Search

Background: Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiotherapy and therefore may reduce the risks. However, clinical evidence is lacking. Methods: A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published 2000-2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones estimated using meta-analysis. Results: Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow up ranged from 2-59 months. There were no published randomized trials comparing PBT with photon radiotherapy. Scattering PBT was delivered in seven studies (258 patients) starting 2003-2015 and scanning PBT in 22 studies (1041 patients) starting 2000-2019. Two studies (123 patients) starting 2011 used both PBT types. For one study (30 patients) PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall +/- regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis which occurred in 5.7% (95% CI 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%). Conclusions: This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiotherapy.

BackgroundSeveral studies report increases in the incidences of primary central nervous system (CNS) tumors. The reasons for this are unclear.MethodsData on all 188 340 individuals diagnosed with a primary CNS tumor in England (1993–2017) were obtained from the National Cancer Registration and Analysis Service. Data on all computerized tomography (CT) head and magnetic resonance imaging (MRI) brain scans in England (2013–2017) were obtained from the National Health Service Digital. Age-sex-standardized annual incidence rates per 100 000 population (ASR) were calculated by calendar year, tumor behavior, tumor location, and method of diagnosis. Temporal trends were quantified using average annual percent change (AAPC).ResultsThe ASR for all CNS tumors increased from 13.0 in 1993 to 18.6 in 2017 (AAPC: +1.5%, 95% CI: 1.3, 1.7). The ASR for malignant tumors (52% overall) remained stable (AAPC: +0.5%, 95% CI: −0.2, 1.3), while benign tumors (37% overall) increased (AAPC: +2.6%, 95% CI: 1.2, 4.0). Among the 66% of benign tumors that were microscopically confirmed, the ASR increased modestly (AAPC: +1.3%, 95% CI: 0.5, 2.1). However, among the 25% of benign tumors that were radiographically confirmed, the ASR increased substantially (AAPC: 10.2%, 95% CI: 7.9, 12.5), principally driven by large increases in those who are aged 65+ years. The rate of CT head scans in Accident & Emergency (A&E) increased during 2013–2017, with especially large increases in 65–84 and 85+-year-olds (AAPCs: +18.4% and +22.5%).ConclusionsIncreases in CNS tumor incidence in England are largely attributable to the greater detection of benign tumors. This could be the result of the increasing use of neuroimaging, particularly CT head scans in A&E in people who are aged 65+ years.

Background Adjuvant and neoadjuvant breast cancer treatments can reduce breast cancer mortality but may increase mortality from other causes. Information regarding treatment benefits and risks is scattered widely through the literature. To inform clinical practice we collated and reviewed the highest quality evidence. Methods Guidelines were searched to identify adjuvant or neoadjuvant treatment options recommended in early invasive breast cancer. For each option, systematic literature searches identified the highest-ranking evidence. For radiotherapy risks, searches for dose-response relationships and modern organ doses were also undertaken. Results Treatment options recommended in USA and elsewhere included chemotherapy (anthracycline, taxane, platinum, capecitabine), anti-human epidermal growth factor 2 therapy (trastuzumab, pertuzumab, trastuzumab emtansine, neratinib), endocrine therapy (tamoxifen, aromatase inhibitor, ovarian ablation/suppression with varying durations) and bisphosphonates. Radiotherapy options were after breast conserving surgery (whole breast, partial breast, tumour bed boost, regional nodes) and after mastectomy (chest wall, regional nodes). Treatment options were supported by randomised evidence, including >10,000 women for eight treatment comparisons, 1,000-10,000 for fifteen and

Given the gaps between EU ambitions regarding energy community development and the current reality of clean energy communities in Europe, we explore a research framework enabling viable multi- and interdisciplinary research into new clean energy communities. We offer a definition of new clean energy communities, discuss their potential for wider dissemination and identify four factors that contribute to the current mismatch between ambitions and reality in energy community development. As a broader framework for interdisciplinary research into the field of new clean energy communities, we propose polycentric governance theory, considering the fact that the area of community energy systems is essentially multi-scalar, and that the rules of engagement in such systems are of great significance. This opens up four avenues for research on energy communities, which we outline in terms of enabling institutional contexts, potential for learning and transferability, business models and value propositions, and evaluation of outcomes and processes.

