Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy.

The optimal management for patients with stage II neuroblastoma has not yet been established. In order to determine the impact of adding chemotherapy and/or radiation therapy to surgery, we reviewed by questionnaire 156 patients with stage II neuroblastoma treated by 28 Childrens Cancer Study Group (CCSG) institutions from 1978 to 1985. Survival and progression-free survival (PFS) were analyzed by life-table methods with respect to age at diagnosis, site and size of primary tumor, spinal cord involvement, extent of initial resection, and treatment in addition to surgery. The overall 5-year survival was 96%; the PFS was 90%, similar to previous CCSG studies. Age at diagnosis had a small impact on PFS, with 92% PFS for patients less than 2 years of age at diagnosis, and 84% for those greater than 2 (P = .10). The only site with an adverse outcome was the head and neck (n = 11), with a PFS of 68% compared with 93% for the remaining sites (P = .02). Size of primary and intraspinal extension of primary did not affect PFS. The extent of resection and subsequent treatment with radiation therapy and/or chemotherapy did not affect the PFS. The outcome for 75 patients treated with surgery alone (6-year PFS, 89%) was not significantly different from that of 66 patients receiving radiation therapy (6-year PFS, 94%). There was no significant difference between 40 patients with gross or microscopic residual disease treated with surgery alone (PFS, 92%) and 59 patients with residual disease who also received radiation (PFS, 90%). Five of seven patients who progressed after surgery alone have been salvaged with further therapy and are now free of disease. One survives with disease, so that the 6-year survival is 98% for those treated initially with surgery alone, compared with 95% for those receiving radiation therapy and/or chemotherapy. These data suggest that surgery alone, even if complete resection is not achieved, is sufficient initial therapy for stage II neuroblastoma. The data also identify another stage of neuroblastoma, in addition to stage IV-S, for which almost all patients have a favorable prognosis because their tumor may be biologically limited in growth.

Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma: a report of two concurrent Children's Cancer Group studies.

PURPOSE: To compare event-free survival (EFS) for patients with stage IV neuroblastoma who were treated with induction chemotherapy followed by additional courses of the same chemotherapy or by intensive chemoradiotherapy and autologous bone marrow transplantation (ABMT). METHODS: Two hundred seven children who were diagnosed with stage IV neuroblastoma after 1 year of age were given five to seven courses of induction chemotherapy consisting of cisplatin, etoposide, doxorubicin, and cyclophosphamide (CCC-321-P2). This chemotherapy was continued for 13 total courses for some patients, whereas intensive chemoradiotherapy with ABMT was given to others (CCG-321-P3). The decision to continue chemotherapy versus to consolidate with chemoradiotherapy was not randomized but was made by parents and physicians. Marrow used for ABMT was purged ex vivo and was free of immunocytologically detectable neuroblastoma cells. RESULTS: One hundred fifty-nine of 207 patients (77%) remained event-free during induction therapy. Of these, 67 received chemoradiotherapy/ABMT (CCG-321-P3) and 74 continued chemotherapy (CCG-321-P2). Using Cox regression analysis, the relative risk (RR) of an event after chemoradiotherapy/ABMT was estimated to be 58% of that for patients who continued chemotherapy (P = .01). Similarly, Kaplan-Meier analysis estimated EFS at four years for the chemoradiotherapy/ABMT and chemotherapy groups to be 40% and 19% respectively (P = .019). Subgroups appearing to benefit from chemoradiotherapy/ABMT were those with only a partial tumor response to induction chemotherapy (RR = 0.43; P = .008; EFS, 29% v 6%) and those whose tumors had amplification of the N-myc gene (RR = 0.26; P = .112; EFS, 67% v 0%). CONCLUSION: Consolidation with intensive, myeloablative chemoradiotherapy followed by purged ABMT may be more effective than continuing chemotherapy for patients with stage IV neuroblastoma.

Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study.

