INCIDENTAL NEUROBLASTOMA

The diagnosis of neuroblastoma in its early stage, especially in asymptomatic children, with the so-called incidentally diagnosed disease, may be associated with a good prognosis. The aim of this study is an attempt at analyzing this problem. Between 1 January 1993 and 30 April 1998, 40 children with newly diagnosed neuroblastoma started therapy at the authors' department. The disease was diagnosed incidentally in 5 (12.5%) patients. In no incidentally diagnosed child was stage IV disease detected, while in the remaining patients its incidence was 71%. All the children (median age 2 months) with incidental diagnosis have remained alive (median 39 months) in continuos remission without treatment. Among 35 children (median age 2 years and 7 months) with overt neuroblastoma, 18 died (median survival time 14.5 months). Seventeen patients have remained alive (median 45 months). The results show that children with incidentally diagnosed neuroblastoma are characterized by a more favorable prognosis than children with clinical disease.     

Chemotherapy of advanced neuroblastoma: does adriamycin contribute?

Between 1970 and 1977, 69 children with newly diagnosed stage III or IV neuroblastoma were treated with pulses of either cyclophosphamide and vincristine (CV) (n = 23), or cyclophosphamide, vincristine, and adriamycin (CVA) (n = 46). The ''complete'' and partial response rates were 35 and 22% to CV, and 43 and 26% to CVA. For ''complete'' responders the median time to relapse was 18 months for those treated with CV, and 17 months for those treated CVA; for partial responders the times were 5 and 7 months respectively. At 2 1/2 years only 17% of the CV patients and only 13% of the CVA patients were alive and free of disease, giving a 15% overall survival rate. The addition of adriamycin to cyclophosphamide and vincristine did not significantly improve the response rate, duration of response, or survival in these children with advanced neuroblastoma. The previously noted favourable effects of age less than 1 year at diagnosis and of female sex were confirmed. The equally poor survival for stage III and stage IV patients justifies the inclusion of stage III patients in a bad prognosis group.     

Stage II neuroblastoma—does adjuvant irradiation contribute to cure?

Twenty-one children with Stage II neuroblastoma diagnosed between 1973 and 1983 were analyzed retrospectively. Median age at diagnosis was eleven months (1 week to 153 months). Primary tumor was above the diaphragm in 67% and below the diaphragm in 33%. All patients underwent surgical resection and pathologic diagnosis was neuroblastoma in 76% and ganglioneuroblastoma in 24%. Regional lymph nodes were positive in three of eleven patients sampled. Sixty-seven percent had gross residual disease, and thirty-three percent had microscopic residual disease. Seventeen patients received postoperative irradiation and none has relapsed (median follow-up 57 months). Four patients received surgery alone (median follow-up 24 months); one local relapse occurred in this group and was subsequently treated with irradiation. All patients are alive and disease free, with a median length of follow-up of 55 months. Radiation dosage was 1000-1800 rad in patients less than 12 months of age, and 1800-3000 rad in those greater than 12 months of age at diagnosis. The high disease-free survival rate in both groups of patients, but especially in the group receiving adjuvant irradiation, emphasizes the need for a controlled, prospective study to determine which Stage II neuroblastoma patients, if any, would be benefitted by postoperative irradiation.     

Stage II neuroblastoma--does adjuvant irradiation contribute to cure?

Twenty-one children with Stage II neuroblastoma diagnosed between 1973 and 1983 were analyzed retrospectively. Median age at diagnosis was eleven months (1 week to 153 months). Primary tumor was above the diaphragm in 67% and below the diaphragm in 33%. All patients underwent surgical resection and pathologic diagnosis was neuroblastoma in 76% and ganglioneuroblastoma in 24%. Regional lymph nodes were positive in three of eleven patients sampled. Sixty-seven percent had gross residual disease, and thirty-three percent had microscopic residual disease. Seventeen patients received postoperative irradiation and none has relapsed (median follow-up 57 months). Four patients received surgery alone (median follow-up 24 months); one local relapse occurred in this group and was subsequently treated with irradiation. All patients are alive and disease free, with a median length of follow-up of 55 months. Radiation dosage was 1000-1800 rad in patients less than 12 months of age, and 1800-3000 rad in those greater than 12 months of age at diagnosis. The high disease-free survival rate in both groups of patients, but especially in the group receiving adjuvant irradiation, emphasizes the need for a controlled, prospective study to determine which Stage II neuroblastoma patients, if any, would be benefitted by postoperative irradiation.     

