344
persons employed in pointing needles in the needle manufacture. Mem Med Soc Lond 1799; 5: 89-93. 3. Greenhow EH. Specimen of potter’s lung. Trans Path Soc Loud 1866; 17: 36-38. 4. Bailey WC, Brown M, Buechner HA, et al. Silico-mycobacterial disease in sandblasters. Am Rev Respir Dis 1974; 110: 115-25. 5. Warrell DA, Harrison BDW, Fawcett IW, et al. Silicosis among grindstone cutters in the north of Nigeria. Thorax 1975; 30: 389-98. 6. Saiyed HN, Chatterjee BB. Rapid progression of silicosis in slate pencil workers, II: a follow-up study. Am J Indust Med 1985; 8: 135-42. 7. Silicosis and Silicate Disease Committee. Diseases associated with exposure to silica and nonfibrous silicate minerals. Arch Path Lab Med 1988; 112: 673-720.
A, Seaton D, Leitch AG. Crofton and Douglas’s respiratory diseases, 4th ed. Oxford: Blackwell Scientific, 1989: 808-15. Seaton A, Lamb D, Brown WR, et al. Pneumoconiosis of shale miners.
8. Seaton 9.
Thorax 1981; 36: 412-18. 10. Seaton A, Dick JA, Dodgson J, Jacobsen M. Quartz and pneumoconiosis in coal miners. Lancet 1981; ii: 1272-75. 11. Seaton A, Ruckley VA, Addison J, Brown WR. Silicosis in barium miners. Thorax 1986; 41: 591-95. 12. Suratt PM, Winn WC, Brody AR, et al. Acute silicosis in tombstone sandblasters. Am Rev Respir Dis 1977; 115: 521-29. 13. Buechner HA, Ansari A. Acute silico-proteinosis: a new pathologic variant of acute silicosis in sandblaster, characterised by histologic
features
resembling alveolar proteinosis. Dis Chest 1969; 55: 274-84.
CONSENSUS Do children benefit from mass screening for neuroblastoma? Consensus Statement from the American Cancer Society Workshop on Neuroblastoma Screening
A panel of experts met in Chicago on Sept 27, 1990, to discuss the potential value of mass screening for neuroblastoma. The workshop was organised in response to a request by the American Cancer Society (ACS) task force on children and cancer to decide whether children benefit from neuroblastoma screening, and if the ACS should support widespread screening in the US. Data were presented from the Japanese, Quebec and North American, and UK neuroblastoma screening experience. The results of the Pediatric Oncology Group’s modem risk-related therapy for unscreened neuroblastoma were presented, and the biology and genetics of this tumour were also discussed. In addition, investigators with experience of newborn screening and screening for adult forms of cancer discussed the benefit and risks of screening trials. We now summarise the findings, conclusions, and recommendations of this
workshop. The overall 5-year survival rate for neuroblastoma patients has improved over the past 25 years from 25 % up to 50-5 5 %. However, the outlook for patients presenting over 1 year-of-age with advanced disease remains dismal ( < 20% 5-year survival) .1,3 Children who present clinically under that age have a better outlook than older children, and patients with localised disease fare better than those with advanced disease.4 Thus, one might assume that diagnosing neuroblastoma in children, both before 1 year and before their disease is advanced, would lead to a decrease in mortality. Because over 90% of patients who present clinically with this tumour excrete increased quantities of catecholamine metabolites that can be measured in random urine samples obtained from diapers (nappies), it is possible to screen and detect symptom-free children who have neuroblastoma. Extensive data from Japan as well as
preliminary findings from the UK and Quebec have unequivocally shown that urine screening for increased catecholamines (vanillylmandelic acid [VMA] and homovanillic acid [HVA]) is technically feasible by highperformance liquid chromatography (HPLC) or thin-layer chromatography linked to gas chromatography-mass spectrometry.5-7 However, there are no population-based data from controlled studies that show reduced overall mortality from mass screening for neuroblastoma. Before screening data can be interpreted, the biology of this cancer must be considered. Neuroblastoma is a heterogeneous disease. In addition to stage of disease and age at diagnosis, biological features of the tumour, such as DNA content or ploidy, the presence of chromosome lp abnormalities, and the number of copies of the N-myc oncogene, are also powerful prognostic