting toxicities were hepatic and hematologic. One patient with ALL achieved a complete remission and partial responses were observed in three patients with soft-tissue sarcomas. The data indicate that bisantrene, at the doses and schedule used in this study, has limited antitumor activity in pretreated children with cancer.

Treatment of patients with metastatic osteogenic sarcoma: a report from the Children's Cancer Study Group.

Fifty-three patients with metastatic osteogenic sarcoma were treated with vincristine, high-dose methotrexate with citrovorum factor rescue, and cisplatin. Metastases were surgically removed in most patients, either prior to chemotherapy or following initial response to therapy. Among 29 previously treated patients, responses to initial chemotherapy included two complete remissions, six partial remissions, and eight patients with stable disease. Twenty-three patients were disease-free, six for greater than 12 months. Toxicity was moderate, but usually reversible. There were two toxic deaths and one unexplained death 48 hours following a dose of cisplatin.

Evaluation of cyclocytidine in reinduction and maintenance therapy of children with acute nonlymphocytic leukemia previously treated with cytosine arabinoside: a report from Children's Cancer Study Group.

A study of children in relapse with acute nonlymphocytic leukemia (ANLL) previously maintained in remission with combination chemotherapy including cytosine arabinoside (Ara-C) was undertaken by Children's Cancer Study Group (CCSG) to assess the efficacy of cyclocytidine (Cyclo-C), a depot Ara-C, compared to parenteral Ara-C given every 12 hr. The reinduction protocol consisted of daunomycin combined with either Ara-C (Regimen 1) or Cyclo-C (Regimen 2). One-hundred thirty eligible patients were entered on the randomized study. Hematologic toxicity was significant in both regimens and resulted in four drug-related deaths. Cardiac toxicity was observed in five patients, manifested only by abnormal echocardiogram or electrocardiogram patterns in three and congestive heart failure in two patients. Seventy-seven of 112 evaluable patients achieved M-1 or M-2A marrow remissions (69%): 46 of 60 on Regimen 1 (75%), 30 of 52 on Regimen 2 (60%). The remission rate between the two regimens was not significantly different. There was no significant difference in the duration of remission comparing maintenance cyclophosphamide combined with Ara-C or with Cyclo-C. Addition of VP-16 and CCNU to the maintenance therapy did not prolong the duration of remission. This study indicates that patients with childhood ANLL previously treated with Ara-C and daunomycin can obtain a successful second remission. A single daily subcutaneous dose of Cyclo-C was found to be as efficacious as Ara-C given intravenously every 12 hr. The single dose schedule provides a convenient way to treat patients with relapsed ANLL in the outpatient setting.

Rhabdomyosarcoma of the middle ear: a wolf in sheep's clothing.

A 3-year-old boy with inflammatory granulation tissue in the ear canal and typanometric evidence of middle-ear effusion was examined. Subsequently, rhabdomyosarcoma of the middle ear was diagnosed. The insidious, deceptive presentation of this common pediatric tumor in an uncommon location is discussed with indication that early diagnosis and aggressive multimodal antitumor therapy seems to be improving the hitherto gloomy prognosis for these highly lethal middle-ear-neoplasms.

Antiplatelet antibodies in childhood idiopathic thrombocytopenic purpura.

The serotonin release test using platelets from a panel of donors and autologous platelets after recovery was used to detect platelet antibodies in 42 children with idiopathic thrombocytopenic purpura. The test was done with sera obtained in the thrombocytopenic phase, in partial recovery, and after recovery. The test results for sera from 23 (55%) of 42 patients with thrombocytopenia were positive against platelets from the donors; 14 (61%) of 23 were positive against autologous platelets; and 28 (88%) of 32 were positive against either donor or autologous platelets. Complete recovery occurred in 17 (52%) of 33 patients whose sera had positive tests against the donor platelets at the time of diagnosis. Postrecovery sera from all patients had negative tests against donor platelets, and two (12%) had positive tests against autologous platelets. These results indicate that childhood idiopathic thrombocytopenic purpura is an autoimmune disease caused by platelet antibody that usually disappears with recovery from the thrombocytopenia.

Surface membrane determinants on childhood acute lymphocytic leukemia cells: immunoglobulin, Fc and C3 receptors.

