EDITORIALEarly Detection of Neuroblastoma In Infants:

Research? Yes. Routine Screening? No.

Neuroblastoma (NBL) is the second commonest solidmalignancy in childhood. It arises in the adrenal medullaand peripheral sympathetic nervous tissue. Pathologicand biologic investigations suggest that there are favor-able and unfavorable subgroups in both localized anddisseminated neuroblastomas [1]. Unfavorable histologyaccording to the Shimada classification, amplifiedMYCN oncogene, deleted chromosome 1p and absenceof CD44 expression all correlate with a poor clinicaloutcome. There is, however, some inconsistency in thedefinition of NBL risk groups [1]. There are attempts inlocalized neuroblastoma to reduce treatment in biologi-cally favorable casees, not only to use surgery alone buteven to a “wait-and-see” strategy [2]. In patients withmetastatic tumors that often have unfavorable biologicfeatures, intensification of treatment by multi-modalitytherapy including megatherapy with hematopoietic stemcell rescue has improved survival [3,4]. In short, the“natural history” of NBL remains uncertain as does theneed for therapy and its efficacy in the various riskgroups.

It is therefore valid to consider whether early detectionof neuroblastoma may influence the course of the dis-ease. There are at least some cases of neuroblastoma thatappear to progress from good to poor prognosis disease,but such progression may not be characteristic of allneuroblastomas [5]. Consequently, the question as towhether “screening” in infants is the correct approach toimproving the prognosis of neuroblastoma patients can-not at present be answered with any degree of certainty[6–11].

A Pre-Consensus Conference on the question ofscreening infants for neuroblastoma was held in Lyon,December 7–8, 1997. It was convened by the Associationpour le Depistage du Neuroblastome and with the sup-port of the Centre d’Etudes, d’Echanges et de RechercheRhone-Alpes-Canada-Quebec of the Centre JacquesCartier, Lyon.

The title of the conference was “Should infants bescreened for neuroblastoma?” The issue was examined indepth, with reviews of the biology of neuroblastoma, thestatistical methods appropriate to screening, the clini-cians’ expectations, the ethical and psychologic aspects,and the latest appropriate technical methods. A review ofthe first 30 years of screening, pioneered by investigatorsin Japan, provided an overview of what has been accom-plished and learned to date. The detailed manuscriptsdealing with these important matters were collected andpublished in the November, 1998 issue of Medical andPediatric Oncology (12). These were the bases of theConsensus Conference held in Lyon at the InternationalAgency for Cancer Research (I.A.R.C.). December 8–10,1998, during which a jury was asked to consider evi-dence to be presented there anew.

The Jury was chaired by Professor Giulio J. D’Angioand co-chaired by Professor He´lene Sancho-Garnier. Itcomprised 14 people including three epidermiologists,two geneticists, one pathologist, four pediatric oncolo-gists (two chemotherapists, one surgeon, one radiothera-pist), two parents of children with neuroblastoma (one ascientist and the other the head of a neuroblastoma foun-dation), one psychiatrist and one pediatrician specializingin metabolic diseases. The 65 experts who discussed allthe questions for the jury came from 10 different coun-tries and included most of the experts on the managementof neuroblastoma and its biology. Three major questionswere addressed to the Jury, to which the Jury added threeof their own. The Proceedings of the Conference includ-ing the names and topics of all participants, are to be foundin the Report of the jury elsewhere in this issue (13).

The logo that heads this Editorial and the Report of the 1998 Consen-sus Conference on Neuroblastoma Screening identifies the supportgroup that made these activities possible. It is the Centre d’Etudes,d’Echanges et de Recherche Rhoˆne-Alpes-Canada-Quebec of the Cen-tre Jacques Cartier, Lyon. All concerned wish to express their gratitudeto the Centre for its invaluable encouragement and help.

Medical and Pediatric Oncology 33:355–356 (1999)

© 1999 Wiley-Liss, Inc.