PURPOSE: To determine prospectively whether surgery alone is sufficient therapy for Evans stages I and II neuroblastoma and to define biologic and clinical features having prognostic potential for this group. PATIENTS AND METHODS: Between June 1989 and August 1995, 374 eligible children (age range, 0 to 18 years) with newly diagnosed stage I (n = 141) and stage II (n = 233) neuroblastoma were registered onto Children's Cancer Group trial 3881. Surgical resection was the only primary therapy except in cases with spinal cord compression, where radiation therapy was allowed. Event-free survival (EFS) and overall survival (OS) were analyzed by life-table methods according to clinical and biologic features. RESULTS: EFS and OS (mean +/- SE) for all stage I patients were 93% +/- 3.0% and 99% +/- 1.0%, respectively, compared with 81% +/- 4.0% and 98% +/- 2. 0%, respectively, for stage II patients. The significantly higher recurrence rate among stage II patients was managed successfully in 38 of 43 children with either surgery or multimodality treatment. There was one death among stage I patients and six among stage II. For stage II patients tumor MYCN gene amplication, unfavorable histopathology, an age greater than 2 years, and positive lymph nodes predicted a lower OS (P <.05). CONCLUSION: Children with stages I and II neuroblastoma have 98% survival with surgery alone as primary therapy. Supplemental treatment was necessary in only 10% of stage I patients and 20% of stage II patients. In children with localized neuroblastoma, a subset of patients that are at higher risk for death can be defined as those with stage II disease who have tumor MYCN amplification or who are >/= 2 years of age with either unfavorable histopathology or positive lymph nodes.

Allogeneic versus autologous purged bone marrow transplantation for neuroblastoma: a report from the Childrens Cancer Group.

PURPOSE: We have compared the toxicity, relapse rate, and progression-free survival (PFS) of high-risk neuroblastoma patients receiving identical induction therapy and myeloablative chemotherapy plus total-body irradiation (TBI) followed by allogeneic or autologous purged bone marrow transplantation (BMT). PATIENTS AND METHODS: Fifty-six patients with high-risk neuroblastoma underwent BMT at investigator and parent option if they did not have progressive disease after induction chemotherapy with cisplatin, cyclophosphamide, doxorubicin, and etoposide. After surgery and local radiation to residual tumor, myeloablative therapy consisting of etoposide, melphalan, cisplatin, and TBI was given followed by BMT. Patients with human leukocyte antigen (HLA)-compatible siblings received allogeneic bone marrow (n = 20). The remaining patients (n = 36) received autologous bone marrow that had undergone multimodality purging and had no remaining detectable tumor cells by immunocytology. RESULTS: Four of 20 allogeneic patients had a treatment-related death, compared with three of 36 autologous patients (P = .21). The relapse rate among allogeneic BMT patients was 69%, compared with 46% for autologous BMT patients (P = .14). The estimated PFS rates 4 years after BMT were 25% for allogeneic BMT patients and 49% for autologous BMT patients (P = .051). CONCLUSION: Overall outcome for patients with neuroblastoma given this same induction therapy followed by autologous purged marrow was similar to that with allogeneic marrow, although bias in patients selection cannot be excluded in a nonrandomized comparison.

Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study.

PURPOSE: To identify a biologically favorable and unfavorable subset of patients with Evans stage III neuroblastoma and to determine whether treatment stratification would improve the event-free survival (EFS) for high-risk patients and maintain excellent EFS for the lower-risk patients. PATIENTS AND METHODS: Risk stratification was performed by age, MYCN gene copy number, Shimada histopathologic classification, and serum ferritin level. Lower-risk patients were treated on the less intensive Children's Cancer Group (CCG)-3881, whereas high-risk patients were treated on CCG-3891, which included more intensive multimodality therapy and, in some cases, autologous bone marrow transplantation (ABMT). RESULTS: Of 228 Evans stage III patients entered onto the study, 92% also met the definition of International Neuroblastoma Staging System (INSS) stage 3. One hundred forty-three patients met the lower-risk criteria, which included 89 patients less than 1 year of age and 54 patients 1 year of age or greater, and favorable biology, whereas 85 patients were 1 year of age or greater and biologically unfavorable. Biologically unfavorable patients 1 year of age or greater who underwent gross surgical resection had improved survival, whereas the outcome of infants or biologically favorable older patients did not change according to resection. The EFS rate at 4 years was 100% for the patients with favorable biology of any age, 90% for those less than 1 year of age but with at least one unfavorable characteristic, and 54% for Evans stage III patients 1 year of age or greater with unfavorable biology. Age, ferritin level, MYCN copy number, Shimada histopathology, primary site, and intraspinal extension were significant univariate prognostic factors for all patients, but only MYCN copy number and age were independent factors in multivariate analyses. CONCLUSION: The excellent survival of the biologically favorable group and the historically improved EFS of the biologically unfavorable group suggest that biologic staging should be used to define the prognosis and treatment of stage III neuroblastoma.

Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study.

PURPOSE: A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. PATIENTS AND METHODS: One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 (n = 116) received four-drug chemotherapy for 9 months (cisplatin, cyclophosphamide, doxorubicin, and etoposide), with surgery and local radiation to residual disease. After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. RESULTS: The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. CONCLUSION: Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.

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.

Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: Children younger than 24 months with small (< 550 g), favorable histology (FH) Wilms tumors (WTs) were shown in a pilot study to have an excellent prognosis when treated with nephrectomy only. PATIENTS AND METHODS: A study of nephrectomy only for the treatment of selected children with FH WT was undertaken. Stringent stopping rules were designed to insure closure of the study if the true 2-year relapse-free survival rate was 90% or lower. RESULTS: Seventy-five previously untreated children younger than 24 months with stage I/FH WTs for which the surgical specimen weighed less than 550 g were treated with nephrectomy only. Three patients developed metachronous, contralateral WT 1.1, 1.4, and 2.3 years after nephrectomy, and eight patients relapsed 0.3 to 1.05 years after diagnosis (median, 0.4 years; mean, 0.51 years). The sites of relapse were lung (n = 5) and operative bed (n = 3). The 2-year disease-free (relapse and metachronous contralateral WT) survival rate was 86.5%. The 2-year survival rate is 100% with a median follow-up of 2.84 years. The 2-year disease-free survival rate (excluding metachronous contralateral WT) was 89.2%, and the 2-year cumulative risk of metachronous contralateral WT was 3.1%. CONCLUSION: Children younger than 24 months treated with nephrectomy only for a stage I/FH WT that weighed less than 550 g had a risk of relapse, including the development of metachronous contralateral WT, of 13.5% 2 years after diagnosis. All patients who experienced relapse on this trial are alive at this time. This approach will be re-evaluated in a clinical trial using a less conservative stopping rule.

Role of myeloablative therapy in improved outcome for high risk neuroblastoma: review of recent Children's Cancer Group results.

The use of new strategies for dose intensification using peripheral blood stem cell or autologous purged bone marrow rescue has raised expectations for cure in advanced neuroblastoma, although conflicting reports exist regarding the efficacy of these approaches. Using risk groups based on both biological and clinical staging, the Children's Cancer Group (CCG) has conducted a series of pilot studies to test new induction, consolidation and myeloablative regimens to attempt to improve outcome. We summarise below the outcome and prognostic factor analysis for the pilot chemotherapy trial, CCG-(CCG-321P2), and the use of high dose myeloablative chemoradiotherapy with allogeneic (CCG-321P1) or autologous purged bone marrow rescue (CCG-321P3) for high risk neuroblastoma patients who were progression-free at the end of induction chemotherapy. After autologous bone marrow transplantation (ABMT), progression-free survival (PFS) at 4 years was 38% (median follow-up 4 years). Prognostic factors for relapse after ABMT included pre-BMT disease status, bone marrow tumour content at harvest, extent of primary resection at diagnosis, and time to ABMT. MYCN amplification, age, stage, and pre-BMT myeloablative regimen were not significant. Allogeneic BMT did not have a better outcome than ABMT. In a retrospective, non-randomised comparison of ABMT and chemotherapy, there was a significant difference in PFS for stage IV patients. High risk subgroups possibly benefiting from ABMT could be identified, including those with tumour MYCN amplification, over 2 years at diagnosis, and those not in complete remission at the end of induction. A randomised prospective trial comparing myeloablative therapy with ABMT to continuous infusion consolidation chemotherapy is currently underway in CCG to determine the relative benefit.

An alternative approach to management of Fogarty catheter disruption associated with endobronchial foreign body extraction.

