522 such assertion is made it is difficult to see in what way they were exposed to asbestos. It is suggestedthat mesothelioma in the other patients was a consequence of their having laundered the asbestos-contaminated work clothing of their husbands and/or fathers. Three husbands were brake-lining workers and an exposure to asbestos, albeit minimal, is nearly certain; one husband was a shoemaker and that he was not exposed to asbestos would seem almost equally certain. The likelihood that the rest were occupationally exposed to asbestos varies-the heat-insulation workers very probably were but what does a heat-electric wire worker do and how does an elevatorinsulation worker go about insulating his elevators? The care with which the authors matched controls to their cases is vitiated by their apparent failure to blind the field investigators, who presumably knew whether they were dealing with a case or a control. One would have expected blinding to be fairly effective since all the cases were dead before the study was
undertaken.
The data, for what they are worth, are statistically overworked ; P=0006 may look impressive but is meaningless when it relates to a difference between a single case-control pair. James Hardie and Co. Ltd, Camellia, New South Wales, 2142
F. MCCULLAGH, S. c c-
Australia
*.* This letter has been shown
Chief Medical Officer
to
Dr Vianna and Adele Polan
whose reply follows.-ED. L. Dr McCullagh that a completely adeof asbestos definition exposure is lacking. But to dismiss quate the list provided by Hamilton and Hardy as incomplete and haphazard is unfair and somewhat nihilistic. Their list indicates most of the major, well established uses of this mineral. Its use as an objective definition of asbestos-related occupations is therefore wholly acceptable in our study. We apologise for the use of the term "milliner". This was a typographical error and should read "miller" (the patient milled talc containing asbestos). We do not apologise for the term "shoemaker" since asbestos is used as a filler, and grinding in the finishing process generates much dust.McCullagh would do well to add this occupation to his list. The four textile workers did work in factories where spun fibre was woven into asbestos fabric. We reiterate our suggestion that proper laundering of asbestos-contaminated work clothing is a simple preventive measure which "might" reduce the frequency of malignant mesothelioma. The likelihood of asbestos exposure probably does vary with occupation. We also suggested (discussion section) that the magnitude of dust exposure might not be the only important factor in the induction of mesotheliomas. Field work was done blind: investigators had no knowledge of the hypothesis being tested or of which interviews were cases and which were controls. To ensure comparability of information, however, each case and her matched control were interviewed by the same investigator. We too would not be over-impressed with a probability value of 0-006, based on eleven pairs, not on one as McCullagh suggests, if this were the only study suggesting an association between non-occupational asbestos exposure and malignant mesothelioma. But, to date, there have been 37 case-reports favouring this relationship.23 A relative risk of 10 should not
SIR,-We agree with
SEX AND PROGNOSIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKÆMIA SIR,-Dr Baumer and Dr Mott (July 15, p. 128) in a series of 67 children with acute lymphoblastic leukxmia (A.L.L.) described a shorter duration of first remission in boys. Over the past seven years we have made a prospective study of our cases of A.L.L. and our results do not confirm these findings. We treated 209 children, almost all the cases in the region, according to the UKALL I to v schedules or the St Jude’s total v regimen. All children received standard induction therapy, prophylactic cranial irradiation, and four-drug maintenance. There was no difference between the sexes for length of complete remission (P=0.74) or survival (P=0.92) (see figure). The lack of any effect of sex on prognosis was independent of total white-cell count, extent of bony disease, mediastinal mass, central-nervous-system disease at diagnosis, age, haemoglobin, blast-cell periodic-acid-Schiff positivity, and treatment schedule. Baumer and Mott did not take into account the known larger percentage of boys (39%) than girls (29%) with a whitecell count above 20 000/jI, and the fact that 87% of the boys were aged 2-8 years compared with only 68% of the girls. They failed to establish whether sex is a prognostic factor in itself or whether the better prognosis of girls is simply a consequence of the association with that sex of better prognostic features (such as low white-cell count and age 2-8 years). In our series we still found no sex difference even after carrying out the logrank adjustment’ for the concomitant effects of white-cell count and age (length of first remission, p=0.63; survival,
P=0.95). They also speculated
that their results might be due to subclinical disease in the testis. The point was taken up by Dr Eden (July 29, p. 259), who also postulated that tissue damage in the testis predisposed to the survival of leuksemic cells there, and reported that no patient with a negative testicular biopsy had shown hxmatological or meningeal relapse in the year after biopsy. This does not accord with our experience either: a boy had a normal biopsy before stopping treatment and relapsed with testicular disease eleven months later. We do not accept the hypothesis that prophylactic testicular irradiation will reduce the incidence of occult testicular disease and lead to better survival in boys. As you pointed out (July 15, p. 136) the testis is probably only one of several sites likely to contain leuksemic foci in patients in apparent clinical remission. If we accept Dr Eden’s hypothesis, is it not also possible that irradiation too might damage the testis, so that residual blasts from other sites might re-seed and produce localised disease? The effects of X-rays and alkylating agents such as cyclophospha-
be ignored. Bureau of Occupational Health and Chronic Disease Research, Albany, N.Y. 12237, U.S.A.
