Nancy B. McWilliams

Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study.

A prospective study was designed to evaluate the outcome of patients with localized resectable neuroblastoma without regional lymph node involvement when no therapy beyond surgical resection was administered. One hundred one patients observed for 3 to 60 months had a 2-year disease-free survival of 89% (SE = 5%). Of the nine patients experiencing relapse, only three have died. There were no apparent distinguishing characteristics of the nine failures. Due to the favorable prognosis of the subset of neuroblastoma patients, prognostic factor analysis had very limited power and lacked clinical importance. Complete gross removal of the localized tumors is adequate therapy to ensure the survival of the majority of these patients.

Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma.

Children older than 1 year of age who have neuroblastoma with complete or partial removal of the primary tumor and positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) are a small but higher-risk subset of patients. To further evaluate the importance of identifying patients with POG stage C neuroblastoma and to assess the efficacy and toxicity of adding concurrent radiation therapy (RT) to chemotherapy (CT) in these children, a randomized study was conducted. Eligible patients received cyclophosphamide 150 mg/m2 orally days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR) every 3 weeks for five courses with or without RT to primary tumor and regional lymph nodes (24 to 30 Gy/16 to 20 fractions). Second-look surgery was advised to evaluate response and to remove residual disease. Continuation therapy alternated CYC/ADR every 3 weeks with cisplatin 90 mg/m2 day 1 followed by teniposide 100 mg/m2 day 3 (CDP/VM) for two courses each. Secondary CT with CDP/VM alone was available for patients not achieving complete response (CR) following induction treatment and second-look surgery. Of 29 eligible patients randomized to CT alone, 13 achieved CR, and nine are disease-free (NED) 1 to 52 months (median, 35 months) off therapy. Twenty-two of 33 eligible cases treated with CT/RT attained CR, and 19 are NED 1 to 77 months (median, 23 months) off therapy. Local and metastatic relapses occurred in both arms. Differences in CR, event-free survival, and survival rates were significant, P = .013, .009, and .008, respectively. Surgical compliance was excellent and complications uncommon. Therapy was tolerable in both groups but hematopoietic toxicity was more common in the CT/RT arm. We conclude that POG stage C neuroblastoma in children older than 1 year of age is a higher-risk group that should be identified, that CT/RT provides superior initial and long-term disease control compared with CT alone in this patient subset, and that the occurrence of metastatic failures in both treatment groups suggests a need for more aggressive chemotherapy.

Thoracic neuroblastoma: A pediatric oncology group study

Ninety-six patients with thoracic neuroblastoma were studied in a prospective fashion. Median age at presentation was 0.9 years. Forty-eight percent of the patients presented with stage A disease, 20% stage B, 13% stage C, 17% stage D, and 2% stage DS. Seventy-five patients have been followed for greater than 4 years. A posterior mediastinal mass was diagnosed on incidental chest roentgenograms performed for nontumor-related symptoms in 49% of the cases. Sixteen percent of the cases presented with neurological symptoms and 14% of the patients presented with acute respiratory distress. Urinary catecholamines were elevated in 76% of the cases. Complete surgical resection was carried out in 47% of the cases, while incomplete resection or biopsy was performed in 45%. No operation was performed in 3 patients. Minor surgical complications occurred in 20% of the patients, and 3% of the patients had significant perioperative complications. One patient died as a complication of therapy. Overall actuarial survival was 88% at 4 years. This study confirms the favorable outcome in children with mediastinal neuroblastoma. The basic biology of thoracic neuroblastomas seems to differ from that of other sites in that the majority of patients present at a younger age with localized disease or regional lymph node metastases, and have an improved survival even after correcting for age and stage. While complete excision is recommended, if possible, radical surgical procedures are not indicated since an excellent prognosis is associated with combined modality therapy.

