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Biomedical subjects

M M Hawkins

Publications and source records attributed to M M Hawkins.

At least 37 records · Page 2Linked to original sources
PubMed1996

The long-term survivors.

Recent research indicates that approximately 60% of children diagnosed with cancer in Britain are cured and as a result, about 1 in a 1000 of the general population will soon be survivors of childhood cancer. Unfortunately some elements of the therapies which are responsible for this remarkable success are associated with serious complications, sometimes decades after their administration. Therefore, a comprehensive knowledge of the risks and benefits of different therapies will only be obtained by monitoring the health of survivors indefinitely. With such therapeutic success, increasingly the composition of future treatment protocols will be influenced by knowledge of the risks of long term morbidity and mortality associated with past therapies. An awareness of the long term risks of complications of treatment is also important for estimating the future demand on the health services of this increasing proportion of the general population who together represent many life years of care. This chapter reviews what is known concerning the long term risks of complications of different treatments. Appropriate strategies for future clinical and epidemiological follow-up of the survivor population are discussed and the need for indefinite follow-up of the survivor population is emphasised.

Adolescent↗
PubMed1995

Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin lymphomas.

Understanding the extent to which childhood leukaemia and non-Hodgkin lymphomas are heritable is important to the survivors of these diseases, their families and clinicians who provide genetic counselling. Such understanding is also relevant to the possibility raised by Gardner et al. (1990, Br. Med. J., 300, 423-429) that paternal preconception irradiation may be an aetiological factor in these diseases. No malignant neoplasm was diagnosed among 382 offspring of survivors of childhood leukaemia and non-Hodgkin lymphoma followed up for a median period of 5.8 years, the largest available cohort of such offspring. These data indicate that it is unlikely that the risk of a malignant neoplasm occurring in the offspring exceeds eight times that expected in the general population. Similarly, the risk of leukaemia and non-Hodgkin lymphoma among offspring is unlikely to exceed 21 times that expected. The proportion of survivors of childhood leukaemia and non-Hodgkin lymphoma with the heritable form of these diseases is unlikely to exceed 5%, assuming an autosomal dominant pattern of transmission, with penetrance of at least 70% and that all heritable cases develop by age 15 years. The best (i.e. at present most likely) estimates of these risks are of course much lower. There was no evidence of an excess of congenital abnormalities among the offspring and the sex ratio was similar to that expected from the general population.

Adolescent↗
PubMed1994

Late deaths and survival after childhood cancer: implications for cure.

OBJECTIVES: To investigate causes of death and survival in subjects who had survived at least five years after diagnosis of childhood cancer; to compare observed mortality with that expected in the general population; and to compare results with a corresponding cohort diagnosed earlier. DESIGN: Retrospective cohort study. SETTING: Population based National Register of Childhood Tumours. SUBJECTS: 9080 five year survivors of childhood cancer diagnosed in Britain during 1971-85, of whom 793 had died. Comparison with corresponding cohort diagnosed during 1940-70. MAIN OUTCOME MEASURES: Cause of death established from all available sources of information (including hospital and general practitioner records and postmortem reports) and underlying cause of death coded on death certificate. RESULTS: Of the 781 deaths for which sufficient information was available, death was attributed to recurrent tumour in 578 (74%) cases, treatment related effect in 121 (15%), second primary tumour in 52 (7%), and other causes in 30 (4%). Comparison of observed mortality with that expected in the general population indicated a fourfold excess of deaths from non-neoplastic causes. The risk of dying of recurrent tumour in the next 10 years after surviving five years from diagnosis during 1940-70 and 1971-85 fell from 12% to 8%. The risk of dying from a treatment related effect increased slightly from 1% to 2%. CONCLUSION: Improvements in five year survival after childhood cancer have been accompanied by a reduction in risk of dying from recurrent tumour during the subsequent 10 years and by a slight increase in risk of dying from treatment related effects. The results provide information relevant to decisions concerning balance between effective treatments and their potentially harmful effects.

Adolescent↗
PubMed1992

Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

OBJECTIVE: To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN: Cohort study and a case-control study. SETTING: Britain and population based National Register of Childhood Tumours. SUBJECTS: Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES: Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS: Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS: Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer.

