Report of the 1998 Consensus Conference on Neuroblastoma Screening

A consensus conference concerning screening for neu-roblastoma was convened in Lyon on December 8–10,1998, under the aegis of the Centre Jacques Cartier andwas guided by Prof. Thierry Philip. The 1998 conferencewas based on a preliminary meeting held in 1997, also inLyon and also under the guidance of Prof. Philip. At thattime, several experts were asked to consider the pros andcons of screening children of various ages, and the resultsof those presentations were published inMedical andPediatric Oncology(Vol. 32, No. 3, November, 1998). Ajury was then selected and was convened for the 1998conference to consider the evidence published in thatissue ofMPO and to hear additional data presented byexperts in the field of neuroblastoma screening.

Background information concerning the clinical as-pects, the biology, and the epidemiology/statistics ofneu-roblastoma was presented by Drs. A. Evans and G. Brodeur(United States) and J. Este`ve (France) respectively. Thejury was then asked to consider three specific questions:

• Is neuroblastoma one, two, or three diseases?Evi-dence concerning this point was presented by thespeakers listed in Appendix A.1

• Should screening of infants under the age of 7months be continued? Accrued data and argumentspro and con were advanced by the speakers listed inAppendix B.

• How can the question of a possible effect of screen-ing at 12 months or later be answered? This issuewas considered by the speakers listed in Appendix C.

The jury directed its attention to the three questions itwas asked to consider. It also weighed three additionalpoints it believed to be appropriate and germane to theissues involved in screening childhood populations forneuroblastoma. They were:

• Is there evidence there is a group of neuroblastomapatients in whom early intervention decreases themortality rate?

• What are the psychosocioeconomic impacts ofscreening for neuroblastoma?

• Is there a role for mass screening of the populationas a public health measure?

The members of the jury considered all these six ques-tions and reported as follows:

IS THERE EVIDENCE THAT THERE IS A GROUP OFNEUROBLASTOMA PATIENTS IN WHOM EARLYINTERVENTION DECREASES THE MORTALITY RATE?

The jury’s opinion was: It had not heard or read anyevidence to support or reject the hypothesis underlyingthe premise, which is the basis for screening for anymalignant disease. That proposition is that there is agroup of patients in whom early detection and treatmentinterrupts progression of the disease from a curable to anincurable state. The premise is critically important in thecase of neuroblastoma. This is because neuroblastomahas been considered by many and for years to be made uplargely of two categories that are inherently “good” and“bad,” neither of which has been influenced appreciablyif at all by currently available therapies. It is thereforeessential for any neuroblastoma screening study to estab-lish 1) whether there is, in fact, a transition from one tothe other and 2) that early treatment alters that transition.

At present there is no persuasive evidence for oragainst the hypothesis that early detection of neuroblas-toma patients through screening would lessen the mor-tality rate.

IS NEUROBLASTOMA ONE, TWO, ORTHREE DISEASES?

The jury responded as follows: The diagnosis “neuro-blastoma” identifies a neoplasm that affects more thantwo sets of patients as defined by the evolution of theneoplasm and/or its response to currently available thera-pies. These sets include:

A) A group of patients in whom the neoplasm dis-appears and/or matures to ganglioneuroma spon-taneously or after minimal therapy;

B) A group of patients in whom the neoplasm iscurable by currently available therapy; within this1In Appendices A–C, names are listed in order of appearance.

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© 1999 Wiley-Liss, Inc.

group is the putative target population of anyNBL screening program;

C) A group of patients in whom the neoplasm isincurable by currently available therapy.

SHOULD SCREENING OF INFANTS UNDER THEAGE OF 7 MONTHS BE CONTINUED?

The jury responded as follows: The screening pro-grams performed thus far have yielded a large body ofnew insights into the epidemiology of neuroblastoma buthave not shown a beneficial effect on mortality rate, al-though due to study size, a small effect cannot be ex-cluded. Any potential beneficial effect of screening chil-dren under 7 months of age must be balanced against theadverse effects of frequent overdiagnosis, i.e., the iden-tification of patients in whom the tumor would otherwisehave regressed spontaneously, without ever becomingclinically overt. As a consequence, neuroblastomascreening under seven months of age cannot be recom-mended as a public health measure, nor do new screeningprograms in that age group appear to be justified on thebasis of current evidence.

