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Neuroblastoma Screening (PDQ®): Screening - Health Professional Information [NCI]

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Neuroblastoma Screening

Summary of Evidence

Note: Separate PDQ summaries on Neuroblastoma Treatment and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Intervention

Screening, usually at age 6 months, for urine vanillylmandelic acid and homovanillic acid, which are metabolites of the hormones norepinephrine and dopamine.

Benefits

Based on solid evidence, screening for neuroblastoma does not lead to decreased mortality.

Description of the Evidence

  • Study Design: Evidence obtained from nonrandomized controlled trials.
  • Internal Validity: Good.
  • Consistency: Good.
  • Magnitude of Effects on Health Outcomes: No effect on mortality.
  • External Validity: Fair.

Harms

Based on solid evidence, screening infants for neuroblastoma leads to an increase in incidence of early-stage neuroblastoma. There is no concurrent decrease in incidence in screened children of advanced-stage disease, which typically does poorly, or of incidence in children older than 1 year. The cases identified by screening almost exclusively have biologically favorable properties.

Based on solid evidence, screening infants for neuroblastoma results in overdiagnosis (diagnosis of some neuroblastomas detectable by mass screening that would not have been clinically diagnosed later). This leads to unnecessary diagnostic and therapeutic procedures with consequent physical and psychological morbidity, including death from treatment complications.

Description of the Evidence

  • Study Design: Evidence obtained from nonrandomized controlled trials.
  • Internal Validity: Good.
  • Consistency: Good.
  • Magnitude of Effects on Health Outcomes: No effect on mortality. Screening may overdiagnose as many as seven cases per 100,000 infants screened.
  • External Validity: Fair.

Significance

Incidence and Mortality

About 7% of all malignancies in children younger than 15 years are neuroblastomas. About one quarter of cancers in the first year of life are neuroblastomas, making this the most frequent histological type of infant cancer.[1,2] The incidence rate of the disease in children younger than 1 year is about 35 per million but declines rapidly with age to about 1 per million between ages 10 and 14 years.[3] Males appear to be affected slightly more commonly than females, with about five cases occurring in boys to every four occurring in girls.

Screening Method and Sensitivity

The risk factors for and causes of neuroblastoma have not been established, and therefore it is not possible to provide information or advice for the primary prevention of this disease. It is generally thought that many neuroblastomas are present and detectable at birth, thereby allowing for detection of tumors by a single, once-in-a-lifetime screening test, such as those used for neonatal screening for noncancerous conditions (e.g., phenylketonuria). Screening is performed through biochemical tests for metabolites of norepinephrine and dopamine (i.e., vanillylmandelic acid [VMA], and homovanillic acid [HVA]). Seventy-five percent to 90% of cases of neuroblastoma excrete these substances into the urine, which can be measured in urine specimens.[4] There is no known optimal age for screening, but the most commonly discussed and studied age for a one-time screen has been 6 months. Screening at 12 months has also been evaluated in a population-based study in Germany.[5] Approximately 65% of cases are present before 6 months.[6] Furthermore, the clinical significance of screen-detected neuroblastomas is in question since stage I and II localized tumors less than 5 cm have been observed to regress without treatment in an observational study.[7]

Testing of liquid urine samples or of samples collected on filter paper for VMA and HVA is possible.[8] The first attempts to conduct mass screening through urinary testing occurred in Japan in the early 1970s.[9] The VMA and HVA levels are usually measured by gas chromatography, thin layer chromatography, and/or high performance liquid chromatography.