Side effects of metoclopramide as an antiemetic in childhood cancer chemotherapy

In this study of tobramycin serum concentrations in newborn infants younger than 1 week, we demonstrated that intravenous drug infusion systems or the port of entry into the system can markedly influence tobramycin serum concentrations. We found substantial differences in the peak serum concentrations and the times to achieve these peaks after infusion of tobramycin by AutoSyringe vs three other methods. These in vivo observations support the theoretical values derived by Gould and Roberts from in vitro studies of gentamicin infusion using various entry ports and rates of drug delivery) Variations in the time to achiev e peak serum concentrations may be particularly important in clinical monitoring of tobramycin therapy, b~cause blood for measurement of peak serum concentrations is often drawn at a fixed arbitrary time regardless of the drug delivery system, t.4 Our data suggest that this approach may result in inaccurate information that could lead to potentially harmful alterations in the tobramycin dose. These observations must be considered when monitoring and interpreting serum concentrations of tobramycin in newborn infants.

The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma.

This report provides strong evidence for conducting a controlled randomized clinical trial of autologous bone marrow transplantation versus conventional chemotherapy in childhood neuroblastoma, which is disseminated beyond the intracavity nodes, and which is diagnosed in children older than 12 months of age. On the basis of two Pediatric Oncology Group (POG) studies, one a surgery plus conventional chemotherapy study (POG 8441) and the other an elective autologous transplant pilot protocol (POG 8340), there was no significant prognostic benefit of switching in remission from the surgery plus chemotherapy protocol to the transplant protocol (P = .91) or of switching in remission from the surgery plus chemotherapy protocol to any transplant (P = .75). The analysis is based on 116 patients achieving a complete or partial remission, 32 of whom received transplants on the pilot protocol, and 17 of whom received transplants outside the pilot protocol. While potential selection bias precludes cause-effect conclusions, these data strongly suggest that a large randomized trial of autologous bone marrow transplantation should be conducted before accepting this form of therapy as standard.

Multifocal ganglioneuroblastoma coexistent with total colonic aganglionosis.

Neuroblastoma and Hirschsprungs disease are considered aberrations of neural crest cell growth, migration, or differentiation. Their coexistence, however, is rare. We present the case of an only child with total colon Hirschsprungs disease diagnosed shortly after birth, who was found to have noncontiguous ganglioneuroblastomas without metastases at age 16 months. The spectrum of neural crest anomalies, long segment Hirschsprungs disease and multifocal neuroblastoma, in this child is unique and previously unreported.

Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study.

PURPOSE Infants less than or equal to 1 year of age with neuroblastoma (NB) have a favorable outlook with minimal to moderate therapy. Patients with complete or partial removal of the primary tumor but positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) have a higher risk for recurrent disease. To determine the importance of distinguishing infants with POG stage C NB from those with POG stage B disease and to assess the efficacy and toxicity of treating POG stage C infants with limited, postoperative chemotherapy, a study was conducted by the POG. PATIENTS AND METHODS Forty-four eligible POG stage C infants received cyclophosphamide 150 mg/m2 orally on days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR), every 3 weeks for five courses followed by second-look surgery. No continuation therapy was given if surgical and pathologic complete response (CR) was achieved. Secondary therapy with five courses of cisplatin 90 mg/m2 on day 1 followed by teniposide (VM-26) 100 mg/m2 on day 3 (CDP/VM) was given to infants with gross residual tumor after CYC/ADR and second-look surgery. RESULTS Thirty-four infants achieved CR after CYC/ADR alone, three after CYC/ADR and second-look surgery, two after CYC/ADR, surgery, and maintenance therapy, and two after alternative treatment with CDP/VM (total CR rate, 42 of 44). The 3-year survival and disease-free survival are both 93%. Toxicity was nominal. CONCLUSIONS Infants with POG stage C NB have a favorable outlook, which is similar to infants with POG stage B NB; the surgical staging procedure for distinguishing these infant subsets may not be necessary. Future studies should focus on the reduction of treatment toxicity and efficacy maintenance, and address methods to identify infants at risk for failure.

