Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study.

Offspring of childhood cancer survivors may be at risk of genetic disease due to the mutagenic cancer treatments received by their parents. Congenital malformations were evaluated in a population-based cohort study of 1715 offspring of 3963 childhood cancer survivors and 6009 offspring of 5657 survivors' siblings. The Danish Central Population Register, Cancer Registry and Hospital Register were used to identify study subjects and congenital malformations. Gonadal and uterine radiation doses were characterized based on standard radiation-treatment regimens. The prevalence of congenital malformations at birth in offspring of survivors (44 cases, 2.6%) was slightly higher but not statistically different from that of offspring of siblings (140 cases, 2.3%) [prevalence proportion ratio (PPR), 1.1; 95% confidence interval, 0.8-1.5] or of the general population (observed-to-expected ratio, 1.2; 0.9-1.6). Including malformations diagnosed later in life did not change the ratios appreciably. The risk for malformations was slightly higher in the offspring of irradiated parents than in that of non-irradiated parents (PPR 1.2 vs 1.0) but was unrelated to gonadal dose. This study provides evidence that cancer therapy of children does not increase the risk for malformations in their offspring. Continued monitoring of genetic risks among their offspring, however, is warranted.

Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries.

PURPOSE: To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases. PATIENTS AND METHODS: This was a population-based study in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk. RESULTS: The overall SMR was 10.8 (95% confidence interval [CI], 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment. CONCLUSION: Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.

Connective tissue disease and other rheumatic conditions following cosmetic breast implantation in Denmark.

OBJECTIVE: To examine the occurrence of connective tissue diseases (CTDs) as well as ill-defined and other rheumatic conditions among Danish women with cosmetic silicone breast implants. PATIENTS AND METHODS: A total of 2761 women with breast implants and 8807 control subjects were identified from plastic surgery private clinics and from public hospital plastic surgery departments. Women operated on at plastic surgery private clinics were identified through the files of each clinic, while women operated on at public hospitals were identified using the nationwide Danish National Registry of Patients. The control group consisted of women who underwent cosmetic surgery other than breast implantation or who only had a consultation. All women were followed up from January 1, 1977, through December 31, 1996, through the Danish National Registry of Patients for the occurrence of CTD as well as ill-defined and other rheumatic conditions. For the study period January 1, 1977, through December 31, 1994, the Danish National Registry of Patients contains information on hospitalization only, whereas data on outpatient visits are included from 1995 on, thus improving the sensitivity of the data. The implant and control groups were compared with the Danish population rates for CTD and ill-defined and other rheumatic conditions, and a direct comparison between the implant and control groups was also performed. RESULTS: When compared with rates from the general population, no excess of definite CTD was observed in the implant cohorts. For ill-defined and other rheumatic conditions, statistically significant excesses of unspecified rheumatism were observed in both the implant and control cohorts when compared with national rates. A direct comparison between the implant and control cohorts found no material differences between the groups. CONCLUSIONS: The findings of this study support previous investigations and independent review panel conclusions that an association between silicone breast implants and definite CTDs is unlikely. The observation of an excess of unspecified rheumatism among women with implants and among control women suggests that women undergoing cosmetic plastic surgery have hospitalization rates for this condition in excess of those from the general population.

Increased risk of antidepressant use in childhood cancer survivors: a Danish population-based cohort study.