1.
NICHOLAS J. VIANNA ADELE K. POLAN
Beliczky, L. S., Zenz, C. in Occupational Medicine—Principles and Practical Applications; p. 788. Chicago, 1975.
Anderson, H. A., Lilis, R., Dahm, S. M., Fischbein, A. S., Selikoff, I. J. Ann. N. Y. Acad. Sci. 1976, 271, 311. 3. Li, F., Lokich, J., Lapey, Neptune, W. B., Wilkins, E. W. J. Am. med. Ass. 1978, 240, 467.
2.
Life-table 1.
analysis
of survival and remission
Peto, R., and others. Br. J. Cancer, 1977, 35, 1.
by
sex
in A.L.L.
523
mide,
the
drug suspected of causing testicular disease,
are
very
similar.
rightly sound a note of caution in the inof terpretation prognostic features in a small series of cases. At present there are too few reports demonstrating any sex difference in survival in A.L.L. to justify the general adoption of prophylactic testicular irradiation which may have profound effects on endocrine function and fertility. Baumer and Mott
D. I. K. EVANS P. H. MORRIS JONES I. M. HANN
Royal Manchester Children’s Hospital, Pendlebury M27 1HA Christie Hospital and Holt Radium Institute, Manchester M20 9BX
M. K. PALMER
COMBINATION CHEMOTHERAPY FOR CHRONIC GRANULOCYTIC LEUKAEMIA
SIR,-Chronic granulocytic leukaemia (C.G.L.) is conventionally treated with single agent chemotherapy, most commonly busulphan. The risks of busulphan therapy are wellknown and include severe and potentially lethal aplasia of the marrow and, rarely, a diffuse interstitial pulmonary fibrosis, busulphan lung. It is customary to reduce or withdraw busulphan during remission induction, as the nucleated-cell count approaches normal, and thereafter to reintroduce the drug as necessary at a lower dose. One of us (N.C.A.) decided to combine busulphan with 6-mercaptopurine, also a drug known to be effective in treating C.G.L., with the hope that the dose of either drug, in particular busulphan, could be reduced. After some experience, a regimen of busylphan 2 mg daily, 6-mercaptopurine 50 mg daily, with
allopurinol 300 mg daily to control hyperuricaemia was cho
undertaken.
The data, for what they are worth, are statistically overworked ; P=0006 may look impressive but is meaningless when it relates to a difference between a single case-control pair. James Hardie and Co. Ltd, Camellia, New South Wales, 2142
F. MCCULLAGH, S. c c-
Australia
*.* This letter has been shown
Chief Medical Officer
to
Dr Vianna and Adele Polan
whose reply follows.-ED. L. Dr McCullagh that a completely adeof asbestos definition exposure is lacking. But to dismiss quate the list provided by Hamilton and Hardy as incomplete and haphazard is unfair and somewhat nihilistic. Their list indicates most of the major, well established uses of this mineral. Its use as an objective definition of asbestos-related occupations is therefore wholly acceptable in our study. We apologise for the use of the term "milliner". This was a typographical error and should read "miller" (the patient milled talc containing asbestos). We do not apologise for the term "shoemaker" since asbestos is used as a filler, and grinding in the finishing process generates much dust.McCullagh would do well to add this occupation to his list. The four textile workers did work in factories where spun fibre was woven into asbestos fabric. We reiterate our suggestion that proper laundering of asbestos-contaminated work clothing is a simple preventive measure which "might" reduce the frequency of malignant mesothelioma. The likelihood of asbestos exposure probably does vary with occupation. We also suggested (discussion section) that the magnitude of dust exposure might not be the only important factor in the induction of mesotheliomas. Field work was done blind: investigators had no knowledge of the hypothesis being tested or of which interviews were cases and which were controls. To ensure comparability of information, however, each case and her matched control were interviewed by the same investigator. We too would not be over-impressed with a probability value of 0-006, based on eleven pairs, not on one as McCullagh suggests, if this were the only study suggesting an association between non-occupational asbestos exposure and malignant mesothelioma. But, to date, there have been 37 case-reports favouring this relationship.23 A relative risk of 10 should not
SIR,-We agree with