factors.3,8,9 A recent Pediatric Oncology Group study found that, in infants aged under 1 year at diagnosis who were treated with five courses of chemotherapy, cyclophosphamide-doxorubicin hyperdiploidy was associated with long-term disease-free survival in over 90% of cases, while diploid tumours were associated with early treatment failure.2 N-myc gene copy number also identifies children aged under 24 months with ADDRESSES Northwestern University Medical School, USA (Dr S B Murphy, MD, Dr S L. Cohn, MD); University of Newcastle, UK (Dr A W Craft, MD), University of Minnesota, USA (Dr W G Woods, MD); Kyoto Prefectural University of Medicine, Japan (Dr T Sawada, MD); University of Alabama, USA (Dr R P
Castleberry, MD), New England Regional Screening Program, USA (Dr H L Levy, MD), National Cancer Institute, USA (Dr P C Prorok, MD), and University of Southern California, USA (Dr G D Hammond, MD) Correspondence to Dr S B Murphy, 2300 Children Plaza, Children’s Memorial Hospital, Chicago, Illinois 60614, USA
345
disseminated tumours who are unlikely to respond to treatment.2Furthermore, cytogenetic studies have shown
that hyperdiploid neuroblastomas are associated with young age, localised disease, and favourable outcome.9,10 There is no evidence that biologically favourable neuroblastomas progress
by
gene
amplification
to
unfavourable neuroblastomas
or
sequential genetic changes.
Brodeur and colleagues have shown that the N-myc copy number remains unchanged at different sites of a tumour in any one individual as well as serially over time; tumours that lack N-myc amplification at diagnosis remain N-myc
unamplified at second-look surgery or at relapse. A 10-year retrospective study also showed that DNA content was
constant
progression
or
and invariable with respect
to
tumour
therapy. 12
More than 10 years of experimental mass screening of urine samples for increased catecholamines in Japan led to the introduction of a nationwide state-supported mass infant screening programme in that country in 1985. Over 300 cases of neuroblastoma have been detected by screening urine samples at 6 months-of-age, and the outlook for these patients has been excellent.7,13 Of 337 children with neuroblastoma detected in Japan by mass screening up to 1988, 328 (97%) are alive after combined modality treatment, usually surgery and chemotherapy (T. Sawada, unpublished data). Concern was expressed, however, that the excellent survival rate reported for these patients might merely reflect the detection of a high proportion of prognostically favourable cases, especially since these tumours show biologically favourable features--eg, hyperdiploid karyotypes without evidence of 1p deletions and lacking N-myc amplification9,14 (T. Sawada, unpublished data). Kaneko and colleagues lately showed that most neuroblastomas detected in children under 12 months-of-age, either by mass screening or by clinical criteria, had biologically favourable features. is In contrast, the tumours from children presenting clinically over the age of 12 months were generally disseminated, had near-diploid (2n) or near-tetraploid (4n) karyotypes, and about 50% were
N-myc amplified.l5 Reports from Japan
also suggest that the incidence of has neuroblastoma substantially increased after introduction of screening with HPLC, which indicates that the screening programme is detecting (at least in some cases) regressing tumours or tumours that would not otherwise have presented clinically. Cases of neuroblastoma missed by the mass screening programme in Japan have been reported and these patients have largely presented over the age of 12 months with advanced disease. About 50% of the tumours missed by screening have been N-myc amplified, and most of these patients have died from progressive disease .15-17 These data suggest that screening for neuroblastoma at 6 months-of-age detects patients with tumours that have favourable biological features whereas many patients with aggressive disease destined to present clinically at an older age may be missed by the screen. Whether screening children repeatedly or at a later time (such as 12 months) would lead to a higher rate of detection of the biologically unfavourable tumours is unknown. Furthermore, it is uncertain whether earlier detection of biologically aggressive neuroblastoma would improve outlook for this group of patients. Some children detected clinically with advanced disease who do poorly have tumours with favourable biological features such as lack of N-myc amplification and chromosome lp abnormalities. It is
