EurJ Cancer, Vol. 27, No. 6, pp. 682483, 1991. 0277-5379191$3.00 + 0.00
Printed tn Great Britain 0 1991 rergmm Press pit
Neuroblastoma Screening: More Questions than
Answers?
A FURTHER contribution to the growing controversy surrounding toma which, it is suggested, could be a consequence of the
the efficacy of screening infants for the early detection of screening programme [6]. However, a significant component in
neuroblastoma has recently been presented by Kaneko and his changes in both survival and mortality in Japan must be the
colleagues in Japan [ 11. They describe the biology of cases of improvement in treatment which has occurred over the past few
neuroblastoma detected both clinically and by screening and years [7].
conclude that screening at the age of 6 months, as is currently Recent advances in our understanding of the biology of
the case in Japan, may not be optimal. neuroblastoma have lead to speculation as to whether it is in
For almost 2 decades the Japanese have been developing fact one disease or several. Investigations of the biology of the
techniques for the screening of infants for the early detection of disease have highlighted several markers which appear to be
neuroblastoma-that cancer of childhood, the disseminated characteristic of an individual tumour and which are strongly
form of which has remained unyieldingly aggressive in the face correlated with prognosis. Amplification of the n-myc oncogene,
of modern chemotherapy. DNA diploidy, chromosome lp abnormalities, high serum levels
The method of screening which has been developed and of ferritin and neuron specific enolase are all associated with
refined in Japan is based on the assay of catecholamine metab- poor prognosis [8, 91.
olites in urine samples obtained from nappies (diapers). Clearly There is scant evidence that disease of good prognostic
such a straightforward and non-invasive screening test should indicators progresses into disease of poor prognosis; indeed, the
have enormous appeal. evidence suggests that the characteristics of a particular tumour
In 1984 Sawada et al., who had been screening children with are constant. For example serial measurements of n-myc amplifi-
neuroblastoma since 1973, published a report describing the cation have shown that this characteristic is constant over time
effect of neuroblastoma screening on survival from this disease as well as at multiple sites of the same tumour and in both the
in children in Kyoto City [2]. The incautiously optimistic primary tumour and its metastases [lo].
analysis estimated an improvement in S-year survival from 17% The recent paper by Kaneko and his colleagues [l] has
to 73% as a direct consequence of screening at 6 months of age, reported the biological characteristics of 79 patients with neuro-
an improvment of a magnitude hitherto unprecedented in any blastoma, 39 of whom were diagnosed as a result of the Japanese
adult cancer screening programme. The results of these studies screening programme and the remainder when they presented
undoubtedly played a crucial role in the decision to introduce clinically. Some of these had been previously negative on the
national screening in Japan the following year. In 1987 Takeda screening test, i.e. they were false negatives. None of the 34
and his colleagues published a paper showing a similarly striking children detected by screening in whom n-myc amplification was
improvement in survival from 21.3% to 87.5% following the measured were found to have amplification, though this was
introduction of screening in Sapporo City in 1981 [3]. found in 2 of the 6 false negative cases examined. Diploid
Careful study of the reports presented by Sawada and Takeda, tumours were found in 16% (6/37) of cases detected by screening
however, has revealed flaws in the chosen methods of presen- and lp abnormalities in 13% (4130). At the time of writing all
tation of the data which lead to an overestimation of the benefits the children whose disease was detected by screening were alive.
of screening. Some problems were caused by the nature of This contrasts with those children whose disease was detected
neuroblastoma itself. It has long been recognised from post clinically; 38% (9124) had n-myc amplification, 35% (11131) had
morrem studies that in situ neuroblastoma may exist [4] and when diploid tumours and 48% (13127) had lp abnormalities. The
it became apparent that neuroblastoma screening was increasing reduced survival of the group detected clinically reflected the
the incidence of neuroblastoma (T. Sawada, Kyoto University) presence of the poor prognostic indicators.
it was surmised that some of the cases detected must, therefore, It would appear, therefore, that screening infants at the age
have been in the process of regressing spontaneously. When of 6 months detects mainly those children with an inherently
detected by screening, these “silent” cases were indistinguish- good prognosis as demonstrated by the favourable biological
able from true neuroblastoma. The inclusion of these silent characteristics of the tumours, especially the absence of n-myc
cases, which would otherwise have 100% survival and which amplification. The detection of largely good prognosis cases
appear to occur at a similar frequency to neuroblastoma itself, would certainly contribute to the observed survival rate of over
clearly influences the overall survival in the group of children 97% in the 328 children detected by screening so far in Japan,
with neuroblastoma detected by screening. In addition to this following the introduction of national screening [ 111.
problem of silent neuroblastoma, there are problems inherent Kaneko and his colleagues conclude that screening should be
in the interpretation of survival data from any screening pro- repeated at the age of 12 months in order to attempt to detect
gramme, i.e. lead time and length time bias [5]. children who have more aggressive disease. Clearly, this sugges-
There have been continuing reports from Japan of improved tion raises serious economic, ethical and methodological issues.
survival and, more recently, decreased mortality from neuroblas- Firstly, if screening at 6 months detects only children with good
prognosis disease, is there any justification for doing it at all this
Correspondence to A.W. Craft. time? There is great concern about the detection and treatment
Received 22 Feb. 1991; accepted 1 M ar. 1991. of silent cases ofneuroblastoma (i.e. cases which would otherwise
682
Printed tn Great Britain 0 1991 rergmm Press pit
Neuroblastoma Screening: More Questions than
Answers?