HOW CAN THE QUESTION OF A POSSIBLE EFFECTOF SCREENING AT AGE 12 MONTHS OR LATERBE ANSWERED?

The jury responded as follows:

A) The jury cannot answer this question until theresults of ongoing screening trials in childrenolder than 7 months of age are available.

B) The jury cannot advocate screening at any ageunless part of a research program. Any suchstudy must be conducted with clearly defined ob-jectives and specific aims in rigorously designedtrials that include:1) realistic estimates of feasibility2) appropriate experimental design3) identified data and statistics centers and

laboratory and pathology reference centersof highest quality, authority, and responsibility.

C) Any screening study should in its design includeprocedures and methods to answer the questionof whether there is a group of patients in whomearly intervention lessens the mortality rate.

D) Any screening study must include informed con-sent forms comprehensible to lay persons (i.e.,parents) that make clear the intent and conse-quences of identifying disease in the subjects andthe use to be made of the results.

E) Such studies, if meant to answer public healthquestions (e.g., reduction in mortality rates),should be based on randomized prospective trialmodels.

F) Any screening study must, in addition to detailedclinical data, also include epidemiologic, genetic,

molecular biologic, and other laboratory investi-gations in all patients (and when appropriate infamily members) designed to elucidate the natureof this enigmatic disease.

G) Psychological help should be readily availableand provided by trained professionals competentin helping children with cancer and their families.

WHAT ARE THE PSYCHOSOCIOECONOMICIMPACTS OF SCREENING FOR NEUROBLASTOMA?

The jury responded as follows. Relevant data aresparse, and answers to this questions are needed. Esti-mates of the psychosocioeconomic impact of any screen-ing study should be prominent in study concept, conduct,analysis and reporting, and should include methods andprocedures to gather data concerning these issues. Ap-propriate guidelines are appended.

IS THERE A ROLE FOR MASS SCREENING OF THEPOPULATION FOR NEUROBLASTOMA AS A PUBLICHEALTH MEASURE?

The jury responded as follows: We do not supportmass screening for neuroblastoma as a public healthpolicy at the present time because:

1) understanding of the natural history of NBL is stillincomplete;

2) the size of the group that could benefit from screen-ing (if any) is, at present, unclear;

3) the sojourn time for NBL is not known;4) the risk of overdiagnosis is high, which can lead to

unnecessary treatment and consequent severe toxic-ity in some;

5) screening for NBL can be associated with heavy psy-chological burdens for children and family members,

6) there is not yet any evidence of reduction in mortal-ity as a consequence of screening for NBL.

The above represents the unanimous opinions of thejury. The addresses of the jury members are shown inAppendix D.

Helene Sancho-Garnier(Cochairperson)

Paolo BruzziJean-Pierre FarriauxMatti HakamaRoss PinkertonCharles H. ShawChristian Urban

Giulio J. D’Angio(Chairperson)

H.N. CaronJennifer ForbeckD. OppenheimDaniel SatgeYoshiaki TsuchidaRogier Versteeg

GUIDELINES FOR THE STUDY OFPSYCHOSOCIOECONOMIC ISSUES ASSOCIATEDWITH NEUROBLASTOMA SCREENING

• Ethical issues are important in screening for neuroblas-toma, but the first step in resolving these issues is the

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mounting of well-designed studies with clearly definedaims for the research.

• The aim of screening should be clearly explained toparents: Is it for public health, for medical research(experimental), or for better health of the children?

• The psychological burden for children and familiesshould be taken into account in mass screening, par-ticularly in two situations: in false-positive and, moreimportant in false-negative cases.