possible that these children could theoretically benefit from earlier detection. A critical determinant of the success of any nationwide mass screening programme for infants with neuroblastoma is the overall mortality rate. National data from death certificates suggest that the mortality rate from neuroblastoma in Japan parallels the mortality rate in the UK where widespread screening is not currently being conducted. Data collected for over 20 years at the Registry of the Japanese Pediatric Surgeons has not shown any change in the number of patients diagnosed with neuroblastoma over the age of 1 year. The failure to observe a decline in the frequency of neuroblastoma among older children suggests that older children who present clinically with neuroblastoma are not being detected early by mass
screening. Further data from population-based mortality studies that compare screened with unscreened populations-such as the North American trial and the proposed UK trial-are needed before the impact of presymptomatic detection of neuroblastoma on mortality (if any) can be assessed. Physicians and the public need to know that the effectiveness of mass screening remains unproven. The importance of supporting current controlled populationbased screening studies in North America and the UK was emphasised. The workshop participants concluded that the Japanese should be recognised for their pioneering work. Data from their studies as well as preliminary data from Quebec and UK screening programmes have led to valuable information about the clinical behaviour of neuroblastoma as well as the biology of this tumour. However, to date, mass screening of urine for increased catecholamines at six months-of-age has not been shown to reduce mortality, and more widespread implementation of this practice cannot be recommended.
REFERENCES 1.
Silverberg E, Boring CC, Squires TS. Cancer statistics,
1990. CA 1990;
40: 9-26. 2. Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma. J Clin Oncol 1991 (in press).
Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985; 313: 1111-16 4. Evans AE. D’Angio GJ, Randolf J. Proposed staging for children with neuroblastoma: Children’s Cancer Study Group A. Cancer 1971; 27:
3.
374-78. 5. McGill AC, Seviour JA, Dale A, Craft AW.
Screening for neuroblastoma region.
gas chromatography-mass spectrometry in the northern Ann Clin Biochem 1988; 25 (suppl): 1325-33.
by
6. Tuchman M, Lemieux B, Auray-Blais C, et al. Screening for neuroblastoma at three weeks of age: methods and preliminary results from the Quebec neuroblastoma screening project. Pediatrics 1990; 86: 765-73. et al. Effects of the mass screening of Sapporo City. Cancer 1987; 60: 433-36. 8. Look AT, Hayes FA, Nitschke R, McWilliams NB, Green AA. Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 1984; 311: 231-35. 9. Hayashi Y, Kanda N, Inaba T, et al. Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1. Cancer
7. Nishi
M, Miyake H, Takeda T,
neuroblastoma in
1989; 63: 126-32. 10. Kaneko Y, Kanda N, Maseki N, et al. Different karyotypic patterns in early and advanced stage neuroblastomas. Cancer Res 1987; 47: 311-18. 11. Brodeur GM, Hayes FA, Green AA, et al. Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients. Cancer Res 1987; 47: 4248-53.
346
12.
15. Kaneko Y, Kanda N, Maseki N, et al. Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting on a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study. J Clin Oncol 1990; 8: 2005-13. 16. Ishimoto K, Kiyokawa N, Fujita H, et al. Problems of mass screening for neuroblastoma: analysis of false negative cases. J Pediatr Surg 1990; 25: 398-401. 17. Nishi M, Miyake H, Takeda T, et al. Cases of neuroblastoma missed by the mass screening programs. Pediatr Res 1989; 26: 603-07.
Taylor SR, Blatt J, Costantino JP, Roederer M, Murphy RF. Flow cytometric DNA analysis of neuroblastoma and ganglioneuroma.
Cancer 1988; 62: 749-54. 13. Naito H, Sasaki M, Yamashiro
neuroblastoma
through
mass
et al. Improvement in prognosis of population screening. J Pediatr Surg
K,
1990; 25: 245-48. 14.