Background and Purpose: Breast cancer radiotherapy can increase the risk of subsequent primary oesophageal cancer, with risk increasing according to oesophagus radiation dose. We describe oesophagus exposure from modern breast cancer regimens and discuss the risks of oesophageal cancer for women irradiated recently. Materials and Methods: A systematic review was undertaken of oesophagus doses from breast cancer radiotherapy regimens published during 2010-2020. Mean and maximum oesophagus doses were described for different target regions irradiated and different radiotherapy techniques. Results: In 112 published regimens from 18 countries, oesophagus doses varied with target region. For partial breast irradiation, average mean oesophagus dose was 0.2 Gy (range 0.1-0.4) in four regimens; maximum dose was not reported. For breast or chest wall radiotherapy, average oesophagus doses were mean 1.8 Gy (range 0.1-10.4) in 24 regimens and maximum 6.7 Gy (range 0.4-14.3) in seven regimens. For radiotherapy including a nodal region, average oesophagus doses were higher: mean 11.4 Gy (range 1.1-29.3) in 61 regimens and maximum 34.4 Gy (range 3.4-51.3) in 55 regimens. Average mean oesophagus doses were >10 Gy for intensity modulated nodal radiotherapy, but lower for other node techniques. Conclusions: Mean oesophagus doses from partial breast and breast/chest wall regimens were usually less than 2 Gy, hence radiation-risks will be very small. However, for radiotherapy including lymph nodes, average mean oesophagus dose of 11.4 Gy may nearly double oesophageal cancer risk. Consideration of oesophageal exposure during nodal radiotherapy planning may reduce the risks of radiation-related oesophageal cancer for women irradiated today.

Background: We aimed to develop dose–response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies. Methods and Results: A case–control study was performed within a cohort of breast cancer survivors treated during 1980–2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9–13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) −2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7–21.7) compared to Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies.

Highlights • Prescribing was as expected from clinical practice. • 90% received ET prescriptions during the second year after diagnosis. • Prescribing dropped more than five years after diagnosis. • The majority of younger women (under 55) received tamoxifen. • The majority of older women (55+) received AIs., Introduction National cancer registration data were linked to the Primary Care Prescription Database (PCPD) in England. The level of endocrine therapy (ET) prescribed in women after a diagnosis of breast cancer was studied. Materials and methods Cancer registrations for women diagnosed with breast cancer during 1995–2015, who survived to 31st March 2015, were linked to ET prescriptions issued during April–July 2015. Results Among 369 277 survivors of breast cancer diagnosed during 1995–2015, 37% were prescribed ET during April–July 2015. Among women whose breast cancer diagnosis was after 31st July 2010, 81% of those recorded with oestrogen receptor positive (ER+ve) disease were prescribed ET compared with only 6% of those with ER-ve disease. Younger women usually received tamoxifen and older women usually received aromatase inhibitors. Discussion The pattern of ET use observed in these data corresponds to that expected. This provides confidence in the potential of the PCPD for epidemiological research.