Most reports have now described two populations of childhood ALL patients: those with thymic (T) cell receptors and those lacking receptors on their neoplastic cells. Assays for the surface receptors of the T and thymic-independent (B) system were used to study forty-seven patients with ALL whose bone marrow contained a mean of 85% leukaemic cells. Two patients had T-cell disease and thirty-six were non-T and non-B. nine patients were identified whose leukaemic cells had membrane properties associated with the B-cell system: surface immunoglobulin, Fc receptors and/or complement receptors. Combined T and B receptors were found in one case. The same surface characteristics were found on leukaemic cells from these patients' bone marrow, blood, pleural and cerebrospinal fluid. Studies showed that the leukaemic cells were not of monocytic or granulocytic origin. Although a remission was obtained in each patient, the relapse rate of the B-cell group was worse than a similarly treated group of thirty-six non-T, non-B ALL patients (P less than 0.001). Initial total leucocyte counts of the B-cell group were greater than the non-T, non-B group (P 0.05), but when the patients in both groups with total leucocyte counts greater than 25,000/mm3 were compared, the relapse rate of the B-cell patients was significantly worse (P less than 0.025). The results show that patients with leukaemic cells possessing B-cell properties comprise a significant proportion of ALL cases, and their presence on leukaemic cells has an ominous significance.

T and B lymphocytes in leukemia therapy.

In order to evaluate the effect of radio- and chemotherapy on immunity, T and B lymphocyte surface receptors were studies sequentially in the blood from 28 previously untreated leukemic children. Following the initiation of chemotherapy an increase in the percent T and B cells was noted in the peripheral blood. In association with sanctuary therapy and chemotherapy there was a decrease in the total number of circulating T and B cells and a relative increase in lymphocytes lacking markers. Based on total numbers at remission the reduction in B cells was greater than in T cells, and the most marked changes occurred during sanctuary therapy. A reduction in the mean serum immunoglobulin was associated with decreasing B cell numbers.

Lymphocyte surface receptors in childhood acute lymphocytic leukemia.

B and T lymphocyte surface receptors were studied in the bone marrow and peripheral blood of 16 patients with childhood acute lymphocytic leukemia. T cell surface receptors were identified on the blasts of one patient. Increased percentages of T or B cell surface receptors were not found in the bone marrow of the other 15 patients. There was a negative correlation between the percentage of pathologic cells in the peripheral blood and the percentage of cells with T and B surface receptors. The results of this study indicate that childhood acute lymphocytic leukemia is a heterogeneous disease in terms of lymphocyte surface receptors and that the pathologic cells of the majority of patients with this disease cannot be identified as being of thymic or non-thymic origin.

Cyclophosphamide (NSC-26271) maintenance therapy after a second remission of childhood acute lymphoblastic leukemia: comparative clinical trial (standard dose versus intermittent high dose versus cyclophosphamide plus cytosine arabinoside (NSC-63878)).

Children with acute lymphoblastic leukemia who had experienced only one relapse were reinduced into remission using a 6-week induction course of prednisone and vincristine. One hundred fifty-one children who achieved a second complete marrow remission were randomly assigned to one of three cyclophosphamide treatment groups for maintanence. Forty-one children received standard-dose cyclophosphamide (3 mg/kg/day), 55 received intermittent high-dose cyclophosphamide (10 mg/kg/day for 4 days out of 14), and 55 received a combination of oral cyclophosphamide (3 mg/kg/day) plus cytosine arabinoside (3 mg/kg/week im). The standard-dose cyclophosphamide regimen resulted in a remission maintenance time of 109 days and was the least toxic of the three maintenance regimens. Giving cyclophosphamide on an intermittent high-dose schedule or combining it with cytosine arabinoside did not increase the remission maintanence time (105 days).

Dibromodulcitol (NSC-104800) compared with cyclophosphamide (NSC-26271) as remission maintenance therapy in previously treated children with acute lymphoblastic leukemia or acute undifferentiated leukemia: possible effectiveness in reducing the incidence of central nervous system leukemia.

Dibromodulcitol and cyclophosphamide are both alkylating agents. In this study, these two drugs were compared for their effectiveness as remission maintenance therapy for childhood acute lymphoblastic leukemia or acute undifferentiated leukemia. Toxic effects were similar in both groups of patients although cystitis did not occur with the dibromodulcitol treatment. The duration of remission was slightly shorter for dibromodulcitol than for cyclophosphamide (P = 0.04). There was, however, a lower incidence of CNS leukemia in the patients treated with dibromodulcitol, which did not seem to be related to a basic difference in the patient groups.

Prognosis in Black children with neuroblastoma.

Thirty white and 15 black children with neuroblastoma were compared with respect to survival. Patient age and tumor stage at diagnosis were similar in the two groups, as was duration of symptoms prior to diagnosis. There was no significant difference between the white and black children in regard to median duration of survival or percentage of long-term survivors. The results of this study indicate that race is not a factor in the prognosis of this tumor.