Hayashi Y, Inaba T, Hanada R, Yamamoto K. Chromosome findings and prognosis in 15 patients with neuroblastoma found by VMA mass screening. J Pediatr 1988; 112: 567-71.
VIEWPOINT How much
drug
Many recommended drug doses are higher than necessary, for two reasons. Drugs are often introduced at a dose that will be effective in around 90% of the target population, because this helps market penetration. Doses are also partly determined by an irrational preference for round numbers. The dose excess due to such digit preference may be as much as 70% of the correct dose and on average is probably 25%. Needlessly high doses are bound to cause avoidable unwanted effects in a proportion of patients. Rigorous methods must be used to determine the doses recommended and the amount of drug to be put into a tablet or other dosage form. Introduction I have mild angina, which is largely prevented by small doses of slow-release nifedipine twice a day. This causes slight oedema of the legs in the evening, which has gone by the morning. When amlodipine was introduced I thought that the once-daily dosage might be more convenient, and after hesitating for some months I decided to try it. One Sunday morning I took the lowest recommended dose, one 5 mg tablet. It seemed effective. In the evening the oedema was more prominent than after nifedipine, and the following morning it was still there, offending my cosmetic sensibility. The penny dropped: amlodipine has a half-life of 1 -2 days, and the plasma concentration takes about a week to reach a steady state-by then I might have become a Michelin man. I felt cheated and took no more. I wondered how the company had decided on 5 mg as the lowest dose, and why the tablets contained 5 or 10 mg, which are strikingly round numbers.
What is the
right dose? The biological activity, or potency, of different drug molecules varies widely, and the ratio between the doses of two substances that produce the same intensity of effect (the potency ratio) can be any number. The dose required to cause a particular desired effect at a given intensity in a specified proportion of patients (eg, over 90% beta blockade in 95 % of patients with angina pectoris) depends entirely on the biological properties of the drug and is, or should be, derived from clinical pharmacological studies. Usually it lies somewhere between 1 !J.g and a few grammes, expressed
in the tablet?
number in this million-fold range-such as 8 ltg, 130 ltg, 6 mg, 87 mg, Mg. As in other stimulus/response relationships, the intensity of a biological response is proportional to the log of the dose, rather than directly to the dose, at least in the middle of the range of effective doses between the threshold and the ceiling effect. In that part of the range a doubling of the dose will thus increase the intensity of the effect only about 1-3 times. Towards the top of the range the increase is of course less. Increasing a dose by 10% only rarely leads to a measurable increase in effect, except around the threshold dose. This means that for purposes there is no point in specifying doses to more than two significant figures. The most efficient step size for adjusting the dose depends on whether it is near the bottom of the dose range, in the middle, or near the top; whether the dose-response curve is flat or steep; and the therapeutic margin. It may be appropriate to adjust a dose by doubling or halving it, or to use smaller steps-an increase by 50% or 25%, a decrease by 25% or 33%. These basic facts, taken together with the variability of response to the drug, should determine what doses of medicines are recommended and used, and how much of the active substance should be put into one tablet, capsule, or other dosage form. However, the amounts of drug in one dosage form show very strong terminal digit preference (see table). This cannot be explained by any biological property of the drugs. The manufacturers must have decided the dosage on other grounds.
