James B. Atkinson

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 Childrens 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 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 Childrens 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.

Favorable Biology and Outcome of Stage IV-S Neuroblastoma With Supportive Care or Minimal Therapy: A Children’s Cancer Group Study

PURPOSE Stage IV-S neuroblastoma is a metastatic disease associated with spontaneous regression and good survival, but 10% to 20% of infants die from early complications. The purpose of this study was to evaluate outcome and prognostic factors in infants with stage IV-S neuroblastoma treated prospectively with supportive care only or, in symptomatic patients, with low-dose cytotoxic therapy. PATIENTS AND METHODS Eighty eligible infants were studied for response and survival with supportive care or, for symptomatic patients, cyclophosphamide 5 mg/kg/d for 5 days with or without hepatic radiation of 4.5 Gy over 3 days. Staging was reviewed centrally, and MYCN gene copy number, Shimada histopathologic classification, serum ferritin levels, and bone marrow immunocytology were determined. RESULTS Stage IV-S and International Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified in any of the tumors tested (n = 58), and Shimada histopathologic classification was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for all infants was 86% and the survival rate was 92%. Supportive care was the only treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was 100%, compared with 81% survival for those requiring cytotoxic therapy for symptoms (P =.005). Five of six deaths were in infants younger than 2 months of age at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation. Although age </= 3 months at diagnosis was significant for EFS (P =. 043), it was less significant for survival (P =.077). The only other significant factor predictive for improved survival was favorable Shimada histopathologic classification. Sites of metastatic involvement (liver, skin, or bone marrow) and surgical resection of the primary tumor were not significant for survival. CONCLUSION This study confirms the favorable biologic features and excellent survival of infants with stage IV-S neuroblastoma with minimal therapy. Infants younger than 2 months old at diagnosis with rapidly progressive abdominal disease may benefit from earlier and more intensive treatment.

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.

Congenital diaphragmatic hernia. Stabilization and repair on ECMO.

Availability of extracorporeal membrane oxygenation (ECMO) support and the potential advantages of delayed repair of congenital diaphragmatic hernia (CDH) have led several centers to delay CDH repair, using ECMO support if necessary. This study reviews the combined experience of five ECMO centers with infants who underwent stabilization with ECMO and repair of CDH while still on ECMO. All infants were symptomatic at birth, with a mean arterial oxygen pressure (PaO2) of 34 mmHg on institution of bypass despite maximal ventilatory support. A total of 42 infants were repaired on ECMO, with 18 (43%) surviving. Seven infants had total absence of the diaphragm, and 28 required a prosthetic patch to close the defect. Only five infants ever achieved a best postductal PaO2 over 100 mmHg before institution of ECMO. Prematurity was a significant risk factor, with no infants younger than 37 weeks of age surviving. Significant hemorrhage on bypass was also a hallmark of a poor outcome, with 10 of the 24 nonsurvivors requiring five thoracotomies and six laparotomies to control bleeding, whereas only one survivor required a thoracotomy to control bleeding. In follow-up, nine of the 18 survivors (50%) have developed recurrent herniation and seven (43%) have significant gastroesophageal reflux. Importantly, five of the 18 survivors were in the extremely high-risk group who never achieved a PaO2 over 100 mmHg or an arterial carbon dioxide pressure (PaCO2) less than 40 mmHg before the institution of ECMO. In conclusion, preoperative stabilization with ECMO and repair on bypass may allow some high-risk infants to survive. Surviving infants will require long-term follow-up because many will require secondary operations.

Patterns of relapse after autologous purged bone marrow transplantation for neuroblastoma: a Childrens Cancer Group pilot study.

PURPOSE The goal of this investigation was to determine if comparing sites of neuroblastoma at relapse after myeloablative chemoradiotherapy and purged autologous bone marrow transplantation (ABMT) with sites of disease at diagnosis and before ABMT could provide insight to the reasons for treatment failure. PATIENTS AND METHODS Ninety-nine patients with high-risk neuroblastoma underwent ABMT after induction chemotherapy, surgery +/- local radiation (RT) and then myeloablative therapy with teniposide (or etoposide), melphalan, doxorubicin, cisplatin, and total-body irradiation (TBI). RESULTS Forty-one of 84 assessable patients (15 toxic deaths) developed progressive disease 1 to 44 months after ABMT. The overall probability of relapse 36 months after ABMT was 49%. Tumor recurred in primary (n = 22), bone (n = 20), bone marrow (n = 18), lung (n = 3), and other sites (n = 9). Eight patients relapsed in the primary site alone, 14 in primary and distant sites, and 19 in distant sites only. Of 41 patients with progressive disease, 33 have died, with a median interval from relapse to death of 4 months. Both bone and bone marrow involvement at diagnosis correlated with specific relapse in that site (P < .05). Bone marrow tumor content at harvest greater than 0.1% also correlated with bone marrow relapse (P = .001). There was an association between incomplete resection of the primary tumor at diagnosis and relapse in that site (P = .06). CONCLUSION Neuroblastoma normally recurs in multiple sites after ABMT, particularly in areas of previous disease. More intensive treatment to known areas of disease (aggressive early surgery, effective myeloablative consolidation therapy) and post-ABMT therapy for minimal residual disease should be studied for their potential to decrease the frequency of relapse.