ObjectiveTo evaluate the long term risks of invasive breast cancer and death from breast cancer after ductal carcinoma in situ (DCIS) diagnosed through breast screening.DesignPopulation based observational cohort study.SettingData from the NHS Breast Screening Programme and the National Cancer Registration and Analysis Service.ParticipantsAll 35 024 women in England diagnosed as having DCIS by the NHS Breast Screening Programme from its start in 1988 until March 2014.Main outcome measuresIncident invasive breast cancer and death from breast cancer.ResultsBy December 2014, 13 606 women had been followed for up to five years, 10 998 for five to nine years, 6861 for 10-14 years, 2620 for 15-19 years, and 939 for at least 20 years. Among these women, 2076 developed invasive breast cancer, corresponding to an incidence rate of 8.82 (95% confidence interval 8.45 to 9.21) per 1000 women per year and more than double that expected from national cancer incidence rates (ratio of observed rate to expected rate 2.52, 95% confidence interval 2.41 to 2.63). The increase started in the second year after diagnosis of DCIS and continued until the end of follow-up. In the same group of women, 310 died from breast cancer, corresponding to a death rate of 1.26 (1.13 to 1.41) per 1000 women per year and 70% higher than that expected from national breast cancer mortality rates (observed:expected ratio 1.70, 1.52 to 1.90). During the first five years after diagnosis of DCIS, the breast cancer death rate was similar to that expected from national mortality rates (observed:expected ratio 0.87, 0.69 to 1.10), but it then increased, with values of 1.98 (1.65 to 2.37), 2.99 (2.41 to 3.70), and 2.77 (2.01 to 3.80) in years five to nine, 10-14, and 15 or more after DCIS diagnosis. Among 29 044 women with unilateral DCIS undergoing surgery, those who had more intensive treatment (mastectomy, radiotherapy for women who had breast conserving surgery, and endocrine treatment in oestrogen receptor positive disease) and those with larger final surgical margins had lower rates of invasive breast cancer.ConclusionsTo date, women with DCIS detected by screening have, on average, experienced higher long term risks of invasive breast cancer and death from breast cancer than women in the general population during a period of at least two decades after their diagnosis. More intensive treatment and larger final surgical margins were associated with lower risks of invasive breast cancer.

BACKGROUND AND PURPOSE:Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses. MATERIALS/METHODS:We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships. RESULTS:For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses. CONCLUSIONS:These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.

Background Improved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment. Methods We assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged Results CVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93–1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9–17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6–2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07–5.69), emerging Conclusions Women treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.

Purpose Incidental cardiac irradiation can cause cardiac injury, but little is known about the effect of radiation on specific cardiac segments. Methods For 456 women who received breast cancer radiotherapy between 1958 and 2001 and then later experienced a major coronary event, information was obtained on the radiotherapy regimen they received and on the location of their cardiac injury. For 414 women, all with documented location of left ventricular (LV) injury, doses to five LV segments were estimated. For 133 women, all with documented location of coronary artery disease with ≥ 70% stenosis, doses to six coronary artery segments were estimated. For each segment, numbers of women with left-sided and right-sided breast cancer were compared. Results Of women with LV injury, 243 had left-sided breast cancer and 171 had right-sided breast cancer (ratio of left v right, 1.42; 95% CI, 1.17 to 1.73), reflecting the higher typical LV radiation doses in left-sided cancer (average dose left-sided, 8.3 Gy; average dose right-sided, 0.6 Gy; left minus right dose difference, 7.7 Gy). For individual LV segments, the ratios of women with left- versus right-sided radiotherapy were as follows: inferior, 0.94 (95% CI, 0.70 to 1.25); lateral, 1.42 (95% CI, 1.04 to 1.95); septal, 2.09 (95% CI, 1.37 to 3.19); anterior, 1.85 (95% CI, 1.39 to 2.46); and apex, 4.64 (95% CI, 2.42 to 8.90); corresponding left-minus-right dose differences for these segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy, respectively ( Ptrend < .001). For women with coronary artery disease, the ratios of women with left- versus right-radiotherapy for individual coronary artery segments were as follows: right coronary artery proximal, 0.48 (95% CI, 0.26 to 0.91); right coronary artery mid or distal, 1.69 (95% CI, 0.85 to 3.36); circumflex proximal, 1.46 (95% CI, 0.72 to 2.96); circumflex distal, 1.11 (95% CI, 0.45 to 2.73); left anterior descending proximal, 1.89 (95% CI, 1.07 to 3.34); and left anterior descending mid or distal, 2.33 (95% CI, 1.19 to 4.59); corresponding left-minus-right dose differences for these segements were −5.0, −2.5, 1.6, 3.5, 9.5, and 38.8 Gy ( Ptrend = .002). Conclusion For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized.