by
a
practical
Choices in
setting the dose For a new drug to penetrate the market quickly, it should be rapidly effective in a high proportion of patients and simple to use. To achieve this, the dosage of the first prescription is therefore commonly set at about the ED level-ie, the dose which the early clinical (phase II) studies have shown to be effective in 90% of the target population, provided that the unwanted effects at this dose are considered acceptable. In 25 % of patients a smaller, perhaps much smaller, dose (the EDzs) will be effective. The patients in this quartile are the most sensitive to the drug and are liable to receive far more than they need if they are given the ADDRESS Department of Clinical Pharmacology and Therapeutics, Charing Cross and Westminster Medical School, Charing Cross Hospital, London W6 8RF, UK (A Herxheimer, FRCP)
persons employed in pointing needles in the needle manufacture. Mem Med Soc Lond 1799; 5: 89-93. 3. Greenhow EH. Specimen of potter’s lung. Trans Path Soc Loud 1866; 17: 36-38. 4. Bailey WC, Brown M, Buechner HA, et al. Silico-mycobacterial disease in sandblasters. Am Rev Respir Dis 1974; 110: 115-25. 5. Warrell DA, Harrison BDW, Fawcett IW, et al. Silicosis among grindstone cutters in the north of Nigeria. Thorax 1975; 30: 389-98. 6. Saiyed HN, Chatterjee BB. Rapid progression of silicosis in slate pencil workers, II: a follow-up study. Am J Indust Med 1985; 8: 135-42. 7. Silicosis and Silicate Disease Committee. Diseases associated with exposure to silica and nonfibrous silicate minerals. Arch Path Lab Med 1988; 112: 673-720.
A, Seaton D, Leitch AG. Crofton and Douglas’s respiratory diseases, 4th ed. Oxford: Blackwell Scientific, 1989: 808-15. Seaton A, Lamb D, Brown WR, et al. Pneumoconiosis of shale miners.
8. Seaton 9.
Thorax 1981; 36: 412-18. 10. Seaton A, Dick JA, Dodgson J, Jacobsen M. Quartz and pneumoconiosis in coal miners. Lancet 1981; ii: 1272-75. 11. Seaton A, Ruckley VA, Addison J, Brown WR. Silicosis in barium miners. Thorax 1986; 41: 591-95. 12. Suratt PM, Winn WC, Brody AR, et al. Acute silicosis in tombstone sandblasters. Am Rev Respir Dis 1977; 115: 521-29. 13. Buechner HA, Ansari A. Acute silico-proteinosis: a new pathologic variant of acute silicosis in sandblaster, characterised by histologic
features
resembling alveolar proteinosis. Dis Chest 1969; 55: 274-84.
CONSENSUS Do children benefit from mass screening for neuroblastoma? Consensus Statement from the American Cancer Society Workshop on Neuroblastoma Screening
A panel of experts met in Chicago on Sept 27, 1990, to discuss the potential value of mass screening for neuroblastoma. The workshop was organised in response to a request by the American Cancer Society (ACS) task force on children and cancer to decide whether children benefit from neuroblastoma screening, and if the ACS should support widespread screening in the US. Data were presented from the Japanese, Quebec and North American, and UK neuroblastoma screening experience. The results of the Pediatric Oncology Group’s modem risk-related therapy for unscreened neuroblastoma were presented, and the biology and genetics of this tumour were also discussed. In addition, investigators with experience of newborn screening and screening for adult forms of cancer discussed the benefit and risks of screening trials. We now summarise the findings, conclusions, and recommendations of this
workshop. The overall 5-year survival rate for neuroblastoma patients has improved over the past 25 years from 25 % up to 50-5 5 %. However, the outlook for patients presenting over 1 year-of-age with advanced disease remains dismal ( < 20% 5-year survival) .1,3 Children who present clinically under that age have a better outlook than older children, and patients with localised disease fare better than those with advanced disease.4 Thus, one might assume that diagnosing neuroblastoma in children, both before 1 year and before their disease is advanced, would lead to a decrease in mortality. Because over 90% of patients who present clinically with this tumour excrete increased quantities of catecholamine metabolites that can be measured in random urine samples obtained from diapers (nappies), it is possible to screen and detect symptom-free children who have neuroblastoma. Extensive data from Japan as well as