The Fogarty balloon catheter is a useful adjunct in removing aspirated foreign bodies, but its use is not without risks. A case is presented of Fogarty catheter disruption while attempting to remove a foreign body. The resulting debris in the distal airway was inaccessible to bronchoscopic retrieval. An effective treatment plan is outlined to deal with this problem.

Hyperparathyroidism following parathyroid autotransplantation.

A patient with primary hyperparathyroidism underwent cervical exploration and hemithyroidectomy. Only one normal parthyroid gland was found and was removed. Hypercalcemia persisted and subsequent arteriography localized a large mediastinal adenoma which was excised. Parathyroid autotransplantation of a small part of this tissue was performed and the patient was well for over a year. He again became markedly hypercalcemic and graft-dependent elevation of parathromone levels was demonstrated. Autograft resection resulted in normocalcemia. Nineteen months later hypercalcemia and elevated parathormone levels prompted re-exploration of the graft site and another enlarged implant was removed. This restored normocalcemia and normal parathromone levels. Parathyroid adenomatous tissue has the potential for autonomous hyperfunction, and caution must be exercised in its use in autotransplantation.

Selective management of injured spleen.

During the past 6 years, 68 consecutive children suffering from splenic trauma have been treated according to a selective management plan. Twenty-two patients (32%) underwent splenectomy, parenchymal repair was performed on 16 occasions (24%), and nonoperative treatment was employed in 30 children (44%). Overall results have been good in all three groups. Two children (3%) died as a result of their injuries, and 10 complications were recorded. Both deaths and 7 of the 10 complications occurred in the patients undergoing splenectomy. By utilization of a basic management plan that favors nonoperative treatment over splenic repair and repair over splenectomy, splenic salvage has been successfully accomplished in 86% of the 49 patients treated since 1977.

Prospective, randomized evaluation of the efficacy of fibrin sealant as a topical hemostatic agent at the cannulation site in neonates undergoing extracorporeal membrane oxygenation.

BACKGROUND: The topical hemostatic effect of fibrin sealant that has been solvent/detergent treated and plasminogen depleted was evaluated in a multicenter prospective, randomized controlled study at the cannulation site wound of infants undergoing extracorporeal membrane oxygenation (ECMO). METHODS: The test group received standard cauterization and Fibrin sealant, while the control group was given cauterization alone to control hemostasis at this site. Efficacy data were available on 173 randomized study subjects of whom 149 met study entry criteria. All were managed according to standard ECMO practice. RESULTS: Fibrin sealant reduced the risk of bleeding, was associated with less shed blood, and was associated with shorter duration of hemorrhage. Further, control infants showed an increased bleeding risk with less depressed fibrinogen levels and prothrombin time elevations >18 seconds prior to ECMO. CONCLUSION: Fibrin sealant is useful as a topical hemostatic agent in patients with coagulopathy not responding to standard surgical techniques.

Head and neck neuroblastoma.

Primary neuroblastoma of the head and neck is rare. The clinical presentation and physical findings are related to the child's age, the stage and location of the primary tumor, and its attendant biological behavior. The differential diagnosis is varied, and initial evaluation includes a thorough physical examination, selected laboratory studies, and specific high-yield imaging techniques. The prognosis of these lesions has been increasingly favorable, even when the disease is not localized. Carefully planned surgical approaches provide local control, and radiation and chemotherapy may be beneficial in more extensive tumors. Second malignancies occur after treatment, and long-term follow-up is necessary.

Nephroblastoma.

Effective diagnosis, staging, and multimodality therapies dramatically decreased the morbidity and mortality of children with Wilms Tumor. Increasing awareness of the disease, biology, genetics, and epidemiology improved assessment of clinical syndromes and led to more risk-based treatment. The role of tumor imaging is being defined, and primary exploration with nephrectomy remains of value to confirm histological diagnosis and disease stage. Primary chemotherapy with delayed resection is evolving into the preferred approach for large inoperable tumors, bilateral disease, and those tumors with extensive intravascular involvement. Current therapeutic trials will be nonrandomized and emphasize biological tumor features for future patient stratification. A selected group of young patients with small localized favorable histology tumors will be treated with surgery alone.

Acute abdomen. Special considerations for the neurologically and immunologically impaired child.