Purpose The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen. Methods We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000–2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded. Results Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3–18.1) were upstaged to IBC and a further 14.6% (11.3–18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference

Hodgkin lymphoma (HL) survivors treated with radiotherapy and/or chemotherapy are known to have increased risks of heart failure (HF), but a radiation dose-response relationship has not previously been derived. A case-control study, nested in a cohort of 2617 five-year survivors of HL diagnosed before age 51 years during 1965 to 1995, was conducted. Cases (n = 91) had moderate or severe HF as their first cardiovascular diagnosis. Controls (n = 278) were matched to cases on age, sex, and HL diagnosis date. Treatment and follow-up information were abstracted from medical records. Mean heart doses and mean left ventricular doses (MLVD) were estimated by reconstruction of individual treatments on representative computed tomography datasets. Average MLVD was 16.7 Gy for cases and 13.8 Gy for controls (Pdifference = .003). HF rate increased with MLVD: relative to 0 Gy, HF rates following MVLD of 1-15, 16-20, 21-25, and ≥26 Gy were 1.27, 1.65, 3.84, and 4.39, respectively (Ptrend < .001). Anthracycline-containing chemotherapy increased HF rate by a factor of 2.83 (95% CI: 1.43-5.59), and there was no significant interaction with MLVD (Pinteraction = .09). Twenty-five-year cumulative risks of HF following MLVDs of 0-15 Gy, 16-20 Gy, and ≥21 Gy were 4.4%, 6.2%, and 13.3%, respectively, in patients treated without anthracycline-containing chemotherapy, and 11.2%, 15.9%, and 32.9%, respectively, in patients treated with anthracyclines. We have derived quantitative estimates of HF risk in patients treated for HL following radiotherapy with or without anthracycline-containing chemotherapy. Our results enable estimation of HF risk for patients before treatment, during radiotherapy planning, and during follow-up.

Background: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. Methods: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. Results: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4–5.2) decreasing to 1.2 (95% confidence interval, 1.1–1.3) for individuals aged 35 to 39 years (2 P for trend Conclusions: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines.

In the present study, we report on the full range of physical diseases acquired by survivors of Hodgkin lymphoma diagnosed in adolescence or young adulthood. In a Danish nationwide population‐based cohort study, 1,768 five‐year survivors of Hodgkin lymphoma diagnosed at ages 15–39 years during 1943–2004 and 228,447 comparison subjects matched to survivors on age and year of birth were included. Hospital discharge diagnoses and bed‐days during 1977–2010 were obtained from the Danish Patient Register for 145 specific disease categories gathered in 14 main diagnostic groups. The analysis was conducted separately on three subcohorts of survivors, that is, survivors diagnosed 1943–1976 for whom we had no information on rehospitalisation for Hodgkin lymphoma and survivors diagnosed 1977–2004, split into a subcohort with no expected relapses and a subcohort for whom a rehospitalisation for Hodgkin lymphoma indicated a relapse. The overall standardised hospitalisation rate ratios (RRs) were 2.0 [95% confidence interval (CI), 1.9–2.1], 1.5 (1.4–1.6) and 2.9 (2.6–3.1) respectively, and the corresponding RRs for bed‐days were 3.5 (3.4–3.5), 1.8 (1.8–1.9) and 10.4 (10.3–10.6). Highest RRs were seen for nonmalignant haematological conditions (RR: 2.6; 3.1 and 9.7), malignant neoplasms (RR: 3.2; 2.5 and 4.7) and all infections combined (RR: 2.5; 2.2 and 5.3). Survivors of Hodgkin lymphoma in adolescence or young adulthood are at increased risk for a wide range of diseases that require hospitalisation. The risk depends on calendar period of treatment and on whether the survivors were rehospitalised for Hodgkin lymphoma, and thus likely had a relapse., What's new? Excellent survival rates for Hodgkin lymphoma have allowed increasing numbers of patients to enjoy a normal, disease‐free life expectancy. Nonetheless, for some, premature death remains a concern, owing to the risk of late effects, including second malignant neoplasms, from curative therapy. The authors of the present study quantified the burden of new diagnoses in Hodgkin lymphoma survivors, showing that among 1,768 five‐year survivors diagnosed in adolescence or young adulthood from 1943 to 2004, a significant proportion later suffered conditions requiring hospitalisation. Malignant neoplasms, infections and circulatory diseases accounted for the majority of new diagnoses.