preliminary findings from the UK and Quebec have unequivocally shown that urine screening for increased catecholamines (vanillylmandelic acid [VMA] and homovanillic acid [HVA]) is technically feasible by highperformance liquid chromatography (HPLC) or thin-layer chromatography linked to gas chromatography-mass spectrometry.5-7 However, there are no population-based data from controlled studies that show reduced overall mortality from mass screening for neuroblastoma. Before screening data can be interpreted, the biology of this cancer must be considered. Neuroblastoma is a heterogeneous disease. In addition to stage of disease and age at diagnosis, biological features of the tumour, such as DNA content or ploidy, the presence of chromosome lp abnormalities, and the number of copies of the N-myc oncogene, are also powerful prognostic factors.3,8,9 A recent Pediatric Oncology Group study found that, in infants aged under 1 year at diagnosis who were treated with five courses of chemotherapy, cyclophosphamide-doxorubicin hyperdiploidy was associated with long-term disease-free survival in over 90% of cases, while diploid tumours were associated with early treatment failure.2 N-myc gene copy number also identifies children aged under 24 months with ADDRESSES Northwestern University Medical School, USA (Dr S B Murphy, MD, Dr S L. Cohn, MD); University of Newcastle, UK (Dr A W Craft, MD), University of Minnesota, USA (Dr W G Woods, MD); Kyoto Prefectural University of Medicine, Japan (Dr T Sawada, MD); University of Alabama, USA (Dr R P
Castleberry, MD), New England Regional Screening Program, USA (Dr H L Levy, MD), National Cancer Institute, USA (Dr P C Prorok, MD), and University of Southern California, USA (Dr G D Hammond, MD) Correspondence to Dr S B Murphy, 2300 Children Plaza, Children’s Memorial Hospital, Chicago, Illinois 60614, USA
345
disseminated tumours who are unlikely to respond to treatment.2Furthermore, cytogenetic studies have shown
that hyperdiploid neuroblastomas are associated with young age, localised disease, and favourable outcome.9,10 There is no evidence that biologically favourable neuroblastomas progress
by
gene
amplification
to
unfavourable neuroblastomas
or
sequential genetic changes.
Brodeur and colleagues have shown that the N-myc copy number remains unchanged at different sites of a tumour in any one individual as well as serially over time; tumours that lack N-myc amplification at diagnosis remain N-myc
unamplified at second-look surgery or at relapse. A 10-year retrospective study also showed that DNA content was
constant
progression
or
and invariable with respect
to
tumour
therapy. 12
More than 10 years of experimental mass screening of urine samples for increased catecholamines in Japan led to the introduction of a nationwide state-supported mass infant screening programme in that country in 1985. Over 300 cases of neuroblastoma have been detected by screening urine samples at 6 months-of-age, and the outlook for these patients has been excellent.7,13 Of 337 children with neuroblastoma detected in Japan by mass screening up to 1988, 328 (97%) are alive after combined modality treatment, usually surgery and chemotherapy (T. Sawada, unpublished data). Concern was expressed, however, that the excellent survival rate reported for these patients might merely reflect the detection of a high proportion of prognostically favourable cases, especially since these tumours show biologically favourable features--eg, hyperdiploid karyotypes without evidence of 1p deletions and lacking N-myc amplification9,14 (T. Sawada, unpublished data). Kaneko and colleagues lately showed that most neuroblastomas detected in children under 12 months-of-age, either by mass screening or by clinical criteria, had biologically favourable features. is In contrast, the tumours from children presenting clinically over the age of 12 months were generally disseminated, had near-diploid (2n) or near-tetraploid (4n) karyotypes, and about 50% were
N-myc amplified.l5 Reports from Japan
also suggest that the incidence of has neuroblastoma substantially increased after introduction of screening with HPLC, which indicates that the screening programme is detecting (at least in some cases) regressing tumours or tumours that would not otherwise have presented clinically. Cases of neuroblastoma missed by the mass screening programme in Japan have been reported and these patients have largely presented over the age of 12 months with advanced disease. About 50% of the tumours missed by screening have been N-myc amplified, and most of these patients have died from progressive disease .15-17 These data suggest that screening for neuroblastoma at 6 months-of-age detects patients with tumours that have favourable biological features whereas many patients with aggressive disease destined to present clinically at an older age may be missed by the screen. Whether screening children repeatedly or at a later time (such as 12 months) would lead to a higher rate of detection of the biologically unfavourable tumours is unknown. Furthermore, it is uncertain whether earlier detection of biologically aggressive neuroblastoma would improve outlook for this group of patients. Some children detected clinically with advanced disease who do poorly have tumours with favourable biological features such as lack of N-myc amplification and chromosome lp abnormalities. It is