During the meeting, a special award was presented toProfessor T. Sawada of Kyoto, Japan. He is the pioneerof screening infants for neuroblastoma, which he haspursued with diligence for more than two decades. Hiscompatriots, Professor Y. Tsuchida of Gumma and Pro-fessor T. Takeda of Sapporo, were recognized at thesame time for their notable contributions to this effortwhich has captured the attention of investigators aroundthe world.

The Jury report leads this investigator to certain con-clusions:

• Considering the amount of data on neuroblastomascreening at six months and earlier already available, itis clear this research should be stopped. Mortality isnot modified and overdiagnosis is obvious. Moreover,the psycho-socio-economic impact of these studies istoo high. Further research protocols are unnecessaryand the early screening policy in Japan for this agegroup should not continue.

• The question of whether screening at 12 months willbe successful is not yet resolved despite evidence thatoverdiagnosis will still occur. Well-designed proto-cols, such as the one currently in progress in Germany,are perfectly ethical and should help bring a definiteanswer to the question.

The possible benefits of early detection of neuroblas-toma in children is still an important area of research.Screening for neuroblastoma at a national level is, how-ever, unacceptable outside a prospective study protocolwith clearly defined objectives and thoroughly informedconsent. This is, in effect, a re-affirmation of the 1991consensus statement [14].

Early detection of neuroblastoma: ROUTINESCREENING? No. RESEARCH? Yes. These are theclear answers to me from the 1998 Lyon Consensus Con-ference.

Thierry PhilipPediatric Department

Centre Leon Berard-28 rue Lae¨nnec69008 Lyon, France

REFERENCES

1. Philip T, Shillling FII. Editorial: objective approach of the screen-ing question. Med Pediatr Oncol 1998;31:419–420.

2. Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the in-ternational criteria for Neuroblastoma diagnosis, staging and re-sponse to treatment. Advances in neuroblastoma research 4. NewYork: Wiley-Liss, Inc., 1994. p 363–9.

3. Evans AF, Silber J, Shpilsky A, et al. Successful management oflow-stage neuroblastoma without adjuvant therapies. Abstract 4thInternational meeting-Stuttgart (9–11 November 95).

4. Berthold F, Burdach S, Kremens R, et al. The role of chemo-therapy in the treatment of children with neuroblastoma stage IV:the GPO (German Pediatric Oncology Society) experience. Klini-cal Padiatrical 1990;202:262–269.

5. Philip T, Zucker JM, Bernard JL, et al. Improved survival at 2 and5 years in the LMCEI unselected group of 72 children with stageIV neuroblastoma older than 1 year of age at diagnosis: Is curepossible in a small subgroup? J Clin Oncol 1991;9:1037–1049.

6. Bessho F. Where should neuroblastoma masse screening go? Lan-cet 1996;348:1672.

7. Chauvin F, Mathieu P, Frappaz D, et al. Screening for neuroblas-toma in France: methodological aspects and preliminary observa-tions. Med Pediatr Oncol 1997;28:81–91.

8. Kerbl R, Urban CF. Neuroblastoma mass screening in children.Lancet 1997;349:730.

9. Nishi T, Miyake II, Takeda T, et al. Effects of the mass screeningof neuroblastoma in Sapporo City. Cancer 1997;60:433–436.

10. Sawada T, Nakata T, Takasugi N, et al. Mass screening of neu-roblastoma in infants in Japan. Lancet 1984;ii:271–273.

11. Schilling FII, Erttinann R, Ambros PF, Strehl S, et al. Screeningfor neuroblastoma. Lancet 1994;344:1157–1158.

12. Special Issue: Neuroblastoma Screening in Infants. Med PediatrOncol 1998;31:393–470.

13. Report of the 1998 consensus conference on neuroblastomascreening. Med Pediatr Oncol 1999 (this issue).

14. Murphy SB, Cohn SL, Craft AW, et al. Do children benefit frommass screening for neuroblastoma? Lancet 1991;337:344–346.

356 Editorial