Age and prognosis in neuroblastoma. Review of 112 patients younger than 2 years

The results of 112 children with neuroblastoma treated at the Memorial Sloan-Kettering Cancer Center between 1949 and 1980 were analyzed. Of these children, 58 were 0-11 months old and 54 were 12-23 months old and there was a median follow-up of 111 months. All 10 patients with Stage I are alive, 21/27 with Stages II and III (78%) are alive, 5/67 patients (7%) with Stage IV are alive, and 7/8 patients with Stage IVS are alive. Age of the children is an independent prognostic factor. The survival of infants with Stage IV is significantly better than it is for older children of the same stage. Two of 15 infants in Stages II and III died, both of early complications, whereas 4/12 older children with the same stages died. Minimal individualized treatment is recommended for children 0-11 months old who have localized and Stage IVS neuroblastoma. Children less than 1 year old with localized and Stage IVS neuroblastoma had an extremely good prognosis (90% survival) and were usually cured without intensive chemotherapy. Surgical removal of the primary tumor was sufficient for Stage I, and partial tumor removal followed by conservative radiation or chemotherapy was sufficient in most Stage II and III patients. Gentle, individualized treatment was adequate for Stage IVS. Children less than 1 with Stage IV neuroblastoma had a significantly better prognosis than older children of the same stage, but their prognosis was still poor (18% survival).     

Retinoblastoma in children older than 5 years of age

BACKGROUND: Retinoblastoma is a malignant tumor of the embryonic neural retina. About 80% of cases are diagnosed before age 4, with a median age at diagnosis of 2 years. OBJECTIVE: To determine characteristics and prognosis of retinoblastoma in children older than 5 years. PROCEDURES: From 1986 to 2002, medical records of 16 patients out of 453 cases referred to Hospital do Cancer AC Camargo, S?o Paulo, Brazil. RESULTS: Median age at diagnosis was 73.7 months (range 65-144) and there was an equal gender distribution. Fifteen patients presented with unilateral disease. The mean time between first symptoms and diagnosis was 9.6 months (range 0-48). Most cases were diagnosed in advanced stages and 15 eyes were enucleated. Eleven patients presented with intraocular tumor (1 Reese II and 10 Reese V) and five presented with extraocular disease (one CCG II and four CCG III). Twelve patients are still alive with a median follow-up of 92 months (range 65-199). CONCLUSIONS: Because of its low incidence at this age, diagnosis of retinoblastoma is usually delayed due to low level of suspicion. Therefore, it is important that physicians are aware of this disease in order to perform an earlier diagnosis, and decrease treatment-related morbidity.     

Prognostic influence of minimal residual disease detected by flow cytometry and peripheral blood stem cell transplantation by CD34+ selection in childhood advanced neuroblastoma

OBJECTIVE: To determine whether neuroblastoma (NB) minimal residual disease (MRD) in bone marrow (BM) detected by flow cytometry could predict prognosis and whether tumor cell purging by CD34(+) cell selection prior to transplantation will impact on disease-free survival. METHODS: NB MRD in BM was evaluated by flow cytometry with CD45-FITC-/CD81-PE+/CD56-PECy5+ monoclonal antibodies cocktail. Peripheral blood stem cell (PBSC) was enriched via positive CD34(+) cell selection by magnetic-activated cell separation system (MACS). RESULTS: Eleven of 31 patients with CD45(-)/CD81+/CD56+ cells by flow cytometry at diagnosis became negative after an average of four courses of chemotherapy. All 11 patients remained alive without evidence of disease. Thirteen of the 20 patients with positive MRD relapsed and 1 patient died from disease (mean 25.8 months). There was a significant difference between these two groups. MRD in BM was tested before PBSC transplantation (PBSCT) for 19 NB patients. Fourteen was negative, 4 of them relapsed and 10 patients remained alive without evidence of disease. Another 5 patients with positive MRD, all of them relapsed (mean 17 months after PBSCT) with a significant difference between these two groups. Fourteen of 19 PBSC were purged with CD34(+) selection procedure. Six of 14 relapsed (mean 18.43 months after PBSCT). Five patients did not purge for CD34(+) selection, and 3 of them relapsed with no significant difference between these two groups. CONCLUSIONS: Positive MRD in BM after an average of four courses of chemotherapy and before PBSCT is an unfavorable factor for stage IV NB. CD34(+) selection purging for PBSCT may not improve the prognosis for children with neuroblastoma in advanced stage.     