possible that these children could theoretically benefit from earlier detection. A critical determinant of the success of any nationwide mass screening programme for infants with neuroblastoma is the overall mortality rate. National data from death certificates suggest that the mortality rate from neuroblastoma in Japan parallels the mortality rate in the UK where widespread screening is not currently being conducted. Data collected for over 20 years at the Registry of the Japanese Pediatric Surgeons has not shown any change in the number of patients diagnosed with neuroblastoma over the age of 1 year. The failure to observe a decline in the frequency of neuroblastoma among older children suggests that older children who present clinically with neuroblastoma are not being detected early by mass
screening. Further data from population-based mortality studies that compare screened with unscreened populations-such as the North American trial and the proposed UK trial-are needed before the impact of presymptomatic detection of neuroblastoma on mortality (if any) can be assessed. Physicians and the public need to know that the effectiveness of mass screening remains unproven. The importance of supporting current controlled populationbased screening studies in North America and the UK was emphasised. The workshop participants concluded that the Japanese should be recognised for their pioneering work. Data from their studies as well as preliminary data from Quebec and UK screening programmes have led to valuable information about the clinical behaviour of neuroblastoma as well as the biology of this tumour. However, to date, mass screening of urine for increased catecholamines at six months-of-age has not been shown to reduce mortality, and more widespread implementation of this practice cannot be recommended.
REFERENCES 1.
Silverberg E, Boring CC, Squires TS. Cancer statistics,
1990. CA 1990;
40: 9-26. 2. Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma. J Clin Oncol 1991 (in press).
Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985; 313: 1111-16 4. Evans AE. D’Angio GJ, Randolf J. Proposed staging for children with neuroblastoma: Children’s Cancer Study Group A. Cancer 1971; 27:
3.
374-78. 5. McGill AC, Seviour JA, Dale A, Craft AW.
Screening for neuroblastoma region.
gas chromatography-mass spectrometry in the northern Ann Clin Biochem 1988; 25 (suppl): 1325-33.
by
6. Tuchman M, Lemieux B, Auray-Blais C, et al. Screening for neuroblastoma at three weeks of age: methods and preliminary results from the Quebec neuroblastoma screening project. Pediatrics 1990; 86: 765-73. et al. Effects of the mass screening of Sapporo City. Cancer 1987; 60: 433-36. 8. Look AT, Hayes FA, Nitschke R, McWilliams NB, Green AA. Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 1984; 311: 231-35. 9. Hayashi Y, Kanda N, Inaba T, et al. Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1. Cancer
7. Nishi
M, Miyake H, Takeda T,
neuroblastoma in
1989; 63: 126-32. 10. Kaneko Y, Kanda N, Maseki N, et al. Different karyotypic patterns in early and advanced stage neuroblastomas. Cancer Res 1987; 47: 311-18. 11. Brodeur GM, Hayes FA, Green AA, et al. Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients. Cancer Res 1987; 47: 4248-53.
346
12.
15. Kaneko Y, Kanda N, Maseki N, et al. Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting on a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study. J Clin Oncol 1990; 8: 2005-13. 16. Ishimoto K, Kiyokawa N, Fujita H, et al. Problems of mass screening for neuroblastoma: analysis of false negative cases. J Pediatr Surg 1990; 25: 398-401. 17. Nishi M, Miyake H, Takeda T, et al. Cases of neuroblastoma missed by the mass screening programs. Pediatr Res 1989; 26: 603-07.
Taylor SR, Blatt J, Costantino JP, Roederer M, Murphy RF. Flow cytometric DNA analysis of neuroblastoma and ganglioneuroma.
Cancer 1988; 62: 749-54. 13. Naito H, Sasaki M, Yamashiro
neuroblastoma
through
mass
et al. Improvement in prognosis of population screening. J Pediatr Surg
K,
1990; 25: 245-48. 14.