AIM: Childhood cancer survivors are at risk of both somatic and mental late effects, but large population-based studies of depression are lacking. METHODS: Risk of antidepressant use was evaluated in a population-based cohort of 5452 Danish children treated for cancer in 1975-2009 by linkage to the National Prescription Drug Database, which worldwide is the oldest nationwide registry of prescription medication. Hazard ratios (HRs) for antidepressant use were estimated in a Cox proportional hazards model stratified on sex, with population comparisons as referents. RESULTS: Overall, childhood cancer survivors were at increased risk of having antidepressants prescribed (HR, 1.4; 95% confidence interval (CI), 1.3-1.5). The excess absolute risk of antidepressant use was 2.5 per 1000 person-years (95% CI, 1.7-3.3), equivalent to an excess of 2.5 survivors for every 100 survivors followed for 10years. Increased HRs of 30-50% were seen for survivors of cancers of all main groups (haematological malignancies, central nervous system (CNS) and solid tumors); the highest risk was among children treated with haematopoietic stem cell transplantation (HR, 1.9; 95% CI, 1.2-3.1). Our data suggested that the risk was most pronounced for children treated in the most recent calendar periods (test for interaction between cancer and calendar periods: P<0.001), especially for survivors of haematological cancers (P=0.007). Interaction analysis of the effect of parental socioeconomic position and psychiatric disease on the association between childhood cancer and antidepressant use indicated no modifying effect. CONCLUSION: Childhood cancer survivors should be followed-up for depression. Our results indicate an increasing need for follow-up especially in survivors treated by more recent, intensive anticancer treatment.

Neurologic disease among women with breast implants.

OBJECTIVE: To investigate the risk of neurologic disease among women with silicone breast implants. BACKGROUND: Since 1992, several case series reported an association between silicone breast implants and neurologic diseases. METHODS: Between 1977 and 1992, 1,135 women received cosmetic silicone breast implants, and 7,071 women had breast reduction surgery, as identified by the Danish National Register of Patients (NRP). NRP files provided information on numbers and types of subsequent neurologic disorders at hospital discharge, which were compared with expected numbers, calculated on the basis of national hospital discharge rates. RESULTS: In the two study cohorts, hospital discharge rates for neurologic diseases were raised by some 60% to 70% compared with Danish women in general. Among women with silicone breast implants, 13 subsequently developed a neurologic disorder compared with 7.7 expected; whereas in the comparison group, 63 observed versus 39.1 expected disorders were recorded. These results indicate that relative to the comparison cohort, women with implants had no excessive levels of definite neurologic disease. Furthermore, medical record reviews revealed that the majority of women with implants discharged with a neurologic diagnosis had either symptoms before implant surgery or neurologic symptoms secondary to degenerative diseases. CONCLUSIONS: Our findings do not support the hypothesis of silicone-induced neurologic disease. The reasons for the elevated rates of neurologic disease in both the exposed and comparison cohorts remain unclear, but may reflect selection processes associated with these women seeking medical care more often than the general population.

[Cancer and prevention]. / Kraeft og forebyggelse i Danmark.

INTRODUCTION: The aim of the study was to estimate the preventable potential of various types of cancer in Denmark on the basis of present knowledge. MATERIAL AND METHODS: The well-documented factors in lifestyle and environment causing cancer in Denmark were identified from the IARC Monograph series. The population attributable risk per cent (PAR%) and the annual number of preventable cancers were calculated for each aetiology and cancer type around the year 2000. RESULTS: A large proportion of the cancers occurring in the lungs, larynx, upper digestive tract, skin, lower urinary tract, and the uterine cervix is potentially avoidable, whereas only a small proportion of breast and colorectal cancers is preventable on the given knowledge. The main causative factors include active and passive smoking, alcohol intake, exposure to asbestos and other occupational carcinogens, solar and ionising radiation, obesity, human papillomavirus infection in the female genital tract, and infection with Helicobacter pylori. More than 5000 cancers in men and almost 3500 in women annually in Denmark could have been avoided by eliminating exposure to these known carcinogens. This is equivalent to 39% and 23% of all cancers occurring respectively in men and women, around the year 2000. Smoking habits account for more than half of these avoidable cases. DISCUSSION: The incidence of cancer could be greatly reduced through primary prevention, especially of tobacco smoking, which is the major single factor. A large proportion of the cancers occurring in the lungs, larynx, upper digestive tract, skin, lower urinary tract, and the uterine cervix are potentially avoidable. More research in the field of aetiological factors causing female breast cancer and colorectal cancer is much needed in order to be able to prevent these types of cancer.