Prognostic significance of DNA di-tetraploidy in neuroblastoma

BACKGROUND: Identification of biological factors may provide tools to discriminate poor risk neuroblastoma patients of diagnosis, to ultimately offer risk adapted treatment intensity. PROCEDURES: Tumour cell DNA content, MYCN amplification (NMA), deletion of the short arm of chromosome 1 (del 1p) as well as three serological markers were assessed in 179 children with neuroblastoma. RESULTS: Localised regional disease (stage 1 to 3) was diagnosed in 98 patients, and disseminated disease in 81 patients (65 with stage 4, 16 with stage 4s). Median age at diagnosis was 12 months and the median observation time 4 years. Sixty-seven of 179 patients had near di-tetraploid tumours (37%), with a significantly worse prognosis of 44% overall survival at 4 years in comparison with 88% in near triploid tumours (P < .001). The near di-tetraploid group showed a significant correlation with additional adverse biological factors (NMA, del 1p: P < 0.001), age over 1 year (P< 0.001), clinical stage 4 (P< 0.001), elevated ferritin (P = 0.023), and elevated LDH (P< 0.001). Multivariate analysis based on the overall (OS) and event free survival (EFS) estimations revealed that near di-tetraploidy was the most powerful biological factor, with a P-value of <0.001 for EFS and OS, followed by NMA (P = 0.015) for OS and del 1p (P= 0.047) for EFS. CONCLUSIONS: This analysis underlines the important influence of near di-tetraploidy on prognosis, and suggests that more efforts should be undertaken to implement this factor in future studies.     

Neuroblastoma: A 32-year population-based study—implications for screening

This paper describes a retrospective population-based study of neuroblastoma in the West Midlands Health Authority Region—childhood population 1.12 million (OPCS, census 1981)—in which 239 cases were diagnosed between 1st January 1957 and 31st December 1988. The age standardised rate of tumour incidence has remained constant at 7.2 cases per million children per year. The median age at diagnosis was 2 years with 18% of children presenting before the age of 6 months. Fifty children (21%) presented before the age of one year, and for this group of children, the prognosis has improved significantly over the 32-year period (10 year survival increasing from 63% in 1957–67 to 87% in 1978–88), whereas for the 189 (79%) children who presented after one year of age, the prognosis has remained very poor during the study period (10 year survival 1957–67 = 9.5%, 1978–88 = 8.5%). This study supports the need for a prospective study of mass screening at several intervals rather than only at 6 months of age. © 1993 Wiley-Liss, Inc.     

High-risk neuroblastoma in Ontario: a report of experience from 1989 to 1995

PURPOSE: We did a population-based study of children with high-risk neuroblastoma to determine their survival and look for factors that had an impact on survival. METHODS: We carried out a retrospective cohort study of patients diagnosed in Ontario from 1989 to 1995. 162 cases of neuroblastoma were diagnosed in the province with 70 (43%) considered high-risk: all were older than one year of age, with 15 patients classified as International Neuroblastoma Staging System (INSS) stage 3, and 55 INSS stage 4. RESULTS: Stage 3 patients did significantly better than Stage 4 patients with a 5-year overall survival of 67.7% and 22.7% respectively (P = 0.015). In stage 4 patients achieving at least a partial response to up-front therapy and surviving for at least 9.5 months after diagnosis (the median time to transplant), there was no difference in survival between the 19 transplant patients and the 17 treated with chemotherapy alone (P = 0.75). However, patients transplanted by peripheral stem cell (PSC) collection did significantly better than both the bone marrow transplantation (P = 0.002) and chemotherapy-alone group (P = 0.047). There was a significant difference in up-front chemotherapy and use of radiation in the three groups (P < 0.001 and P = 0.01 respectively), but no difference in the incidence of bone and bone marrow metastases, MYCN amplification or unfavorable histology. CONCLUSIONS: In this nonrandomized study, we found that stage 4 neuroblastoma patients alive more than 9.5 months after diagnosis, with at least a partial response to initial therapy, did significantly better with PSC transplant compared with bone marrow transplantation or chemotherapy alone.     