Alkylating Agents↗
PubMed1992

Patterns of risk of hereditary retinoblastoma and applications to genetic counselling.

A registry including information about nearly 1,600 cases of retinoblastoma diagnosed in Britain has been created at the Childhood Cancer Research Group. Cases have been classified as 'old germ cell mutation', 'new germ cell mutation' or 'sporadic non-hereditary'. For a population-based group of 918 cases diagnosed between 1962 and 1985 we have calculated the proportions of unilateral/bilateral and hereditary/non-hereditary cases. Bilateral cases represent 40% of the total number over this period; the proportion known to be hereditary is 44%, a higher proportion than has been reported elsewhere. By following up selected groups of cases, an estimate has been made of the proportions of siblings of retinoblastoma patients and offspring of survivors from retinoblastoma who are themselves affected with the disease. Where there is no previous family history, the risk for siblings of retinoblastoma patients of developing the disease is approximately 2% if the disease in the affected child is bilateral and 1% if it is unilateral, assuming that there are no other siblings; if there are unaffected siblings the risks for subsequent children are lower. Children of patients with hereditary retinoblastoma have a one in two chance of carrying the germ cell mutation and for those who are carriers the probability of developing retinoblastoma is very close to the accepted figure of 90% if the parents have bilateral retinoblastoma but probably less if they have the unilateral form. For children of patients not known to be carriers, the probability of developing retinoblastoma is estimated to be about 1%, considerably lower than the previously accepted figure of about 5%. Retinoblastoma kindreds consist mainly of bilateral cases but there is evidence that some kindreds have a high proportion of unilateral cases. The ways in which these findings may be used in conjunction with modern techniques of molecular biology for prenatal and postnatal genetic counselling are discussed.

Child↗
PubMed1992

Completeness of cancer and death follow-up obtained through the National Health Service Central Register for England and Wales.

For the last 20 years the National Health Service Central Register (NHSCR) has been used as the principal source of follow-up for mortality, and often for cancer incidence, in many cohort and clinical follow-up studies in England and Wales. Completeness of notification of childhood cancer registrations and deaths from the NHSCR was investigated by comparison between cancers and deaths notified to the Childhood Cancer Research Group (CCRG) from this source and notifications received directly from regional cancer registries and the national death registry. Six thousand, seven hundred and seventy-six (91.8%) of 7,379 cancers incident 1971-84, and 588 (95.8%) of 614 deaths occurring 1953-88, were successfully notified. Failures in cancer notification occurred mainly between the regional cancer registries and the National Cancer Register (3.3%), and between the National Cancer Register and the NHSCR (3.0%). An additional 1.9% of cancer notifications failed between the NHSCR and the CCRG. Incompleteness of registration of childhood cancers by regional cancer registries was estimated to be 4.7%. A total of 12.5% of incident childhood cancers were not notified by NHSCR. Incompleteness of notification may be greater for adults, for whom registration and record linkage may be more difficult. Failures in death notifications occurred mostly because deaths entered on the NHSCR were not notified to the CCRG (3.3%). This incompleteness of notification needs to be taken into account in the interpretation of published studies and in the analysis of studies using NHSCR flagging. It also implies similar incompleteness in published national cancer survival data, which use the same system of flagging. Nevertheless it is a notable achievement that NHSCR has successfully monitored such a high proportion of a population of 50 million people, by entirely clerical procedures, for 40 years.

Adult↗
PubMed1992

Fitting the Armitage-Doll model to radiation-exposed cohorts and implications for population cancer risks.