The increasing complexity and cost of conducting randomized trials1 have stimulated interest in using observational data sets to evaluate cancer treatments.

Background and purpose The risk of heart disease subsequent to breast cancer radiotherapy was examined with particular focus on women receiving anthracycline-containing chemotherapy. Material and methods Women diagnosed with early-stage breast cancer in Denmark, 1977–2005, were identified from the register of the Danish Breast Cancer Cooperative Group, as was information on cancer-directed treatment. Information on heart disease was sought from the Danish National Patient and Cause of Death Registries. Incidence rate ratios were estimated comparing left-sided with right-sided cancer (IRR, LvR), stratified by calendar year, age, and time since breast cancer radiotherapy. Results Among 19,464 women receiving radiotherapy, the IRR, LvR, was 1.11 (95% CI 1.03–1.20, p = 0.005) for all heart disease and among those also receiving anthracyclines the IRR, LvR, was 1.32 (95% CI 1.02–1.70, p = 0.03). This risk was highest if the treatment was given before the age of 50 years (IRR, LvR, 1.44, (95% CI 1.04–2.01) but there was no significant trend with age or time since treatment. Conclusions Radiotherapy for left-sided breast cancer is associated with a higher risk of heart disease than for right-sided with the largest increases seen in women who also received anthracycline-containing chemotherapy.

Purpose To quantify the radiation doses received by the heart and coronary arteries from contemporary tangential breast or chest wall radiotherapy. Methods and Materials Fifty consecutive patients with left-sided breast cancer and 5 consecutive patients with right-sided breast cancer treated at a large United Kingdom radiotherapy center during the year 2006 were selected. All patients were irradiated with 6- or 8-MV tangential beams to the breast or chest wall. For each dose plan, dose–volume histograms for the heart and left anterior descending (LAD) coronary artery were calculated. For 5 of the left-sided and all 5 right-sided patients, dose–volume histograms for the right and circumflex coronary arteries were also calculated. Detailed spatial assessment of dose to the LAD coronary artery was performed for 3 left-sided patients. Results For the 50 patients given left-sided irradiation, the average mean (SD) dose was 2.3 (0.7) Gy to the heart and 7.6 (4.5) Gy to the LAD coronary artery, with the distal LAD receiving the highest doses. The right and circumflex coronary arteries received approximately 2 Gy mean dose. Part of the heart received >20 Gy in 22 left-sided patients (44%). For the 5 patients given right-sided irradiation, average mean doses to all cardiac structures were in the range 1.2 to 2 Gy. Conclusions Heart dose from left-tangential radiotherapy has decreased considerably over the past 40 years, but part of the heart still receives >20 Gy for approximately half of left-sided patients. Cardiac dose for right-sided patients was generally from scattered irradiation alone.