A FURTHER contribution to the growing controversy surrounding toma which, it is suggested, could be a consequence of the
the efficacy of screening infants for the early detection of screening programme [6]. However, a significant component in
neuroblastoma has recently been presented by Kaneko and his changes in both survival and mortality in Japan must be the
colleagues in Japan [ 11. They describe the biology of cases of improvement in treatment which has occurred over the past few
neuroblastoma detected both clinically and by screening and years [7].
conclude that screening at the age of 6 months, as is currently Recent advances in our understanding of the biology of
the case in Japan, may not be optimal. neuroblastoma have lead to speculation as to whether it is in
For almost 2 decades the Japanese have been developing fact one disease or several. Investigations of the biology of the
techniques for the screening of infants for the early detection of disease have highlighted several markers which appear to be
neuroblastoma-that cancer of childhood, the disseminated characteristic of an individual tumour and which are strongly
form of which has remained unyieldingly aggressive in the face correlated with prognosis. Amplification of the n-myc oncogene,
of modern chemotherapy. DNA diploidy, chromosome lp abnormalities, high serum levels
The method of screening which has been developed and of ferritin and neuron specific enolase are all associated with
refined in Japan is based on the assay of catecholamine metab- poor prognosis [8, 91.
olites in urine samples obtained from nappies (diapers). Clearly There is scant evidence that disease of good prognostic
such a straightforward and non-invasive screening test should indicators progresses into disease of poor prognosis; indeed, the
have enormous appeal. evidence suggests that the characteristics of a particular tumour
In 1984 Sawada et al., who had been screening children with are constant. For example serial measurements of n-myc amplifi-
neuroblastoma since 1973, published a report describing the cation have shown that this characteristic is constant over time
effect of neuroblastoma screening on survival from this disease as well as at multiple sites of the same tumour and in both the
in children in Kyoto City [2]. The incautiously optimistic primary tumour and its metastases [lo].
analysis estimated an improvement in S-year survival from 17% The recent paper by Kaneko and his colleagues [l] has
to 73% as a direct consequence of screening at 6 months of age, reported the biological characteristics of 79 patients with neuro-
an improvment of a magnitude hitherto unprecedented in any blastoma, 39 of whom were diagnosed as a result of the Japanese
adult cancer screening programme. The results of these studies screening programme and the remainder when they presented
undoubtedly played a crucial role in the decision to introduce clinically. Some of these had been previously negative on the
national screening in Japan the following year. In 1987 Takeda screening test, i.e. they were false negatives. None of the 34
and his colleagues published a paper showing a similarly striking children detected by screening in whom n-myc amplification was
improvement in survival from 21.3% to 87.5% following the measured were found to have amplification, though this was
introduction of screening in Sapporo City in 1981 [3]. found in 2 of the 6 false negative cases examined. Diploid
Careful study of the reports presented by Sawada and Takeda, tumours were found in 16% (6/37) of cases detected by screening
however, has revealed flaws in the chosen methods of presen- and lp abnormalities in 13% (4130). At the time of writing all
tation of the data which lead to an overestimation of the benefits the children whose disease was detected by screening were alive.
of screening. Some problems were caused by the nature of This contrasts with those children whose disease was detected
neuroblastoma itself. It has long been recognised from post clinically; 38% (9124) had n-myc amplification, 35% (11131) had
morrem studies that in situ neuroblastoma may exist [4] and when diploid tumours and 48% (13127) had lp abnormalities. The
it became apparent that neuroblastoma screening was increasing reduced survival of the group detected clinically reflected the
the incidence of neuroblastoma (T. Sawada, Kyoto University) presence of the poor prognostic indicators.
it was surmised that some of the cases detected must, therefore, It would appear, therefore, that screening infants at the age
have been in the process of regressing spontaneously. When of 6 months detects mainly those children with an inherently
detected by screening, these “silent” cases were indistinguish- good prognosis as demonstrated by the favourable biological
able from true neuroblastoma. The inclusion of these silent characteristics of the tumours, especially the absence of n-myc
cases, which would otherwise have 100% survival and which amplification. The detection of largely good prognosis cases
appear to occur at a similar frequency to neuroblastoma itself, would certainly contribute to the observed survival rate of over
clearly influences the overall survival in the group of children 97% in the 328 children detected by screening so far in Japan,
with neuroblastoma detected by screening. In addition to this following the introduction of national screening [ 111.
problem of silent neuroblastoma, there are problems inherent Kaneko and his colleagues conclude that screening should be
in the interpretation of survival data from any screening pro- repeated at the age of 12 months in order to attempt to detect
gramme, i.e. lead time and length time bias [5]. children who have more aggressive disease. Clearly, this sugges-
There have been continuing reports from Japan of improved tion raises serious economic, ethical and methodological issues.
survival and, more recently, decreased mortality from neuroblas- Firstly, if screening at 6 months detects only children with good
prognosis disease, is there any justification for doing it at all this
Correspondence to A.W. Craft. time? There is great concern about the detection and treatment
Received 22 Feb. 1991; accepted 1 M ar. 1991. of silent cases ofneuroblastoma (i.e. cases which would otherwise
682