Multiple-type human papillomavirus infection in younger uncircumcised men.

A cohort of 388 young men enrolled for military service in the Danish army was established and the participants underwent a clinical examination with human papillomavirus (HPV) testing. In addition, a questionnaire containing questions regarding sociodemographic variables, sexual habits and lifestyle factors was completed. The prevalence of HPV was 33.4% in this cohort of uncircumcised men aged 18-29 years. Multiple HPV types were prevalent with one-third of the HPV-positive men being positive for more than one HPV type. Number of recent sexual partners and infrequent condom use were strong risk factors, particularly in men having multiple HPV types. Our findings re-emphasize the importance of sexual transmission and also point to a role of factors that may be related to individual susceptibility as genital warts, alcohol intake and, to a lesser extent, smoking were strongly associated with having multiple HPV types.

Molar pregnancy and childhood cancer: a population-based linkage study from Denmark.

We observed a relative risk of 1.40 (95% confidence interval; 0.86-2.16) for cancers diagnosed under the age 20 in 6192 offspring of 3431 mothers with a molar pregnancy, indicating it is not a major determinant of childhood cancer.

G(2) chromosomal radiosensitivity in Danish survivors of childhood and adolescent cancer and their offspring.

In order to investigate the relationship between chromosomal radiosensitivity and early-onset cancer, the G(2) chromosomal radiosensitivity assay was undertaken on a group of 23 Danish survivors of childhood and adolescent cancer, a control group comprising their partners and a group of 38 of their offspring. In addition, the previously reported in-house control group from Westlakes Research Institute (WRI) was extended to 27 individuals. When using the 90th percentile cutoff for the WRI control group, the proportion of individuals with elevated radiosensitivity was 11, 35, 52 and 53% for the WRI control, partner control, cancer survivor and the offspring groups, respectively, with significant differences between the WRI control group and the cancer survivor group (P=0.002) and the offspring group (P<0.001). However, while the comparisons with the WRI control group support an association of chromosomal radiosensitivity with cancer predisposition, when the partner control group was used to define the radiosensitivity cutoff point, no significant differences in radiosensitivity profiles were found between the partner control group and either the cancer survivor group or the offspring group. The failure to distinguish between the G(2) aberration profiles of the apparently normal group of partners and the cancer survivor group suggests that any association with cancer should be viewed with caution, but also raises questions as to the suitability of the partners of cancer survivors to act as an appropriate control group. Heritability of the radiosensitive phenotype was examined by segregation analysis of the Danish families and suggested that 67.3% of the phenotypic variance of G(2) chromosomal radiosensitivity is attributable to a putative major gene locus with dominant effect.

Cancer among teenagers in Denmark, 1943-1987.

A population-based study was carried out on 3,988 tumours in teenagers (aged 10-19 years) diagnosed during the period 1943-87 in Denmark and abstracted from the files of the National Cancer Registry. In that Registry, codes for tumours were based solely on topography until the end of 1977. In order to obtain a uniform data set, coded by the system of the International Classification of Diseases for Oncology (ICD-O) now used at the Cancer Registry, all cases of teenage cancer diagnosed prior to 1978 were re-evaluated, and an ICD-O code was applied. Tumours were further aggregated into diagnostic groups using an internationally agreed scheme. The average incidence rates for all histological types combined were 136 per million for boys and 108 per million for girls, which are close to those reported in Connecticut, USA. Central nervous system tumours, leukaemia and malignant lymphomas accounted for 60% of all cancers among teenagers. An overall excess of cancers among boys was mainly due to more frequent occurrence of leukaemias, malignant lymphomas, sarcomas and germ-cell tumours. Increasing trends with time were seen for malignant lymphomas in both boys and girls and for subtypes of non-seminoma germ-cell tumour among boys aged 15-19. For other diagnostic groups, including the main group of leukaemias, the rates have remained largely unchanged, suggesting that environmental factors associated with modern society play a minor role in the aetiology of cancer among teenagers.