• When an infant is to be enrolled in a mass screeningprogram, the following points should be included indiscussions with the parents:

• a brief explanation of the natural history of neu-roblastoma as it is currently understood, plus fre-quency data, results of other screening studies,and treatment methods and outcomes

• the procedure of the examination• the possibility of false-negative diagnosis and its

consequences• the possibility of overdiagnosis and what it means

practically• the realities of treatment for cancer as it affects the

child, the siblings, and the parents

• When the urine tests show positive results withoutovert evidence of neuroblastoma, a public healthnurse, or an equivalent, should telephone or visit theinfant’s parents to explain the screening results and torecommend further examination at the hospital empha-sizing, “We would like to establish that your babydoesnot have a neuroblastoma.”

• Overdiagnosis of neuroblastoma will, however, con-tinue to be a problem with neuroblastoma screening. Ifa “wait and see” policy is adopted for an infant diag-nosed by mass screening, the parents must be informedof the risks involved with such a policy.

• Special psychological attention and support by quali-fied personnel is needed to help parents confront thesedifficult situations: false-positive results, wait and seepolicy, false-negative results.

• Research psychologists should devise studies andguide research concerning

• the psychological burden for children and fami-lies, especially in the difficult situations de-scribed above

• how well parents understand the information given• how well they remember the information if the

child undergoes treatment.

APPENDIX A

F. Berthold (Germany, chairperson), G. Brodeur(USA), M.C. Favrot (France), P. Ambros (Austria), T.Iehara (Japan), H. Rubie (France), B. De Bernardi (Italy),K. Matthay (USA)

APPENDIX B

T. Philip (France, chairperson), J. Powell (UK), W.A.Woods (USA), B. Lemieux (Canada), M. Bernstein(Canada), M. Nishi (Japan), T. Takeda (Japan), D. Frap-paz (France), T. Tafese (Germany), R. Kerbl (Austria), L.Parker (UK), T. Sawada (Japan)

APPENDIX C

L. Parker (UK, chairperson), C. Bergeron (France), J.Hanai (Japan), Schilling (Germany), C. Spix (Germany),F. Berthold (Germany), J. Este`ve (France)

APPENDIX D. Addresses of the Jury Members

Dr. Paolo BruzziIstituto Nazionale per la Ricerca

sul CancroCentro di Biotecnologie AvanzateServizio di Epidemiologia Clinica e

Sperimentazione ControllataLargo Rosanna Benzi, 1016136 Genova, Italy

Dr. Huib N. CaronDepartment of Human GeneticsAcademic Medical CenterMeibergdreef 151105 Amsterdam A2,The Netherlands

Dr. Giulio J. D’AngioDepartment of Radiation Oncology2 DonnerHospital of the University

of Pennsylvania3400 Spruce StreetPhiladelphia, PA 19104

Dr. Jean Pierre FarriauxService de Pe´diatrie et

Genetique MedicaleHopital Huriez59037 Lille, Cedex, France

Mrs. Jennifer ForbeckWilliam Guy Forbeck

Research Foundation23 Peninsula DriveHilton Head Island, SC 29926

Dr. Matti HakamaTampere UniversitySchool of Public HealthBox 60733101 TampereFinland

Dr. Daniel OppenheimPediatrieInstitut Gustav Roussy39 Rue Camille Desmoulins94805 Villejuif Cedex, France

Dr. Ross PinkertonCentre Leon Berard28 Rue Lae¨nnec690081 Lyon, France

Dr. Helene Sancho-GarnierEPIDAURECRLC Val d’ Aurelle34298 Montpellier Cedex 5,

France

Dr. Daniel SatgeLaboratoire d’Anatomie

PathologiqueCentre Hospitalier19012 Tulle, France

Dr. Charles H. ShawDept. of Biological SciencesScience LaboratoriesSouth RoadDurham DH 1 3LE, U.K.

Dr. Yoshiaki TsuchidaDirectorGunma Children’s Medical

CenterShimohakoda, HokkitsuGumma 377-0061, Japan

Dr. Christian UrbanDepartment of PediatricsUniversitatsklinikum GrazAuenbruggerplatz 30A-8036 Graz, Austria

Dr. Rogier VersteegInstitute of Human GeneticsUniversity of AmsterdamMeibergdreef 151105 AZ Amsterdam,The Netherlands

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