Hayashi Y, Inaba T, Hanada R, Yamamoto K. Chromosome findings and prognosis in 15 patients with neuroblastoma found by VMA mass screening. J Pediatr 1988; 112: 567-71.
VIEWPOINT How much
drug
Many recommended drug doses are higher than necessary, for two reasons. Drugs are often introduced at a dose that will be effective in around 90% of the target population, because this helps market penetration. Doses are also partly determined by an irrational preference for round numbers. The dose excess due to such digit preference may be as much as 70% of the correct dose and on average is probably 25%. Needlessly high doses are bound to cause avoidable unwanted effects in a proportion of patients. Rigorous methods must be used to determine the doses recommended and the amount of drug to be put into a tablet or other dosage form. Introduction I have mild angina, which is largely prevented by small doses of slow-release nifedipine twice a day. This causes slight oedema of the legs in the evening, which has gone by the morning. When amlodipine was introduced I thought that the once-daily dosage might be more convenient, and after hesitating for some months I decided to try it. One Sunday morning I took the lowest recommended dose, one 5 mg tablet. It seemed effective. In the evening the oedema was more prominent than after nifedipine, and the following morning it was still there, offending my cosmetic sensibility. The penny dropped: amlodipine has a half-life of 1 -2 days, and the plasma concentration takes about a week to reach a steady state-by then I might have become a Michelin man. I felt cheated and took no more. I wondered how the company had decided on 5 mg as the lowest dose, and why the tablets contained 5 or 10 mg, which are strikingly round numbers.
What is the
right dose? The biological activity, or potency, of different drug molecules varies widely, and the ratio between the doses of two substances that produce the same intensity of effect (the potency ratio) can be any number. The dose required to cause a particular desired effect at a given intensity in a specified proportion of patients (eg, over 90% beta blockade in 95 % of patients with angina pectoris) depends entirely on the biological properties of the drug and is, or should be, derived from clinical pharmacological studies. Usually it lies somewhere between 1 !J.g and a few grammes, expressed
in the tablet?
number in this million-fold range-such as 8 ltg, 130 ltg, 6 mg, 87 mg, Mg. As in other stimulus/response relationships, the intensity of a biological response is proportional to the log of the dose, rather than directly to the dose, at least in the middle of the range of effective doses between the threshold and the ceiling effect. In that part of the range a doubling of the dose will thus increase the intensity of the effect only about 1-3 times. Towards the top of the range the increase is of course less. Increasing a dose by 10% only rarely leads to a measurable increase in effect, except around the threshold dose. This means that for purposes there is no point in specifying doses to more than two significant figures. The most efficient step size for adjusting the dose depends on whether it is near the bottom of the dose range, in the middle, or near the top; whether the dose-response curve is flat or steep; and the therapeutic margin. It may be appropriate to adjust a dose by doubling or halving it, or to use smaller steps-an increase by 50% or 25%, a decrease by 25% or 33%. These basic facts, taken together with the variability of response to the drug, should determine what doses of medicines are recommended and used, and how much of the active substance should be put into one tablet, capsule, or other dosage form. However, the amounts of drug in one dosage form show very strong terminal digit preference (see table). This cannot be explained by any biological property of the drugs. The manufacturers must have decided the dosage on other grounds.
by
a
practical
Choices in
setting the dose For a new drug to penetrate the market quickly, it should be rapidly effective in a high proportion of patients and simple to use. To achieve this, the dosage of the first prescription is therefore commonly set at about the ED level-ie, the dose which the early clinical (phase II) studies have shown to be effective in 90% of the target population, provided that the unwanted effects at this dose are considered acceptable. In 25 % of patients a smaller, perhaps much smaller, dose (the EDzs) will be effective. The patients in this quartile are the most sensitive to the drug and are liable to receive far more than they need if they are given the ADDRESS Department of Clinical Pharmacology and Therapeutics, Charing Cross and Westminster Medical School, Charing Cross Hospital, London W6 8RF, UK (A Herxheimer, FRCP)