[Causes of cancer in Scandinavia and possible preventive measures]. / Arsager til kraeft i Norden og muligheder for forebyggelse.

The purpose of this work is to address future possibilities for avoiding cancer. We elucidate the most important known causes of cancer in the Nordic countries during the second half of this century and provide estimates of the numbers of cancer cases that might be avoided by the year 2000 if those causes were effectively eliminated. Information on the pattern of carcinogenic exposures in each of the five Nordic countries and the associated relative risk estimates from the scientific literature were obtained. The numbers of avoidable cancers were assessed on the basis of this information together with the associated population attributable risk percent, PAR%, i.e. the proportion of a given cancer that can be avoided upon elimination of the causative factor. The main causes of cancer include smoking, alcohol consumption, exposure to occupational carcinogens, radiation, obesity and infection with human papillomavirus (HPV) and Helicobacter pylori. Annually, more than 18,000 cancers in men and 11,000 in women in the Nordic populations could be avoided by eliminating exposure to known carcinogens which is equivalent to 33 percent and 20 percent of all cancers arising in men and women, respectively, around the year 2000. Smoking habits account for a little more than half of these avoidable cases. Exposure to solar radiation, HPV and Helicobacter pylori, diagnostic and therapeutic radiation and consumption of alcohol play important roles in the causation of cancer, as each of these factors is linked with 1-5 percent of all cancers in men and women. Occupational exposures are also substantial causes in men (3 percent), and obesity is important in women (1 percent). In contrast, current knowledge is insufficient to give reliable estimates of the numbers of cancers that could be avoided by well-described modifications of dietary habits. These figures indicate that the most efficient way of reducing cancer morbidity would be to reduce the prevalence of exposure of the population to cancer-causing agents.

Avoidable cancers in the Nordic countries. Tobacco smoking.

Active smoking is causally associated with cancers of the lung, larynx, oral cavity, pharynx, oesophagus, pancreas, renal parenchyma, renal pelvis and urinary bladder, and passive smoking appears to be causally associated with cancer of the lung. Information on smoking habits for the years 1965, 1975 and 1985 shows that more men than women in the Nordic countries were current smokers. The rates of women were stable over time and those of men were decreasing, approaching those of women. Lung cancer, in particular, is strongly associated with active smoking: by increasing the number of cigarettes smoked per day (lifelong) to 5, 10, 20 and 40 or more, the risk increases by five-, eight-, 16- and 30-fold, respectively, over that of people who have never smoked. Thus, with approximately 35% current smokers and 25% former smokers among Nordic men in 1985 and approximately 30% current smokers and 15% former smokers among Nordic women in that year, by the year 2000 10,000 cases of lung cancer (6,500 in men and 3,500 in women) will be caused by active smoking; this is equivalent to 82% of all cases of lung cancer in these populations. Another 6,000 cancers of other types (4,000 in men and 2,000 in women) are caused annually by active smoking, yielding a total of 16,000 new cases each year around the turn of the century. This implies that 14% (19% in men and 9% in women) of all incident cancers in the Nordic countries around the year 2000 will be caused by active tobacco smoking. In comparison, passive smoking is a minor cause of lung cancer, responsible for approximately 0.6% of all new cases (approximately 70 cases annually) in this area around the turn of the century.

Avoidable cancers in the Nordic countries. Alcohol consumption.

Alcohol intake is causally associated with cancers of the larynx, oral cavity, pharynx, oesophagus and liver. In all five Nordic countries, alcohol consumption increased substantially between 1965 (6.5 litres per adult per year) and 1975 (10 litres), but remained at about 10 litres between 1975 and 1985. The daily consumption of men during the period was substantially higher than that of women, and that of both men and women was higher in Denmark than in the other Nordic countries. In about 2000, an annual total of almost 1,300 cancer cases (1,000 in men and 300 in women) would be avoided if alcohol drinking were eliminated. This corresponds to about 29% of all alcohol-related cancers, i.e. in the oesophagus (37%), oral cavity and pharynx (33%), larynx (29%) and liver (15%). About 2% of all cancers in men and 1% in women in the Nordic countries around the year 2000 will be caused by the drinking habits of the respective populations.