The Armitage-Doll model of carcinogenesis is fitted to Japanese bomb survivors with the DS86 dosimetry and to three other radiation-exposed cohorts. The model is found to provide an adequate description of solid cancer incidence and also, to a lesser extent, of that of leukemia as a function of radiation dose when up to two radiation-affected stages are assumed. For non-leukemias the optimal model is one in which there are two radiation-affected stages separated by two additional stages. In the case of leukemia one radiation-affected stage or two adjacent stages provide suitable fits. There appear to be significant differences between the optimal models fitted to each cohort, although there is no heterogeneity within the Japanese data set by sex, by cancer type, or by age at exposure. Low-dose and low-dose-rate population risks for a population having the cancer and overall mortality rates of the current UK population are calculated on the basis of the optimal models fitted to the Japanese data to be about 8.3 x 10(-2) excess cancer deaths person-1 Sv-1, 10.1 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 1.40 years of life lost person-1 Sv-1. Risks for a population having the mortality rates of the current Japanese population are about 6.5 x 10(-2) excess cancer deaths person-1 Sv-1, 7.8 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 0.89 years of life lost person-1 Sv-1. It is a feature of the Armitage-Doll model, and other multistage models of carcinogenesis, that if radiation acts at more than one stage then (inverse) dose-rate effects may arise as a result of interactions between the effects of a protracted dose at the various radiation-affected stages. However, it is shown in this paper that these three measures of cancer risk in general display fairly slight dependence on administered dose in the range 0.001 to 1.0 Sv and on the length of the time over which the dose is administered in the range 1 to 100 years. Dose-rate effects resulting from the protraction of a radiation exposure over many years acting on (the same) cells at various stages of a multistep process of carcinogenesis are therefore expected to be slight. Dose-rate effects which have been observed in epidemiological studies and cellular radiobiology may thus find their explanation in other phenomena such as short-term intracellular repair.

Child↗
PubMed1991

Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors?

Few studies have examined human population data for evidence of an association between environmental mutagens and genetic disease. Our objective was to determine whether study of pregnancies and offspring of childhood cancer survivors would show evidence that therapy potentially mutagenic to germ cells is associated with increased risk of miscarriage, serious congenital abnormalities, or altered sex ratio. We analyzed information from patients' general practitioners for 2286 survivors of childhood cancer (1049 females and 1237 males) who were exposed or not exposed to direct irradiation of the abdomen or gonads or treatment with an alkylating agent. In addition, external control data based on the general population were used for some of the comparisons relating to congenital abnormalities and sex ratio. Data on reproductive history were complete for 1037 female survivors, who had 944 completed pregnancies, and 1078 male survivors, who produced 537 offspring. For the female survivors given abdominal or gonadal irradiation, there was an excess of miscarriages for the total number of pregnancies (17%) and for first pregnancies (19%), compared with the proportion for the total number of pregnancies in the females with similar neoplasms who were not exposed to such therapy (9%) and for first pregnancies in these females (8%). These results show re-emergence of an association suggested in our previous report of an increased risk of miscarriage as well as low birth weight among off-spring of female survivors of childhood cancer who received abdominal irradiation. In that study, it was considered unlikely that the association was due to germ cell mutation. Data in the present study do not show an association of exposure to therapy potentially mutagenic to germ cells with sex ratio, or with occurrence of serious congenital abnormalities in the offspring of male or female survivors of such therapy. However, the question of a possible germ cell mutagenic effect of therapy will be adequately addressed only through an international collaborative effort.

Antineoplastic Agents↗
PubMed1991

Time variations in the risk of cancer following irradiation in childhood.

The Japanese atomic bomb survivors and three other cohorts of children exposed to radiation are analyzed, and evidence is found for a reduction in the radiation-induced relative risk of cancers other than leukemia with time following exposure. Multiplicative adjustments to the excess risk either of the form exp[-delta.(time since exposure)] or of the form [time since exposure] gamma give equivalent goodness of fit. Using the former type of adjustment an annual overall reduction of 6.9-8.6% in excess relative risk is indicated (depending on the year after which this reduction might take effect). Using the second type of multiplier an adjustment to the excess relative risk varying between [time after exposure]-2.0 and [time after exposure]-3.2 fits best overall. All these reductions are statistically significant at the 5% level. There is no significant variation by cohort, by sex, by cancer type, or by age at exposure group in the degree of annual reduction in excess relative risk. Although time-adjusted relative and absolute risk models give equivalently good fits within each cohort, there is significant variation between cohorts in the degree of increase of risk with time in the absolute risk formulation, in contrast to the lack of such heterogeneity for the relative risk formulation. It is shown that if the range of observed reductions in relative risk is assumed to operate 40 or more years after exposure in the youngest age groups, the calculated UK population risks would be reduced by 30-45% compared to those based on a constant relative risk model.

Adolescent↗