There are no standard cut-off levels between positive and negative VMA and HVA tests. One recommendation is to use a VMA cut-off level of 25 μg/mg creatinine and an HVA cut-off level of 32 μg/mg creatinine. Alternatively, individual laboratories use a level of two standard deviations above that laboratory's age-specific mean to identify specimens for reanalysis. On reanalysis, a level of three standard deviations above the mean is used to determine the need for diagnostic evaluation.[10]

The sensitivity of the screening procedure used in different studies ranges from 40% to 80%.[10,11,12,13] False-positives can be caused by dietary agents such as bananas and vanilla [14] but are rare with quantitative assays such as gas chromatography (specificity approximates 99.9%).[12,15] Because of the low prevalence of the disease, even in the Quebec Neuroblastoma Screening Project in which the specificity of the test was extremely high, the positive-predictive value was only 52%,[11] i.e., for every two children identified by screening as being likely to have neuroblastoma, only one was actually affected. In the German Neuroblastoma Screening Project, the positive-predictive value has been reported as only 8.4%.[5] False-positive cases are generally followed for prolonged periods with serial noninvasive testing before a definitive diagnosis excluding cancer can be offered to the parents.[16]

References:

1. Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995.
2. Gao RN, Levy IG, Woods WG, et al.: Incidence and mortality of neuroblastoma in Canada compared with other childhood cancers. Cancer Causes Control 8 (5): 745-54, 1997.
3. Stiller CA, Parkin DM: International variations in the incidence of neuroblastoma. Int J Cancer 52 (4): 538-43, 1992.
4. Williams CM, Greer M: Homovanillic acid and vanilmandelic acid in diagnosis of neuroblastoma. JAMA 183 (10): 836-840, 1963.
5. 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.
6. Parker L, Craft AW: Neuroblastoma screening: more questions than answers? Eur J Cancer 27 (6): 682-3, 1991.
7. Yamamoto K, Hanada R, Kikuchi A, et al.: Spontaneous regression of localized neuroblastoma detected by mass screening. J Clin Oncol 16 (4): 1265-9, 1998.
8. Tuchman M, Auray-Blais C, Ramnaraine ML, et al.: Determination of urinary homovanillic and vanillylmandelic acids from dried filter paper samples: assessment of potential methods for neuroblastoma screening. Clin Biochem 20 (3): 173-7, 1987.
9. Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-6, 1992.
10. Chamberlain J: Screening for neuroblastoma: a review of the evidence. J Med Screen 1 (3): 169-75, 1994.
11. Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348 (9043): 1682-7, 1996 Dec 21-28.
12. Nishi M, Miyake H, Takeda T, et al.: Mass screening for neuroblastoma and estimation of costs. Acta Paediatr Scand 80 (8-9): 812-7, 1991 Aug-Sep.
13. Chamberlain J: Neuroblastoma. In: Chamberlain J, Moss S, eds.: Evaluation of Cancer Screening. London: Springer, 1996, pp 145-149.
14. Woods WG, Tuchman M: Neuroblastoma: the case for screening infants in North America. Pediatrics 79 (6): 869-73, 1987.
15. Scriver CR, Gregory D, Bernstein M, et al.: Feasibility of chemical screening of urine for neuroblastoma case finding in infancy in Quebec. CMAJ 136 (9): 952-6, 1987.
16. Bernstein ML, Woods WG: Screening for neuroblastoma. In: Miller AB, ed.: Advances in Cancer Screening. Boston, Mass: Kluwer Academic Publishers, 1996, pp 149-163.

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.[1,2,3,4,5,6,7]

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.[1,6,7,10,11,12,13,14,15,16,17] There is evidence that some tumors regress spontaneously in the absence of treatment.[18,19,20,21]

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 [22] 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.[24] 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.[25] 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.[1,26,27,28,29] 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.[1]

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.[31]

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.[32] 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).[1] 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).[1] 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).[7] Similar findings were observed in the German neuroblastoma study.[33] 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).[34]

There is no evidence from controlled studies or randomized trials of decreases in mortality associated with screening.

