EDITORIALObjective Approach of the Screening Question

T. Philip, MD,1,2* and F.H. Schilling, MD2

Considering the amount of data on neuro-blastoma screening, clear conclusions may begiven for the 6 months and before screeningprogram and major questions are to be clarifiedfor the 12 months screening hypothesis. Majorexperts in the field will review evidence-baseddata in the literature and these reviews will bepublished in this issue. A consensus conferencewill be held in Lyon, France in December 1998.Three major questions are addressed to the

jury: is neuroblastoma one, two, or, perhaps,three diseases? Should we stop screening forneuroblastoma at 6 months or earlier? How canthe question of a possible effect of screening at12 months or later be answered? This editorialsummarizes the major issue and objectives ofthe Lyon December 1998 consensus confer-ence on neuroblastoma screening. Med. Pedi-atr. Oncol. 31:419–420, 1998.© 1998 Wiley-Liss, Inc.

It is still valid to consider whether early detection ofneuroblastoma may influence the course of the disease.There are at least some cases of neuroblastoma that prog-ress from good to poor prognosis disease, and diseaseprogression may not be characteristic of all neuroblas-toma.

Neuroblastoma is the second most common single ma-lignancy in childhood. It arises in the adrenal medullaand peripheral sympathetic nervous tissue. Pathologicaland biological investigations suggest that there are fa-vourable and unfavourable neuroblastomas in both loca-lised and disseminated neuroblastomas [1]. Tumors withunfavourable histology according to the Shimada classi-fication, amplified MYCN oncogen, deleted chromo-some 1p, and absence of CD44 expression correlate withpoor clinical outcome. There is, however, some incon-sistency in the definition of risk groups in neuroblastoma[3]. There are attempts in localized neuroblastoma toreduce treatment in biologically favourable cases downto not only surgery alone but to a ‘‘wait-and-see’’ strat-egy [6]. In metastatic tumors, which often have unfa-vourable biological features, intensification of treatmentby multimod therapy, including megatherapy with hema-topoetic stem cell rescue, has improved survival [11].The question as to whether neuroblastoma screening ininfants is the correct approach to improve the prognosisof neuroblastoma patients cannot at present be answeredwith any degree of certainty [2, 4, 8, 10, 12–15].

The reader should understand that the debate is stillongoing on neuroblastoma screening from a scientificpoint of view and some questions are still unanswered.

Is neuroblastoma one disease that progresses, or is it agroup of diseases with fundamentally different charac-teristics? Central to this discussion is the clinical expe-rience with localised neuroblastoma. In general, theprognosis for neuroblastoma in infants is much morefavourable than in children diagnosed after the first year

when the disease often presents in a more advancedstage. However, the results of recent years biological andmolecular research in neuroblastoma suggest that thereare two different entities, one with a favourable and onewith an unfavourable prognosis possibly from the veryonset of the disease and maybe three entity, one being theevolution of the first to the second.

What is the best age to screen children for neuroblas-toma? Most programs screened infants before 6 monthsof age [9]. The available data from the neuroblastomascreening programs in Japan, Canada, and Europe wouldsupport the concept of overdiagnosis of favourable, pos-sibly spontaneously regressing neuroblastomas with noinfluence on the appearance of later resenting cases.Overdiagnosis also risks treatment-related morbidity andmortality if surgery is done on all detected cases. Theexperience of all studies at 6 months or earlier is thatscreening at this age is inadvisable [5].

What can we learn from neuroblastoma screening be-fore 6 months of age? Programs may measure the effec-tiveness of screening through changes in stage-specificincidence or mortality in neuroblastoma. From the resultsof the earlier screening programs, it can be concludedthat asymptomatic neuroblastoma cases are detected [4,5]. However, early screening before the age of 6 monthsresults in an increased incidence of neuroblastoma,

1Centre Leon Berard, Lyon, France2Olgahospital, Stuttgart, Germany

The authors are part of the S.E.N.S.E Group, which is made up of thefollowing European Center: Austria, France, Germany, Italy, Norway,U.K.

*Correspondence to: Thierry Philip, Department of Paediatrics, CentreLeon Berard, 28 rue Lae¨nnec, 69373 Lyon Cedex 08, France.E-mail: Philip@lyon.fnclcc.fr

Medical and Pediatric Oncology 31:419–420 (1998)

© 1998 Wiley-Liss, Inc.

which means that more cases of the disease are diagnosedthan would be manifested clinically [4, 5]. One positiveside effect of the conducted and ongoing trials is the gainin biological knowledge [7] and also in epidemiology ofthe disease (see J. Este`ve, this issue). Another effect isthe change in the management of neuroblastomas in thefirst year of life.

In order to reduce the problem of overdiagnosis ofneuroblastoma, it is proposed that screening should bedone later than 6 months, e.g., 12 months [5]. A directresult is that cases occurring earlier than 12 months willnot be detected. However, this does not appear to be aproblem as children presenting under 1 year have a fa-vourable prognosis that is independent of stage. Whenthe screening is postponed to the 12th month of life, onecan hypothesise that the late presenting cases should bedetected if the tumor has the potential to secrete cate-cholamines [5].

A complete cancer registry is a very important re-quirement for a screening program to follow historic con-trols as well as study and control populations. Also nec-essary is the uniformity of treatment of neuroblastoma inany program.

A concensus conference will be held in Lyon in De-cember 1998. The international jury chairman is Profes-sor Giulio D’Angio, and the jury will hear the followingmain questions: Is neuroblastoma one, two, or, perhaps,three diseases? Should we stop screening for neuroblas-toma at 6 months or earlier? How can the question of apossible effect of screening at 12 months or later beanswered?

The questions are still open and this issue ofMedicaland Pediatric Oncologywill review all available evi-dence on the subject to allow the Lyon jury to make aclear, evidence-based statement. This statement will bepublished inMedical and Pediatric Oncology.

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11. Philip T, Zucker JM, Bernard JL, et al.: Improved survival at 2 and5 years in the LMCE1 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 9:6:1037–1044, 1991.

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13. Woods WG, Tuchman M, Robinson L, et al.: A population-basedstudy of the usefulness of screening for neuroblastoma. Lancet348:1682–1687, 1996.

14. Yammamoto K, Tanimura M, Hanada R, et al.: Screening forneuroblastoma increases incidence of the disease under 1 yearinfants without reducing for 1 to 4 year old children. Med PediatrOncol 27:332, 1996.

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16. Kerbl R, Urban C, Ladenstein R, Ambros MI, et al.: Neuroblas-toma screening in infants postponed after the sixth month of age:a trial to reduce ‘‘overdiagnosis’’ and to detect cases with ‘‘un-favorable’’ biologic features. Med Pediatr Oncol 29:1–10, 1997.

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