Josee Brossard

A population-based study of the usefulness of screening for neuroblastoma

BACKGROUND Neuroblastoma has many characteristics which suggest that preclinical detection might improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. As an early endpoint, we report whether screening could reduce the incidence of poor-prognosis neuroblastoma in children with advanced-stage disease over 1 year of age. METHODS All 476,603 children born in the province of Quebec during the 5-year period of May 1, 1989, to April 30, 1994, were eligible for urinary assay of homovanillic acid and vanillylmandelic acid at 3 weeks and 6 months of age. Children with a positive screen were referred to one of four paediatric cancer centres in the province for uniform evaluation and treatment if necessary. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in the province and two similar population-based controls, the state of Minnesota and the province of Ontario, during the same period of time and with similar ascertainment procedures. FINDINGS Compliance with screening in Quebec province was 91% at 3 weeks (n = 425,816) and 74% at 6 months (n = 349,706). Through July 31, 1995, with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically before screening at 3 weeks of age, and 55 detected clinically after 3 weeks of age having normal screens (52) or never screened (3). Retrospective analysis of stored samples confirmed that 49 of 52 patients missed by screening had levels of catecholamine metabolites that were too low to be detected at 6 months or earlier. Based on US Surveillance, Epidemiology and End Results data, 54.5 cases of neuroblastoma would have been expected in Quebec province during the study period, for an SIR of 2.17 (95% CI 1.79-2.57, p < 0.0001). For the two control groups, 43 and 80 cases of neuroblastoma were detected, respectively, compared with 37.9 and 85.4 expected, overall SIR 1.00 (not significant). SIRs for Quebec province by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR 2.85, 2.26-3.50), with no reduction in incidence in subsequent years. Limiting analysis to only patients diagnosed over 1 year of age with advanced-stage disease, 22 cases were detected in Quebec province versus 14.4 expected (SIR 1.52, 0.95-2.23). Data in the two control groups show no significant increase or decrease in any-stage disease in children under or over the age of 1 year, except for an increase in early-stage disease in Minnesota children over 1 year: 10 versus 3.8 expected (SIR 2.67, 1.27-4.58). INTERPRETATION Screening for neuroblastoma increases the incidence in infants without decreasing the incidence of unfavourable advanced-stage disease in older children. It is unlikely that screening for neuroblastoma in infants will reduce mortality for this disease.

Biological aspects of neuroblastomas identified by mass screening in quebec

BACKGROUND Neuroblastoma has several characteristics that suggest that preclinical diagnosis might improve outcome. Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites. PROCEDURE Over the 5-yr period, 45 tumors were detected by screening, 20 were identified clinically prior to the third week, and 64 were identified clinically at a later time. We analyzed available tumors for Shimada histopathology, tumor ploidy, MYCN copy number and serum ferritin. RESULTS Of the tumors detected by screening, only 2 of 45 tested had unfavorable histology, 2 of 45 had diploid or tetraploid DNA content, 0 of 43 had MYCN amplification, and 4 of 44 had elevated serum ferritin. All of these patients are alive and well. The 20 patients detected prior to the 3-week screen had similar biological characteristics. In contrast, of the patients detected clinically after 3 weeks of age, 19 of 51 testedhad unfavorable histology, 25 of 66 had diploid or tetraploid tumors, 12 of 56 had MYCN amplification, and 14 of 54 had elevated ferritin. CONCLUSIONS The difference between the screened and clinically detected cases was highly significant for each biological variable. Preliminary data on other biological variables, such as neurotrophin expression and allelic loss on 1 p in these patients are consistent with the above findings. These data suggest that mass screening for neuroblastoma at or before 6 months of age detects almost exclusively tumors that have favorable biological characteristics, many of which might have regressed spontaneously. Thus, continued mass screening for neuroblastoma at 6 months is unlikely to accomplish its intended goal, and should probably be discontinued.