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.

A prospective randomized trial of delayed versus immediate repair of congenital diaphragmatic hernia

From March 1990 to January 1993, a randomized prospective study was performed to determine the optimal timing of surgery for infants with high-risk congenital diaphragmatic hernia (CDH). Thirty-two CDH patients who presented with respiratory distress within 12 hours after birth were randomly divided into two groups: Group A had early repair (within 6 hours), and group B had delayed repair (at 96+ hours). Extracorporeal membrane oxygenation (ECMO) was initiated in both groups as necessary. Fourteen patients were assigned to group A, and 18 were assigned to group B. Two patients initially assigned to group A had acute deterioration, and their operations had to be postponed. Data were collected, but these patients were eliminated from the study. The two groups were comparable based on gestational age, birth weight, Bohns criteria, and oxygenation and ventilatory index. Nine of 12 group A patients (75%) survived, and 13 of 18 group B patients (72%) survived (P > .05, not significant). The ECMO requirements for the two groups were not significantly different (8 of 12 (67%) v 16 of 18 (89%); P > .05). Surgical intervention for bleeding complications related to ECMO was required in three of eight (38%) with immediate repair and seven of 16 (44%) with delayed repair (P > .05). There was no difference in survival nor incidence of ECMO between the two groups. This is the first prospective study of timing of hernia repair that supports the conclusions of earlier reports of retrospective studies.

Investigational Use of Tissue Plasminogen Activator (t-PA) for Occluded Central Venous Catheters

Urokinase and streptokinase are commonly used thrombolytic agents for fibrin obstructed central venous catheters. Although proven to be efficacious, these two agents have the potential to induce systemic fibrin breakdown and hemorrhage. We report our initial experience with tissue plasminogen activator (t-PA) for the treatment of occluded central venous catheters which failed urokinase. Of 25 incidents of catheter occlusion in 142 right atrial catheters, six failed to clear after an initial bolus dwell of urokinase. Five of these six catheters cleared following treatment with 2 mg/2 cc of t-PA with a mean of 1.5 bolus installations. The one catheter failure was due to catheter tip position and age of clot. No coagulation abnormalities or bleeding was observed. These data suggest that t-PA may be a safe, effective thrombolytic agent in the treatment of occluded central venous catheters.

ECMO and the management of congenital diaphragmatic hernia with large diaphragmatic defects requiring a prosthetic patch

From 1977 to 1991, 136 neonates have had corrective surgery for diaphragmatic hernia at Childrens Hospital of Los Angeles. A retrospective study was performed to determine how many of the 136 neonates had defects large enough to require the use of a prosthetic patch to repair the defect. Twelve were found. All 12 were symptomatic at birth for respiratory distress. Mean arterial blood gas values at birth were pH 6.95, PCO2 94.8, and PO2 47.2. The mean oxygen index (n = 10) was 61.8. Six of these patients were repaired without extracorporeal membrane oxygenation (ECMO) support while the other six received ECMO bypass perioperatively. All six of the patients who did not receive ECMO support died despite successful diaphragmatic repair. Five of six patients who received ECMO perioperatively survived (83%). These surviving infants are now between 1 month and 4 years of age. In the survivors, four of five required subsequent repair and patch enlargement for a recurrent diaphragmatic hernia. Gastroesophageal reflux, requiring a Nissen fundoplication in two infants, complicated the course of three survivors. Four survivors were discharged with supplemental oxygen therapy lasting less than 13 months. Patch disruption is predicted to occur at approximately 18 months of age in all patients, especially if little or no muscle was available at primary repair for prosthetic attachment. These children should be followed closely for feeding or respiratory symptoms. Diagnosis of patch disruption can be made by chest x-rays and confirmed by contrast studies. Patch expansion by laparotomy and careful search for additional musculature for patch attachment is recommended when reherniation occurs.