Summary Of Evidence

Significance

Evidence Of Benefit

SUMMARY OF EVIDENCE

There is an increase in incidence of early stage neuroblastoma in children who undergo screening compared to children who are not screened. There is no concurrent decrease in incidence in screened children of advanced stage disease which typically does poorly.

The cases identified by screening almost exclusively have biologically favorable properties, and this type of neuroblastoma has a high survival rate, whether detected by screening or detected clinically.

Since the incidence of neuroblastoma among children over 1 year of age appears not to be decreased in screened populations, the increased incidence of neuroblastoma in screened populations likely reflects the diagnosis of cases that would have regressed spontaneously in the absence of treatment. Given these observations, screening is unlikely to cause a decrease in mortality.

Screening infants for neuroblastoma results in overdiagnosis (diagnosis of some neuroblastomas detectable by mass screening which would not have been clinically diagnosed later) with no concomitant reduction in incidence above age 1 and little or no reduction in mortality. This leads to unnecessary diagnostic and therapeutic procedures with consequent physical and psychological morbidity, including death from treatment complications.

Levels of Evidence:

3: Evidence obtained from well-designed and conducted cohort or case-control studies

4: Evidence from ecologic and descriptive studies (e.g., international patterns studies, time series)

5: Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees

SIGNIFICANCE

Incidence and Mortality

Screening Method and Sensitivity

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 of 25 ug/mg creatinine and an HVA cut-off of 32 ug/mg creatinine. Alternatively, individual laboratories use a level of 2 standard deviations above that laboratory's age-specific mean to identify specimens for reanalysis. On reanalysis, a level of 3 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%.[5,10-13] 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 2 children identified by screening as being likely to have neuroblastoma, only 1 was actually affected. In the German Neuroblastoma Screening Project, the positive predictive value has been reported as only 8.5%.[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): 2186-2195, 1995.
2. Gao RN, Levy IG, Woods WG, et al.: Incidence and mortality of neuroblastoma in Canada compared with other childhood cancers. Cancer Causes and Control 8(5): 745-754, 1997.
3. Stiller CA, Parkin DM: International variations in the incidence of neuroblastoma. International Journal of Cancer 52(4): 538-543, 1992.
4. Williams CM, Greer M: Homovanillic acid and vanilmandelic acid in diagnosis of neuroblastoma. JAMA: Journal of the American Medical Association 183(10): 836-840, 1963.
5. Schilling FH, Spix C, Berthold F, et al.: Neuroblastoma screening at one year of age. New England Journal of Medicine 346(14): 1047-1053, 2002.
6. Parker L, Craft AW: Neuroblastoma screening: more questions than answers? European Journal of Cancer 27(6): 682-683, 1991.
7. Yamamoto K, Hanada R, Kikuchi A, et al.: Spontaneous regression of localized neuroblastoma detected by mass screening. Journal of Clinical Oncology 16(4): 1265-1269, 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. Clinical Biochemistry 20(3): 173-177, 1987.
9. Sawada T: Past and future of neuroblastoma screening in Japan. American Journal of Pediatric Hematology/Oncology 14(4): 320-326, 1992.
10. Chamberlain J: Screening for neuroblastoma: a review of the evidence. Journal of Medical Screening 1(3): 169-175, 1994.
11. Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348(9043): 1682-1687, 1996.
12. Nishi M, Miyake H, Takeda T, et al.: Mass screening for neuroblastoma and estimation of costs. Acta Paediatrica Scandinavica 80(8-9): 812-817, 1991.
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): 869-873, 1987.
15. Scriver CR, Gregory D, Bernstein M, et al.: Feasibility of chemical screening of urine for neuroblastoma case finding in infancy in Quebec. Canadian Medical Association Journal 136(9): 952-956, 1987.
16. Bernstein ML, Woods WG: Screening for neuroblastoma. In: Miller AB, Ed.: Advances in Cancer Screening. Boston, Ma: Kluwer Academic Publishers, 1996, pp 149-163.
17. Schilling FH, Berthold F, Erttmann R, et al.: Population-based and controlled study to evalute neuroblastoma screening at one year of age in Germany: interim results. Medical and Pediatric Oncology 35(6): 701-704, 2000.