Screening for neuroblastoma is ineffective in reducing the incidence of unfavourable advanced stage disease in older children

Neuroblastoma exhibits many characteristics which would suggest that preclinical detection may improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. All 476,603 children born in the province of Quebec during a 5-year period of time (1 May 1989 to 30 April 1994) were eligible for determinations of urinary catecholamine metabolites at 3 weeks and 6 months of age. Children with positive screening were referred to one of four paediatric cancer centres in Quebec for uniform evaluation and treatment. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in Quebec and two comparable population-based controls during the same period of time using similar ascertainment procedures. Compliance with screening in Quebec was 91% at 3 weeks (n = 425,816) and 74% at 6 months (n = 349,706). Up to 31 July 1995 with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically prior to screening at 3 weeks of age and 55 detected clinically after 3 weeks of age having normal screens (n = 52) or never screened (n = 3). Based on data from concurrent control populations, 54.5 cases of neuroblastoma would have been expected in Quebec during the study period for an SIR of 2.17 (95% CI 1.79-2.57, P < 0.0001). For the two control groups, the overall SIR was 1.00 (NS). SIRs for Quebec by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR = 2.85, 95% CI 2.26-3.50), with no reduction in incidence in subsequent years. We conclude that screening for neuroblastoma markedly increases the incidence in infants without decreasing the incidence of unfavourable advanced stage disease in older children. It is unlikely that screening for neuroblastoma in infants will reduce the mortality of this disease.

Screening for neuroblastoma in north america. Preliminary results of a pathology review from the quebec project

Background. The Quebec Neuroblastoma Screening Project was initiated to assess clinical and biologic aspects of neuroblastomas detected by screening infants born in the province of Quebec from May 1, 1989, to April 30, 1994.

Treatment Complications in Children Diagnosed With Neuroblastoma During a Screening Program

PURPOSE The Québec Neuroblastoma Screening Program was put in place to investigate the possibility of decreasing mortality from high-risk neuroblastoma through early screening. We assess treatment complications in the patients diagnosed during this screening program. PATIENTS AND METHODS A total of 476,603 patients born during the screening period were eligible. Parents of 425,838 children (89%) agreed to participate in the 3-week screening, and 73% agreed to participate in the 6-month screening. Forty-five patients had neuroblastoma. We reviewed the medical and research charts for all patients diagnosed by screening. Follow-up was available from 8 to 13 years after screening. RESULTS Forty-five patients were diagnosed by screening. All patients were treated according to the Pediatric Oncology Group recommendations of the time. All patients had surgery, and 29 patients received chemotherapy. No patient died from neuroblastoma. Eleven patients suffered complications from treatment. Two patients had life-threatening complications. CONCLUSION In view of the lack of impact of screening programs on neuroblastoma mortality, evidence that many of the tumors detected through screening can be observed without treatment and the serious complications that may arise from therapy, we do not support neuroblastoma screening programs for children.

Incidence of Neuroblastoma After a Screening Program

PURPOSE A significant increase in the incidence of neuroblastoma occurred among a 5-year birth cohort (May 1989 to April 1994) during an active urinary screening program for its early detection. We examined the postscreening incidence of neuroblastoma in the subsequent 5-year birth cohort (May 1994 to April 1999), with follow-up to 2002, to determine whether the incidence remained increased. PATIENTS AND METHODS We reviewed institutional records of patients diagnosed with neuroblastoma during the period from 1994 to 2002 who were born in 1994 to 1999 in the province of Quebec, as well as in the state of Minnesota and the province of Ontario, regions that had served as controls during the screening interval. We calculated and compared incidence rates during the 1994 to 2002 time period. RESULTS For the 5-year birth cohort as a whole, the rate of newly diagnosed neuroblastoma was higher in Quebec than in the control populations of Minnesota and Ontario (standardized incidence ratio, 1.34; 95% CI, 1.03 to 1.70). However, in years 4 and 5 of the interval, population-based incidence declined to the same levels as those seen in the control areas. CONCLUSION The institution of a urinary screening program for neuroblastoma led to increased awareness of the diagnosis and an elevated rate of diagnosis even after the completion of the screening evaluation. However, this halo effect was transient, with diagnostic rates subsequently decreasing within the range seen in control populations.