Clinical and epidemiological characteristics of retinoblastoma: correlation with prognosis in a Turkish pediatric oncology center

Advanced intraocular tumors and metastatic disease in retinoblastoma patients still occur frequently in developing countries. The aim of this retrospective study was to describe the clinical and epidemiological characteristics of patients with retinoblastoma and the effects of these features on disease prognosis in the authors' pediatric oncology unit as a developing country profile to define the problem. A retrospective chart review of 91 patients who presented to the unit between May 1996 and December 2003 was conducted in this study. Patients with unilateral disease presented at a median age of 24 months and those with bilateral disease at a median age of 9.5 months (p < .01). Most of the eyes with retinoblastoma (68.6%) had Reese-Ellsworth stage V disease. Metastatic disease was diagnosed in 19 (20.9%) patients. Cases with metastatic disease presented at a median age of 24 months and those without metastatic disease at a median age of 12.5 months (p < .05). In 31 patients (34.1%) there was a delay in diagnosis. The enucleation ratio in eyes with advanced intraocular stage was significantly higher than in eyes with early intraocular stage (57.9 vs. 3.8%) (p < .001). In patients with metastatic disease, tumor recurrence was more frequent than in the nonmetastatic patients (36.8 vs. 4.2%) (p < .01). Seven children (7.7%) died due to central nervous system (CNS) metastasis (p < .01). Advanced intraocular disease and distant metastases occur more frequently in Turkish children with retinoblastoma than in children in developed countries, causing a higher rate of enucleation and mortality. Late referral might account for the delayed diagnosis.     

Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: A report from the Pediatric Oncology Group

A retrospective data collection was performed on 29 children diagnosed with neuroblastoma and opsoclonus-myoclonus between 1983–1993 from Pediatric Oncology Group institutions. The aim was to describe neurologic outcome in children with neuroblastoma and opsoclonus-myoclonus. Age at diagnosis ranged from one month to 4 years (median age, 18 months). The duration of opsoclonus-myoclonus symptoms prior to the diagnosis of neuroblastoma ranged from 6 days to 17 months (median duration, 6 weeks). There was a prevalence of low stage disease according to the POG staging system; stage A (n = 18), stage B (n = 3), stage C (n = 7), stage D (n = 1). There was a predominance of paraspinal primary tumors. There was no case of N-myc amplification (0/17), and 2/8 cases were diploid. Treatment for neuroblastoma consisted of surgery alone in 19/29 (18 stage A, 1 stage C in thorax), and surgery plus chemotherapy in 10/29. No patient received radiotherapy. Treatment for opsoclonus-myoclonus ranged varied. Six children received no treatment for opsoclonus-myoclonus. The following agents were used aCTH (n = 14), prednisone (n = 12), IV IgG (n = 6), immuran (n = 2), depakote (n = 1), and inderal (n = 1). Eighteen of 29 children (62%) had resolution of opsoclonus-myoclonus symptoms. The range of time for recovery was a few days to 3 years. However the majority recovered over several months. Twenty of 29 children (69%) had persistent neurologic deficits including speech delay, cognitive deficits, motor delay, and behavioral problems. Of the 9 children who had complete recovery of opsoclonus-myoclonus without neurologic sequelae, age at diagnosis and duration of symptoms were not different from the entire group. Interestingly, 6/9 children with complete recovery received chemotherapy as part of their treatment. In conclusion, persistent neurologic deficits are characteristic for children with neuroblastoma and opsoclonusmyoclonus. Treatment with chemotherapy may improve the neurologic outcome. Med. Pediatr. Oncol. 28:284–288. © 1997 Wiley-Liss, Inc.     

Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey"

BACKGROUND AND PROCEDURE: Most deaths from neuroblastoma occur within 2 years of diagnosis but there have been several anecdotal reports of relapse and death after much longer periods of follow up. In order to investigate and quantify the risk of late events we analysed data for patients registered with the European Neuroblastoma Study Group between 1982 and 1990. Out of a total of 1,277 children registered, 427 were alive with follow-up beyond 5 years from diagnosis (median follow-up of 8.8 years, range 5-14 years). Of these 406 were in remission with no prior recurrence, 16 were in remission having experienced a relapse prior to 5 years, and 5 were alive with progressive disease. RESULTS: For the 406 patients in remission with no prior relapse the 10 year progression free survival (PFS) was 96% (CI 94-98). For those aged over 1 year with stage 4 disease at diagnosis 10 year PFS was 88% (CI 79-96) compared to 98% (CI 97-99) for other patients combined, P< 0.001. In a multivariate analysis of all 422 patients in remission at 5 years, significant risk factors for subsequent relapse were age > 1 yr with stage 4 disease at diagnosis (relative risk 10.5, P < 0.001) and prior relapse (RR 4.2, P= 0.01). CONCLUSIONS: The results of this study emphasise the importance of longterm follow-up of patients and the need for late monitoring of clinical trials in children with neuroblastoma. They also provide a baseline for comparison with future and hopefully more effective treatment programmes.     

High-dose chemotherapy and autologous blood stem cell transplantation in children with metastatic neuroblastoma

High-dose chemotherapy (HDC) followed by autologous blood stem cell transplantation (ABSCT) was performed to improve the prognosis of children with metastatic neuroblastoma over 1 year of age at diagnosis. Seven stage IV neuroblastoma patients with a median age of 3.9 years (range 1.6–11.4 years) received conventional chemotherapy before leukapheresis for ABSCT. The median duration of chemotherapy before harvest was 8 months (range 3–23 months). Peripheral blood stem cells (PBSC) were harvested from them after the use of cytotoxic drugs plus granulocyte colony-stimulating factor. The median number of granulocyte-macrophage colony forming units collected after harvest was 23.2 × 10⁴/kg (range 10.1–45.3 × 10⁴/kg). The patients were administered HDC consisting of carboplatin, etoposide, and melphalan followed by ABSCT. Hematopoietic reconstitution after ABSCT was favorable; recovery of granulocytes count > 0.5 × 10⁹/L occurred within 2 weeks and stable platelet engraftment occurred at a median duration of 23 days (range 7–33 days). The toxicity of ABSCT was well tolerable. Two of the four patients who received ABSCT at their first complete remission remained in remission 67 and 68 months after ABSCT. One with partial remission also showed a good response for 8 months. The other two at first relapse showed a transient regression of the tumor. The prognosis of seven patients who received ABSCT was significantly better than that of 13 patients who received conventional therapy alone. These findings suggest that HDC followed by ABSCT is safe and useful as consolidation therapy for the treatment of patients with metastatic neuroblastoma.     

High-dose chemoradiotherapy with bone marrow transplantation as a consolidation treatment of neuroblastoma. Results in 49 unselected patients with stage IV cancer and older than 1 year. Report of the LMCE neuroblastoma group

65 consecutive children over one year of age presenting with neuroblastoma stage IV were unselectively treated with an induction regimen alternating Cis-Platinum/VM 26 and Cyclophosphamide/Adriamycin/Vincristin. After primary surgery two to four months post diagnosis, consolidation consisted of continuous Vincristin, high dose Melphalan and fractionated total body irradiation, followed by bone marrow transplantation (autologous except for 3 allogeneic). Of the 49 children transplanted up to evaluation date, 31 were in partial remission (PR) and 18 in "very good partial remission" (VGPR) or complete remission (CR) at the time of transplantation. The toxic mortality was 20% (14% early, 6% late), the relapse rate 29% and the progressive disease rate 6%. The event-free survival from graft (events being relapse, progression or death) was 33% after a median of 17 months (range: 2-45) without a significant difference between a status at transplantation of PR versus VGPR/CR. The overall actuarial progression-free survival of the complete group of children with neuroblastoma stage IV was 24% after 27 months, including 10 patients who died or relapsed before massive therapy as well as 6 children still in induction. This result must be compared with 6% survival in a similar group diagnosed at the same institutions and treated with conventional chemotherapy before the onset of this trial.     