References:

1. Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348 (9043): 1682-7, 1996 Dec 21-28.
2. Parker L, Craft AW, Dale G, et al.: Screening for neuroblastoma in the north of England. BMJ 305 (6864): 1260-3, 1992.
3. Bessho F, Hashizume K, Nakajo T, et al.: Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children. J Pediatr 119 (2): 237-41, 1991.
4. Takeda T: History and current status of neuroblastoma screening in Japan. Med Pediatr Oncol 17 (5): 361-3, 1989.
5. Chauvin F, Mathieu P, Frappaz D, et al.: Screening for neuroblastoma in France: methodological aspects and preliminary observations. Med Pediatr Oncol 28 (2): 81-91, 1997.
6. Schilling FH, Spix C, Berthold F, et al.: Neuroblastoma screening at one year of age. N Engl J Med 346 (14): 1047-53, 2002.
7. Woods WG, Gao RN, Shuster JJ, et al.: Screening of infants and mortality due to neuroblastoma. N Engl J Med 346 (14): 1041-6, 2002.
8. Sawada T, Matsumura T, Kawakatsu H, et al.: Long-term effects of mass screening for neuroblastoma in infancy. Am J Pediatr Hematol Oncol 13 (1): 3-7, 1991 Spring.
9. Nishi M, Miyake H, Takeda T, et al.: Effects of the mass screening of neuroblastoma in Sapporo City. Cancer 60 (3): 433-6, 1987.
10. Bernstein ML, Woods WG: Screening for neuroblastoma. In: Miller AB, ed.: Advances in Cancer Screening. Boston, Mass: Kluwer Academic Publishers, 1996, pp 149-163.
11. Yamamoto K, Hayashi Y, Hanada R, et al.: Mass screening and age-specific incidence of neuroblastoma in Saitama Prefecture, Japan. J Clin Oncol 13 (8): 2033-8, 1995.
12. Asami T, Otabe N, Wakabayashi M, et al.: Screening for neuroblastoma: a 9-year birth cohort-based study in Niigata, Japan. Acta Paediatr 84 (10): 1173-6, 1995.
13. 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.
14. 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.
15. 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.
16. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst 89 (5): 373-80, 1997.
17. Brodeur GM, Look AT, Shimada H, et al.: Biological aspects of neuroblastomas identified by mass screening in Quebec. Med Pediatr Oncol 36 (1): 157-9, 2001.
18. Yamamoto K, Hanada R, Kikuchi A, et al.: Spontaneous regression of localized neuroblastoma detected by mass screening. J Clin Oncol 16 (4): 1265-9, 1998.
19. Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: s 5-year prospective study at a single institution. J Clin Oncol 18 (16): 3012-7, 2000.
20. Tanaka T, Matsumura T, Iehara T, et al.: Risk of unfavorable character among neuroblastomas detected through mass screening. The Japanese Infantile Neuroblastoma Cooperative Study. Med Pediatr Oncol 35 (6): 705-7, 2000.
21. 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.
22. Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-6, 1992.
23. Hanawa Y, Sawada T, Tsunoda A: Decrease in childhood neuroblastoma death in Japan. Med Pediatr Oncol 18 (6): 472-5, 1990.
24. Cole M, Parker L, Craft A: "Decrease in childhood neuroblastoma death in Japan," Hanawa et al. (1990) Med Pediatr Oncol 20 (1): 84-5, 1992.
25. 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.
26. 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.
27. Hayashi Y, Hanada R, Yamamoto K: Biology of neuroblastomas in Japan found by screening. Am J Pediatr Hematol Oncol 14 (4): 342-7, 1992.
28. 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.
29. 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.
30. Bessho F: Effects of mass screening on age-specific incidence of neuroblastoma. Int J Cancer 67 (4): 520-2, 1996.
31. 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.
32. 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.
33. 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.
34. Kerbl R, Urban CE, Ambros IM, et al.: Neuroblastoma mass screening in late infancy: insights into the biology of neuroblastic tumors. J Clin Oncol 21 (22): 4228-34, 2003.

Changes to This Summary (07 / 23 / 2010)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Evidence of Benefit

Added text about a study that 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 (cited Hiyama et al. as reference 32).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about neuroblastoma screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Levels of Evidence

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National Cancer Institute: PDQ® Neuroblastoma Screening. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/screening/neuroblastoma/HealthProfessional. Accessed <MM/DD/YYYY>.

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