EVIDENCE OF BENEFIT

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.[1,2,12-19,10,11] There is evidence that some tumors regress spontaneously in the absence of treatment.[20-23]

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 under 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 (stages III and 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 to Ontario children).[11] Similar findings were observed in the German neuroblastoma study.[10] Although final mortality rates are only expected in 2008, an interim analysis shows that the death rate from neuroblastoma is similar in screened and control populations (1.3 versus 1.2 deaths per 100,000 children).

Despite these results, some authors have argued that the Japanese experience shows that the number of children over 1 year of age diagnosed with neuroblastoma may have decreased since the inception of screening [24] and that overall mortality has declined during this period.[14,25] 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.[26] In any event, the majority of cases detected by screening at 6 months of age appear to have biologically favorable prognoses independent of stage.[1,27-30] Furthermore, despite the shift in stage distribution of cases detected by screening compared to those that are routinely detected, the evidence of reduction in the incidence of advanced stage cancers in the Japanese experience has been disputed,[4,13,31] and in the Quebec Project, as noted above, no such reduction is observed.[1]

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,[32,33] these observations should be viewed cautiously, since improvements could be due to lead time bias, to length bias, and to identification of cases through screening which would have spontaneously regressed.

There is, as yet, 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): 1682-1687, 1996.
2. Woods WG, Tuchman M, Bernstein ML, et al.: Screening for neuroblastoma in North America: 2-year results from the Quebec Project. American Journal of Pediatric Hematology/Oncology 14(4): 312-319, 1992.
3. Parker L, Craft AW, Dale G, et al.: Screening for neuroblastoma in the north of England. British Medical Journal 305(6864): 1260-1263, 1992.
4. 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. Journal of Pediatrics 119(2): 237-241, 1991.
5. Tuchman M, Fisher EJ, Heisel MA, et al.: Feasibility study for neonatal neuroblastoma screening in the United States. Medical and Pediatric Oncology 17(4): 258-264, 1989.
6. Takeda T: History and current status of neuroblastoma screening in Japan. Medical and Pediatric Oncology 17(5): 361-363, 1989.
7. Chauvin F, Mathieu P, Frappaz D, et al.: Screening for neuroblastoma in France: methodological aspects and preliminary observations. Medical and Pediatric Oncology 28(2): 81-91, 1997.
8. Schilling FH, Erttmann R, Ambros PF, et al.: Neuroblastoma with unfavourable prognostic parameters detected by mass screening: report of the German pilot study. Proceedings of the American Society of Clinical Oncology 13(A-1440): 421, 1994.
9. Schilling FH, Berthold F, Erttmann R, et al.: Population-based and controlled study to evalute neuroblastoma screening at one year of age in Germany: interim results. Medical and Pediatric Oncology 35(6): 701-704, 2000.
10. Schilling FH, Spix C, Berthold F, et al.: Neuroblastoma screening at one year of age. New England Journal of Medicine 346(14): 1047-1053, 2002.
11. Woods WG, Gao RN, Shuster JJ, et al.: Screening of infants and mortality due to neuroblastoma. New England Journal of Medicine 346(14): 1041-1046, 2002.
12. Bernstein ML, Woods WG: Screening for neuroblastoma. In: Miller AB, Ed.: Advances in Cancer Screening. Boston, Ma: Kluwer Academic Publishers, 1996, pp 149-163.