Avoidable cancers in the Nordic countries. Exogenous hormones.

The well-described influence of several aspects of reproductive life on the risk for cancer in the reproductive organs has raised concern regarding the safety of exogenous hormones, particularly since sex hormones have become one of the most widely used drugs among women in the western world. The major areas of application include oral contraception and hormone replacement therapy in women with menopausal symptoms. Since the introduction of oral contraceptives onto the Nordic market in the late 1960s, the number of users has grown steadily, to reach proportions of long-term users among women aged 15-45 years in 1985 ranging between 6% (Norway) and 19% (Sweden) and proportions of current users in 1994 ranging between 20% (Norway) and 28% (Sweden). Such data on the current and long-term use of oral contraceptives by the female populations, linked with relative estimates of adverse (cancers of the breast and uterine cervix) and beneficial effects (protection against cancers of the ovary and endometrium), indicate that 95 cases of breast cancer and 40 of cervical cancer will be caused by oral contraceptives annually around 2000 in the Nordic countries, which corresponds to 0.6% of all breast cancers and approximately 3% of all cervical cancers. The beneficial effects include an annual prevention around the year 2000 of approximately 350 cases of ovarian cancer and a similar number of endometrial cancer, for a total about 700 cancer cases annually. The prevalence of long-term users (> or = 5 years) of hormone replacement therapy among Nordic women aged 40-69 in 1995 was estimated to be 10-11%, which on the basis of an associated relative risk for breast cancer ranging from 1.2-1.5 suggests than an annual total of 260 cases of breast cancer could be avoided in the Nordic countries around the year 2000 if hormone replacement therapy were eliminated. This corresponds to 1.8% of all notified cases of breast cancer among women in these countries.

Avoidable cancers in the Nordic countries. Radiation.

Exposure to solar and ionizing radiation increases the risk for cancer in humans. Some 5% of solar radiation is within the ultraviolet spectrum and may cause both malignant melanoma and non-melanocytic skin cancer; the latter is regarded as a benign disease and is accordingly not included in our estimation of avoidable cancers. Under the assumption that the rate of occurrence of malignant melanoma of the buttocks of both men and women and of the scalp of women would apply to all parts of the body in people completely unexposed to solar radiation, it was estimated that approximately 95% of all malignant melanomas arising in the Nordic populations around the year 2000 will be due to exposure to natural ultraviolet radiation, equivalent to an annual number of about 4700 cases, with 2100 in men and 2600 in women, or some 4% of all cancers notified. Exposure to ionizing radiation in the Nordic countries occurs at an average effective dose per capita per year of about 3 mSv (Iceland, 1.1 mSv) from natural sources, and about 1 mSv from man-made sources. While the natural sources are primarily radon in indoor air, natural radionuclides in food, cosmic radiation and gamma radiation from soil and building materials, the man-made sources are dominated by the diagnostic and therapeutic use of ionizing radiation. On the basis of measured levels of radon in Nordic dwellings and associated risk estimates for lung cancer derived from well-conducted epidemiological studies, we estimated that about 180 cases of lung cancer (1% of all lung cancer cases) per year could be avoided in the Nordic countries around the year 2000 if indoor exposure to radon were eliminated, and that an additional 720 cases (6%) could be avoided annually if either radon or tobacco smoking were eliminated. Similarly, it was estimated that the exposure of the Nordic populations to natural sources of ionizing radiation other than radon and to medical sources will each give rise to an annual total of 2120 cancers at various sites. For all types of ionizing radiation, the annual total will be 4420 cancer cases, or 3.9% of all cancers arising in the Nordic populations, with 3.4% in men and 4.4% in women.

Avoidable cancers in the Nordic countries. Diet, obesity and low physical activity.

