Evidence of Benefit
Evidence of screening effect derives from descriptive studies of local and national programs in Japan, uncontrolled pilot experiences at a number of sites in Europe and the United States, and population-based studies in Canada and Germany.[1-7]
An increase in survival rates among screen-detected cases would be expected if screening was detecting neuroblastoma at an earlier and more curable stage. While improved survival rates after initiation of screening have been reported,[8,9] these observations should be viewed cautiously because improvements could be caused by lead-time bias, length bias, and identification of cases through screening that would have spontaneously regressed.
Screening results in an increased incidence of early-stage disease. The cases detected by screening almost exclusively have biologically favorable properties (unamplified N-myc oncogene, near triploidy, and favorable histology), and this type of favorable neuroblastoma has a high survival rate, whether detected by screening or detected clinically.[1,6,7,10-17] There is evidence that some tumors regress spontaneously in the absence of treatment.[18-21]
Some authors have argued that the Japanese experience shows that the number of children older than 1 year, who are diagnosed with neuroblastoma, may have decreased since the inception of screening  and that overall mortality has declined during this period.[12,23] A true reduction in neuroblastoma mortality may reflect improvements in treatment efficacy as much as a benefit of treating earlier-stage disease. Mortality has decreased in other countries where screening does not occur. In another study of regional comparisons, disease rates were compared between Osaka, Japan, where screenings were initiated in 1985, and Great Britain, where screening was not done. There was little change during this time in the cumulative mortality rates in either region; 52 versus 57.5 per million between 1970 and 1979 versus 1991 and 1994 in Osaka, compared with 78.6 versus 70.1 in the corresponding periods in Great Britain. In any case, the majority of cases detected by screening at 6 months appear to have biologically favorable prognoses independent of stage.[1,26-29] Furthermore, despite the shift in stage distribution of cases detected by screening compared with those that are routinely detected, the evidence of reduction in the incidence of advanced-stage cancers in the Japanese experience has been disputed;[3,11,30] in the Quebec Project, as noted below, no such reduction is observed.
A study of mortality trends before and after the national mass screening program in Japan for neuroblastoma analyzed age-specific mortality rates from 1980 through 2006. Screening began in the mid-1980s and was halted in 2003. Mortality rates were either stable through the entire period for age groups 5 years to 9 years and 10 years to 14 years, or were declining before the initiation of screening and continued to do so through 2006 for age groups less than 1 year and 1 year to 4 years. Because the most recent year of death analyzed was 2006, any increase in age-specific mortality associated with the cessation of mass screening in 2003 would have been expected to occur among children aged less than 1 year or 1 year to 4 years. No such increase was observed. This is the first postscreening analysis to provide evidence that screening had no impact on mortality rates and that stopping screening had no adverse effect.
A study compared neuroblastoma incidence and mortality rates in Japan in three cohorts: children born before screening between 1980 and 1983, and those born during screening between 1986 and 1989, and between 1990 and 1998. Cumulative incidence was higher in the screened cohorts (21.56–29.80 cases per 100,000 births) compared with the prescreening cohort (11.56 cases). Cumulative mortality was lower in the screened cohorts compared with the prescreening cohort (3.90–2.83 vs. 5.38 deaths per 100,000 births). The impact of changes in treatment on these rates is unclear.
The Quebec Neuroblastoma Screening Project compared neuroblastoma incidence and mortality in a 5-year birth cohort (n = 476,603) from Quebec (where urinary screening was offered at 3 weeks and 6 months [overall compliance, 92%]) to various North American birth cohorts in which no screening took place. In this study, the incidence of early-stage disease in children younger than 1 year in the screened population more than doubled that expected, while in the control population, it approximated that expected (standardized incidence ratio, 3.03; 95% confidence interval [CI], 2.30–3.86) in Quebec versus 0.82 in Minnesota (95% CI, 0.41–1.38) and Ontario (95% CI, 0.53–1.17). The incidence of advanced-stage disease (stage III and stage IV) in older children in Quebec showed a statistically nonsignificant increase over that which would have been expected (standard incidence ratio, 1.52; 95% CI, 0.95–2.23). After approximately 8 years of follow-up (range 6–11 years) the neuroblastoma death rate in the screened population was not significantly different from rates in unscreened populations (standardized mortality ratio, 1.11 [95% CI, 0.64–1.92] for the Quebec cohort compared with Ontario children). Similar findings were observed in the German neuroblastoma study. Although final mortality rates are expected in 2008, an interim analysis shows that the death rate from neuroblastoma is similar in screened and control populations (1.6 vs. 1.9 deaths per 100,000 children). A study in Austria yielded a similar conclusion, though screening was performed at age 7 to 12 months. In the screening cohort, neuroblastoma incidence was statistically significantly higher than in children who were not screened (18.2 vs. 11.2 per 100,000 births), while mortality was not statistically significantly different (0.96 vs. 1.57 per 100,000 births).
There is no evidence from controlled studies or randomized trials of decreases in mortality associated with screening.
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- Naito H, Sasaki M, Yamashiro K, et al.: Improvement in prognosis of neuroblastoma through mass population screening. J Pediatr Surg 25 (2): 245-8, 1990. [PUBMED Abstract]
- Takeuchi LA, Hachitanda Y, Woods WG, et al.: Screening for neuroblastoma in North America. Preliminary results of a pathology review from the Quebec Project. Cancer 76 (11): 2363-71, 1995. [PUBMED Abstract]
- Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91, 1991. [PUBMED Abstract]
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- Yoneda A, Oue T, Imura K, et al.: Observation of untreated patients with neuroblastoma detected by mass screening: a "wait and see" pilot study. Med Pediatr Oncol 36 (1): 160-2, 2001. [PUBMED Abstract]
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- Honjo S, Doran HE, Stiller CA, et al.: Neuroblastoma trends in Osaka, Japan, and Great Britain 1970-1994, in relation to screening. Int J Cancer 103 (4): 538-43, 2003. [PUBMED Abstract]
- Hachitanda Y, Ishimoto K, Hata J, et al.: One hundred neuroblastomas detected through a mass screening system in Japan. Cancer 74 (12): 3223-6, 1994. [PUBMED Abstract]
- Hayashi Y, Hanada R, Yamamoto K: Biology of neuroblastomas in Japan found by screening. Am J Pediatr Hematol Oncol 14 (4): 342-7, 1992. [PUBMED Abstract]
- Nakagawara A, Zaizen Y, Ikeda K, et al.: Different genomic and metabolic patterns between mass screening-positive and mass screening-negative later-presenting neuroblastomas. Cancer 68 (9): 2037-44, 1991. [PUBMED Abstract]
- Kaneko Y, Kanda N, Maseki N, et al.: Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study. J Clin Oncol 8 (12): 2005-13, 1990. [PUBMED Abstract]
- Bessho F: Effects of mass screening on age-specific incidence of neuroblastoma. Int J Cancer 67 (4): 520-2, 1996. [PUBMED Abstract]
- Katanoda K, Hayashi K, Yamamoto K, et al.: Secular trends in neuroblastoma mortality before and after the cessation of national mass screening in Japan. J Epidemiol 19 (5): 266-70, 2009. [PUBMED Abstract]
- Hiyama E, Iehara T, Sugimoto T, et al.: Effectiveness of screening for neuroblastoma at 6 months of age: a retrospective population-based cohort study. Lancet 371 (9619): 1173-80, 2008. [PUBMED Abstract]
- Schilling FH, Spix C, Berthold F, et al.: Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany. Cancer Lett 197 (1-2): 19-28, 2003. [PUBMED Abstract]
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