The neurologically or immunologically impaired child suspected of having an acute abdomen presents a formidable challenge. However, a thorough understanding of the underlying pathophysiology of the disease on the normal host response to an intraabdominal disease permits early recognition and initiation of treatment. Classic findings of the acute abdomen are the exception rather than the rule. These children require constant vigilance and repeated examination. Radiographic studies should be used early and often. The advent of minimally invasive surgical techniques offers the opportunity to intervene early both diagnostically and therapeutically. Ultimately, however, the best outcomes will be achieved by those who employ sound surgical judgment and avoid unnecessary therapeutic delay owing to inexperience, inattention, or indecision.

Glucagon in experimental intussusception.

A standard type of ileocolic intussusception was produced in 69 puppies and the effect of glucagon on the hydrostatic reduction of the intussusceptions evaluated in a prospective, double-blind study. The reductions were attempted at intervals varying from 18 to 60 hr following the production of the intussusceptions. The overall reduction rate was 70% and there was no statistical difference in this rate between the animals receiving glucagon and those receiving placebos. None of the gangrenous intussusceptions were reducible with the hydrostatic pressure technique, irrespective of whether glucagon was used or not. A further evaluation was made of those animals in whom successful reductions were accomplished by the hydrostatic pressure method. Glucagon did result in significantly easier reductions, and an earlier return of normal vascular supply as measured by color and by arterial pulsations as compared to the control group.

Partial splenectomy in staging laparotomy for Hodgkin's disease: an alternative approach.

Partial splenectomy, with resection of the lower one-fourth to one-third spleen, was performed in 10 children with Hodgkin's disease as part of an otherwise standard staging laparotomy. The technique proved to be safe and practical, with no postoperative complications. No evidence to date indicates that splenic involvement was missed, and all the children have thus far continued to do well, with no deaths from either underlying disease or postsplenectomy sepsis. The procedure is undergoing a prospective clinical trial in an effort to determine whether or not it is comparable from a diagnostic point of view to total splenectomy. Available data indicate that the risk of missing intraabdominal disease in a staging laparotomy with a partial splenectomy is quite low. Such a procedure should eliminate the substantial risk of postsplenectomy sepsis in such children.

The value of radionuclide scanning in early diagnosis of intestinal infarction.

Small focal areas of intestinal infarction were produced experimentally in mice by two techniques: (1) intussusception and (2) suture strangulation of a loop of jejunum. The radionuclide technetium 99m diphosphonate (99mTc-diphosphonate) was subsequently administered intravenously, and abdominal scans were obtained. The scans demonstrated focal infarcted lesions accurately, and every positive scan was associated with an area of infarction, as demonstrated by pathologic examination. However, negative scans did not definitely exclude an area of infarction: in the intussusception study there were five false negative scans in 25 animals, and in the loop ligation study there were two false negative scans in 28 animals. The technique may have clinical application in such intestinal diseases as necrotizing enterocolitis in infancy in which early diagnosis of small areas of necrosis is currently difficult by clinical and radiologic methods.

Gastric necrosis after fundoplication: a novel approach for esophageal preservation.

An 11-year-old boy presented moribund, with massive abdominal distension. A Nissen fundoplication and gastrostomy tube had been established at age 2 years. After attempts to pass a nasogastric tube were unsuccessful, the old gastrostomy site was used to gain percutaneous access to the stomach resulting in release of gastric contents and stabilization of blood pressure and perfusion. During operation, massive gastric distention with gastric necrosis was found. Subtotal gastrectomy was performed with stapled closure of the distal intraabdominal esophagus and prepyloric region. Sump suction was placed in the proximal esophagus and the abdomen was drained widely. A distal esophageal perforation was apparent on postoperative day 19 confirmed by imaging and endoscopy. A nasoesophageal tube was passed into the abdomen, tied to a Jackson-Pratt drain, and the composite tube repositioned in the midesophagus allowing controlled proximal and distal drainage. Six months later, a Hunt-Laurence esophagojejunal pouch was created. At age 13, the child is clinically well, and enjoys 50% of his nutritional needs orally, with the remainder delivered overnight via tube feedings. This case describes gastric necrosis after gas bloat syndrome as a late complication of Nissen fundoplication. A novel approach to the management of distal esophageal perforation allowed preservation of a functional, intact native esophagus.