631 NASOPHARYNGEAL LYMPHOEPITHELIOMA

Nine previously unreported cases of lymphoepithelioma of the nasopharynx are presented. Mean age at diagnosis was 13.6 yrs. (range 9-19 yrs). Seven patients were black and 5 were male. Symptoms were present from 6 wks.-4 mos. (X 2.7 mos.) prior to diagnosis and included painful adenopathy, carache or trismus in 7 patients. Only one had metastases beyond the cervical nodes (pulmonary) at diagnosis.Treatment consisted of radiation to the nasopharynx (5290-7000 rad) and neck (4780-6500 rad). Chemotherapy regimens varied, but all included adriamycin and cyclophosphamide. The patient with pulmonary metastases also received lung irradiation.Follow-up has ranged from 2-36 mos. (X 20.3 mos.). Two patients have died, 22 and 14 mos. post-diagnosis. The first developed local recurrence and distant metastases at 20 mos. The second, who presented with distant metastases, died of progressive pulmonary disease despite good local control. One patient had cervical and orbital metastases at 8 mos., received an additional 3000 rads, and is disease-free at 32 mos. Six patients remain disease-free from 2-36 mos. (X 19 mos.).We conclude that: 1. Although a delayed diagnosis is common, the prognosis is favorable when disease is localized. 2. The primary treatment is radiation to the tumor and regional lymphatics bilaterally. The benefit of adjunct chemotherapy is in doubt.

809 FAVORABLE RESPONSE TO TRANSFER FACTOR IN GENERALIZED BATTEY BACILLUS INFECTION

An 11 year old white girl presented with an 8-month history of thigh pain and weight loss. Skeletal survey showed multiple lytic lesions with radiographic appearance of “eosinophilic granuloma”. Tibial biopsy showed chronic osteomyelitis. Bone marrow culture grew Mycobacterium avium-intracelluare (Battey bacillus). A PPD-B skin test was positive with 27 mm. induration.A 6-drug anti-mycobacterial regimen was instituted but the disease progressed over the next 9 months with development of new bony lesions and subcutaneous abscesses with sinus tract formation at aspiration sites. Cultures of aspirated material again grew Battey bacillus and PPD-B skin test became negative.Immunologic evaluation revealed leukocytosis, an elevation of gammaglobulins, sed. rate, B-cells and serum lyzozymes. Phagocytosis and monocyte chemotaxis were normal.Nine months after diagnosis she received 2 units of Transfer Factor prepared from a highly reactive PPD-B donor. Four and 6 weeks later one additional unit was given. Over the next few months her clinical status improved dramatically with healing of sinus tracts, weight gain and gradual resolution of bony lesions. Although the sed. rate remains elevated, the leukocyte count and immunoglobulins are approaching normal values.This experience suggests that further clinical trials with Transfer Factor are warranted in such Battey bacillus infection.

STIFFENED ERYTHROCYTES IN POLYCYTHEMIA OF CYANOTIC CONGENITAL HEART DISEASE (CCHD)

As the hct rises above 60% in CCHD, there is an increased threat of thrombotic and hemorrhagic complications due to blood hyperviscosity. Hyperviscosity has been attributed to increased RBC mass. Since RBC deformability is a determinant of viscosity and flow at high hcts, we studied RBC deformability in 22 children with polycythemic CCHD and in 10 controls, using a Ciltration system. Filterability is a function of cell deformability. Washed RBCs resuspended in Ringers lactate-albumin solution were passed through a 3u polycarbonate filter using hydrostatic pressure (at 25°C), and flow velocity was calculated (ul/sec).Controls had a mean hct of 41%± 2, mean MCV of 87f1± 2, and mean RBC flow velocity of 5.0 ul/sec±.7. Children with CCHD were divided into 2 groups: 10 patients with hcts between 50-60% (mean 53±1), and 12 patients with hcts >60% (range 63-74%, mean 67%±1). Mean flow velocity (3.4ul/sec±2) in the group with hcts >60% was significantly (p=.05) reduced as compared to controls and the <60% hct group. The latter had a mean flow velocity of 4.8ul/sec±.7, which was comparable to controls. All groups were similar in age (mean 9.5 yrs), sex ratio and MCV.We conclude that RBCs become stiffened when the hct exceeds 60% in CCHD. Stiffened RBCs may contribute to the thrombotic complications observed in these patients.