SEX AND PROGNOSIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKÆMIA SIR,-Dr Baumer and Dr Mott (July 15, p. 128) in a series of 67 children with acute lymphoblastic leukxmia (A.L.L.) described a shorter duration of first remission in boys. Over the past seven years we have made a prospective study of our cases of A.L.L. and our results do not confirm these findings. We treated 209 children, almost all the cases in the region, according to the UKALL I to v schedules or the St Jude’s total v regimen. All children received standard induction therapy, prophylactic cranial irradiation, and four-drug maintenance. There was no difference between the sexes for length of complete remission (P=0.74) or survival (P=0.92) (see figure). The lack of any effect of sex on prognosis was independent of total white-cell count, extent of bony disease, mediastinal mass, central-nervous-system disease at diagnosis, age, haemoglobin, blast-cell periodic-acid-Schiff positivity, and treatment schedule. Baumer and Mott did not take into account the known larger percentage of boys (39%) than girls (29%) with a whitecell count above 20 000/jI, and the fact that 87% of the boys were aged 2-8 years compared with only 68% of the girls. They failed to establish whether sex is a prognostic factor in itself or whether the better prognosis of girls is simply a consequence of the association with that sex of better prognostic features (such as low white-cell count and age 2-8 years). In our series we still found no sex difference even after carrying out the logrank adjustment’ for the concomitant effects of white-cell count and age (length of first remission, p=0.63; survival,
P=0.95). They also speculated
that their results might be due to subclinical disease in the testis. The point was taken up by Dr Eden (July 29, p. 259), who also postulated that tissue damage in the testis predisposed to the survival of leuksemic cells there, and reported that no patient with a negative testicular biopsy had shown hxmatological or meningeal relapse in the year after biopsy. This does not accord with our experience either: a boy had a normal biopsy before stopping treatment and relapsed with testicular disease eleven months later. We do not accept the hypothesis that prophylactic testicular irradiation will reduce the incidence of occult testicular disease and lead to better survival in boys. As you pointed out (July 15, p. 136) the testis is probably only one of several sites likely to contain leuksemic foci in patients in apparent clinical remission. If we accept Dr Eden’s hypothesis, is it not also possible that irradiation too might damage the testis, so that residual blasts from other sites might re-seed and produce localised disease? The effects of X-rays and alkylating agents such as cyclophospha-
be ignored. Bureau of Occupational Health and Chronic Disease Research, Albany, N.Y. 12237, U.S.A.
1.
NICHOLAS J. VIANNA ADELE K. POLAN
Beliczky, L. S., Zenz, C. in Occupational Medicine—Principles and Practical Applications; p. 788. Chicago, 1975.
Anderson, H. A., Lilis, R., Dahm, S. M., Fischbein, A. S., Selikoff, I. J. Ann. N. Y. Acad. Sci. 1976, 271, 311. 3. Li, F., Lokich, J., Lapey, Neptune, W. B., Wilkins, E. W. J. Am. med. Ass. 1978, 240, 467.
2.
Life-table 1.
analysis
of survival and remission
Peto, R., and others. Br. J. Cancer, 1977, 35, 1.
by
sex
in A.L.L.
523
mide,
the
drug suspected of causing testicular disease,
are
very
similar.
rightly sound a note of caution in the inof terpretation prognostic features in a small series of cases. At present there are too few reports demonstrating any sex difference in survival in A.L.L. to justify the general adoption of prophylactic testicular irradiation which may have profound effects on endocrine function and fertility. Baumer and Mott
D. I. K. EVANS P. H. MORRIS JONES I. M. HANN
Royal Manchester Children’s Hospital, Pendlebury M27 1HA Christie Hospital and Holt Radium Institute, Manchester M20 9BX
M. K. PALMER
COMBINATION CHEMOTHERAPY FOR CHRONIC GRANULOCYTIC LEUKAEMIA
SIR,-Chronic granulocytic leukaemia (C.G.L.) is conventionally treated with single agent chemotherapy, most commonly busulphan. The risks of busulphan therapy are wellknown and include severe and potentially lethal aplasia of the marrow and, rarely, a diffuse interstitial pulmonary fibrosis, busulphan lung. It is customary to reduce or withdraw busulphan during remission induction, as the nucleated-cell count approaches normal, and thereafter to reintroduce the drug as necessary at a lower dose. One of us (N.C.A.) decided to combine busulphan with 6-mercaptopurine, also a drug known to be effective in treating C.G.L., with the hope that the dose of either drug, in particular busulphan, could be reduced. After some experience, a regimen of busylphan 2 mg daily, 6-mercaptopurine 50 mg daily, with
allopurinol 300 mg daily to control hyperuricaemia was cho