In the early 1980s, Doll and Peto estimated that about 35% of all deaths from cancer in the United States were attributable to dietary factors, with a margin of uncertainty ranging from 10 to 70%. Since then, several dietary factors, e.g. fat and meat, have been suggested to increase the risk for cancer, while other factors, e.g. fibre, fruit and vegetables, have been suggested to decrease the risk. The case-control and cohort studies have, however, given ambiguous results, and the overall evidence is far from conclusive. The major findings on dietary factors that increase risk have been reported from case-control studies, but have not been confirmed in large population-based cohort studies. Although the research in this area indicates that diet is important in cancer prevention, current knowledge does not allow reliable estimates of the numbers and proportions of cancers that could be avoided through well-described modifications of dietary habits. During the last 10 years, low physical activity has been pinpointed as a risk factor for cancers at various sites, especially the colon; however, the causal mechanism is still unknown. Obesity, defined as a body mass index of 30 or more, is consistently associated with endometrial and gall-bladder cancers in women and renal-cell cancer in both men and women. As the prevalence of obesity was between 5 and almost 20% in the Nordic populations in 1995, 625 cancer cases (310 endometrial cancers, 270 renal-cell cancers in men and women and 45 gall-bladder and bile-duct cancers among women) can be predicted in the Nordic countries around the year 2000 to be caused by obesity. This implies that about 1% of all cancers in Nordic women and less than 1% of those in Nordic men could be avoided around the year 2000 if a healthy body weight could be maintained by all inhabitants.

Avoidable cancers in the Nordic countries. Biological agents.

Although several biological agents have been linked convincingly with increased risks for cancer in humans, only infection of the lower female genital tract with human papillomavirus (HPV) and colonization of the gastrointestinal tract with Helicobacter pylori are of importance for cancer occurrence in the Nordic countries. HPV types 16 and 18, and probably types 31 and 33, are causally linked with cervical cancer and H. pylori, a Gram-negative bacteria, with gastric cancer. The estimated prevalence of genital infections with oncogenic types of HPV among Nordic women and the associated risk estimates indicate that approximately 45% of all cervical cancers arising in the Nordic countries are caused by such infections. This will be equivalent to about 550 cases in these countries each year around 2000, or 1% of all cancers arising in these populations. Similarly, the 35% prevalence of persistent gastric infection with H. pylori in the adult Nordic population and the associated risk estimates indicate that some 58% of all gastric cancers in the Nordic countries are due to this bacteria. This will correspond to about 2,350 new cases annually around the year 2000, with 1,350 among men and 1,000 among women, or approximately 2% of all cancers arising in the Nordic population.

Sex ratio among offspring of childhood cancer survivors treated with radiotherapy.

It has been postulated that paternal gonadal exposure would increase the sex ratio by inducing X-chromosomal dominant lethals but that maternal gonadal exposure would decrease the sex ratio by inducing recessive sex-linked lethals. We therefore evaluated the sex ratio (male-to-female ratio) of children born to survivors of childhood cancers in Denmark. Children with cancer were identified from the Danish Cancer Registry from 1943 to 1996 and their offspring from the Central Population Registry. Radiation treatments were determined from records within the Cancer Registry and gonadal radiation exposures were estimated based on the cancer being treated and the likely proximity of the radiation fields to the gonads. Overall, 1100 survivors of childhood cancer became the parents of 2130 children. The sex ratio for male (0.99) and female (1.00) cancer survivors was similar and did not differ significantly from the Danish population (1.06). Radiotherapy did not influence the sex ratio of the children of either male or female survivors, and there was no evidence for dose-related changes over categories of estimated dose to parental gonads. We saw no consistent association between the sex ratio and the interval between cancer diagnosis of the parent and birth of the child. This nationwide study provides no support for the hypothesis that radiation exposure to the gonads results in an inherited genetic effect that would be manifested by a change in the sex ratio of children born after exposure. It may be, however, that sex ratio alterations are not a good or even a valid indicator of possible genetic effects in humans.