13. Yamamoto K, Hayashi Y, Hanada R, et al.: Mass screening and age-specific incidence of neuroblastoma in Saitama Prefecture, Japan. Journal of Clinical Oncology 13(8): 2033-2038, 1995.
14. Asami T, Otabe N, Wakabayashi M, et al.: Screening for neuroblastoma: a 9-year birth cohort-based study in Niigata, Japan. Acta Paediatrica 84(10): 1173-1176, 1995.
15. Naito H, Sasaki M, Yamashiro K, et al.: Improvement in prognosis of neuroblastoma through mass population screening. Journal of Pediatric Surgery 25(2): 245-248, 1990.
16. 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): 2363-2371, 1995.
17. 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. Journal of Clinical Oncology 9(4): 581-591, 1991.
18. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. Journal of the National Cancer Institute 89(5): 373-380, 1997.
19. Brodeur GM, Look AT, Shimada H, et al.: Biological aspects of neuroblastomas identified by mass screening in Quebec. Medical and Pediatric Oncology 36(1): 157-159, 2001.
20. Yamamoto K, Hanada R, Kikuchi A, et al.: Spontaneous regression of localized neuroblastoma detected by mass screening. Journal of Clinical Oncology 16(4): 1265-1269, 1998.
21. Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: a 5-year prospective study at a single institution 18(16): 3012-3017, 2000.
22. Tanaka T, Matsumura T, Iehara T, et al.: Risk of unfavorable character among neuroblastomas detected through mass screening. The Japanese Infantile Neuroblastoma Cooperative Study. Medical and Pediatric Oncology 35(6): 705-707, 2000.
23. Yoneda A, Oue T, Imura K, et al.: Observation of untreated patients with neuroblastoma detected by mass screening: a "wait and see" pilot study. Medical and Pediatric Oncology 36(1): 160-162, 2001.
24. Sawada T: Past and future of neuroblastoma screening in Japan. American Journal of Pediatric Hematology/Oncology 14(4): 320-326, 1992.
25. Hanawa Y, Sawada T, Tsunoda A: Decrease in childhood neuroblastoma death in Japan. Medical and Pediatric Oncology 18(6): 472-475, 1990.
26. Cole M, Parker L, Craft A: "Decrease in childhood neuroblastoma death in Japan," Hanawa et al. (1990) [letter]. Medical and Pediatric Oncology 20(1): 84-85, 1992.
27. Hachitanda Y, Ishimoto K, Hata J, et al.: One hundred neuroblastomas detected through a mass screening system in Japan. Cancer 74(12): 3223-3226, 1994.
28. Hayashi Y, Hanada R, Yamamoto K: Biology of neuroblastomas in Japan found by screening. American Journal of Pediatric Hematology/Oncology 14(4): 342-347, 1992.
29. 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): 2037-2044, 1991.
30. 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. Journal of Clinical Oncology 8(12): 2005-2013, 1990.
31. Bessho F: Effects of mass screening on age-specific incidence of neuroblastoma. International Journal of Cancer 67(4): 520-522, 1996.
32. Sawada T, Matsumura T, Kawakatsu H, et al.: Long-term effects of mass screening for neuroblastoma in infancy. American Journal of Pediatric Hematology/Oncology 13(1): 3-7, 1991.
33. Nishi M, Miyake H, Takeda T, et al.: Effects of the mass screening of neuroblastoma in Sapporo City. Cancer 60(3): 433-436, 1987.

Browse and Submit Oncology Conferences

Sponsors: Health on the Net Foundation (Geneva) Landesregierung NRW (im Rahmen von HSP III) FAST Multimedia AG  Schnittpunkt

<A HREF ="deutsch/CancernetDSL.ram">Play clip using the stand-alone RealPlayer!</A><A HREF ="http://www.real.com/products/player/d1.html">Click here to download the latest RealPlayer!</A> small video clip about our work (200 Kbit/s)

Back to the Cancernet contents overview Questions? Mail them to us!

We subscribe to the HONcode principles of the Health On the Net Foundation

This page was last modified on Sunday, 02-Nov-2003 15:59:18 CET