Neuroblastoma screening: arguments from retrospective analysis of three German neuroblastoma trials

The justification for a neuroblastoma screening program has been discussed controversially. The analysis of 701 patients of the German neuroblastoma trials NB 79, 82, and 85 provides additional information on this subject. The basis of our investigation was the good prognosis of stage I and II patients (92% survival 5-10 years after diagnosis) compared with 66% in stage III and 11% in metastatic disease. The correlation of age and stage (p less than 0.0001), a median progression time of 14.6 months (range 3.4-33.5 mo) from localized to metastatic disease as observed in 18 patients, the high incidence of asymptomatic diseases in stages I (49%) and II (30%) patients and the cost-benefit estimation arguments in favor of a screening program. The key problem for the lab part is the lower incidence of abnormal catecholamine metabolite excretion in stage I and II patients. The origin of 89% of metastatic disease from intraabdominal sites suggests that ultrasonography may be of additional value.     

儿童Ⅳ期神经母细胞瘤远期随访报告

目的总结分析儿童Ⅳ期神经母细胞瘤(NB)诊断治疗方案的远期疗效及影响预后的因素,为方案的改进提供依据。方法研究对象为1996年4月1日至2005年12月31日新诊断的Ⅳ期NB患儿,年龄1个月至15岁,共69例。其中Ⅳ期67例,Ⅳs期2例。根据年龄将患儿分为中危组和高危组,综合治疗方案包括根据分组采用不同强度化疗、完成化疗后全顺式维甲酸诱导分化治疗及适时肿瘤根治性切除术,起病年龄>1岁的患儿在停药前造血干细胞支持下超剂量化疗(ASCT),部分术后有残留者接受局部放疗。结果16/69例在接受44疗程后好转中放弃治疗。53例按计划治疗>4个疗程,22例接受了ASCT(中危组3例,高危组19例)。获得非常好的部分缓解(very good partial remission,VGPR)49例(92.45%),获得部分缓解(PR)4例(7.55%)。中位随访期28个月(7个月至79个月)。末次随访时在VGPR中13例(24.53%),中位VGPR时间为38个月。带病生存病情稳定5例。疾病进展、复发或已死亡35例(66.04%)。2年总体生存率(OS)和VGPR生存率(VGPRS)分别为64.4%和60.4%,3年OS和VGPRS分别为43.9%和41.2%,4年OS和VGPRS分别为19.8%和14.4%。肿瘤原发于后腹膜、骨髓转移对预后的影响达统计学有效水平,P值均<0.05。结论Ⅳ期NB在强烈化疗等综合治疗下远期预后仍然极差,原发于后腹膜并有骨髓转移者预后更差,需进一步探索研究新的治疗手段,以改善其预后。     

Age-related profile of neuroblastoma: A comparison of tumors detected by mass-screening with those detected clinically

Infants with neuroblastoma are known to have a favorable prognosis compared to those over 1 year of age. However, there is little biological information about the age-related heterogeneity of neuroblastoma. We evaluated the biological profile comparing cases detected by mass screening with those detected clinically. A total of 238 patients with neuroblastoma were classified into four groups according to their age at diagnosis. Patients in group A were 0–5 months of age (n = 31). Patients in group B were detected clinically and were 6–11 months of age (n = 25). Patients in group C were 6–11 months of age and were detected by mass-screening (n = 97). Patients in group D were more than 12 months of age (n = 85). The age-related heterogeneity was evaluated by Kaplan-Meier survival analysis, several clinical markers (neuron specific enolase, ferritin, vanillylmandelic acid and homovanillic acid) at diagnosis, tumor Ha-ras p21 expression and tumor N-myc amplification. Infant neuroblastoma had unique features in comparison to neuroblastoma diagnosed over 12 months of age. Clinical outcome of the patients in groups A and C was quite favorable. Even patients with stage III or IV disease in group A had a favorable prognosis. However, stage IVs disease in group A was not necessarily associated with a good prognosis and the early death after diagnosis was also characteristic. The biological profile of tumors in group C was similar to that in group A but different from the profile in groups B and D. Tumors in group B had a biological profile intermediate between groups A and D. Cases detected by mass screening (group C) provided a new clinical entity with a good prognosis. The difference in biological profiles might affect their clinical outcome of respective age group. These analyses confirm the significance of prognostic markers and may help to direct an appropriate modality of treatment for the individual patient.