The decline in death rates from ischaemic heart disease (IHD) (ICD 410-413) in the United States is now well documented. Over-the period 1963-75 the drop in age-specific mortality varied from 27 2"O for those aged 35-44 to 19-30o for the over-85s.1 Concurrent with these changes have been reductions in the consumption of tobacco products, milk and cream, butter, eggs, and animal fats and oils and an increase in the use of vegetable fats and oils. In England and Wales no similar encouraging change in IHD mortality has been described. In the Royal College of Physicians' report2 annual death rates for IHD in men aged 35-44, 45-54, and 55-64 showed a pronounced increase from the period 1950-2 to 1973. There was, on the other hand, little change in the rates for women. Similar findings were presented for the Republic of Ireland, Northern Ireland, and Scotland, the latter two having substantially higher rates than England and Wales. A detailed analysis of mortality from heart disease in England and Wales for the years 1950-73'3 4has confirmed the general upward trend for men even after allowing for the possibility of an iatrogenic transfer of diagnosis from the rubrics for hypertension and myocardial insufficiency to that of IHD. The mortality trends for women are less clear. Clayton et al3 concluded that no change in death rates took place during the period 1950-73 in women aged 50 and over, but that there was a consistent increase for young women. The combination of IHD with other rubrics in this analysis has been questioned by Wald and Mann,; who believe that there was no justification for combining deaths from hypertension with those of IHD. The trends for IHD alone indicated an increase for all women up to age 64. We present mortality data for 1968-76 for England and Wales and for Scotland that suggest that IHD death rates for men stabilised in about 1972 and since then have started to decline. No similar decline was found for mortality in women.

Studies of underground miners occupationally exposed to radon have consistently demonstrated an increased risk of lung cancer in both smokers and non-smokers. Radon exposure also occurs elsewhere, especially in houses, and estimates based on the findings for miners suggest that residential radon is responsible for about one in 20 lung cancers in the UK, most being caused in combination with smoking. These calculations depend, however, on several assumptions and more direct evidence on the magnitude of the risk is needed. To obtain such evidence, a case-control study was carried out in south-west England in which 982 subjects with lung cancer and 3185 control subjects were interviewed. In addition, radon concentrations were measured at the addresses at which subjects had lived during the 30-year period ending 5 years before the interview. Lung cancer risk was examined in relation to residential radon concentration after taking into account the length of time that subjects had lived at each address and adjusting for age, sex, smoking status, county of residence and social class. The relative risk of lung cancer increased by 0.08 (95% CI -0.03, 0.20) per 100 Bq m(-3) increase in the observed time-weighted residential radon concentration. When the analysis was restricted to the 484 subjects with lung cancer and the 1637 control subjects with radon measurements available for the entire 30-year period of interest, the corresponding increase was somewhat higher at 0.14 per 100 Bq m(-3) (95% CI 0.01, 0.29), although the difference between this group and the remaining subjects was not statistically significant. When the analysis was repeated taking into account uncertainties in the assessment of radon exposure, the estimated increases in relative risk per 100 Bq m(-3) were larger, at 0.12 (95% CI -0.05, 0.33) when all subjects were included and 0.24 (95% CI -0.01, 0.56) when limited to subjects with radon measurements available for all 30 years. These results are consistent with those from studies of residential radon carried out in other countries in which data on individual subjects have been collected. The combined evidence suggests that the risk of lung cancer associated with residential radon exposure is about the size that has been postulated on the basis of the studies of miners exposed to radon.

We have examined the relationship between diet and lung cancer in a case–control study of 982 cases of lung cancer and 1486 population controls in south-west England in which subjects were interviewed personally about their smoking habits and their consumption of foods and supplements rich in retinol or carotene. Analyses were performed for 15 dietary variables, including intake of pre-formed retinol and carotene. There were significant associations (P< 0.01) with lung cancer risk for 13 of the variables, eight of which remained after adjustment for smoking. When the 15 variables were considered simultaneously, independent significant associations remained for 5: pre-formed retinol (increased risk), and fish liver oil, vitamin pills, carrots and tomato sauce (decreased risk). It is unlikely that all five associations represent biological effects, or that they can all be explained by residual confounding by smoking, or by biases. We conclude that there is at least one as yet unidentified factor that is causally related to lung cancer risk and of considerable importance in terms of attributable risk in this population. © 2001 Cancer Research Campaign http://www.bjcancer.com

BACKGROUND: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. METHODS: We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. FINDINGS: In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2pINTERPRETATION: 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. FUNDING: Cancer Research UK; British Heart Foundation; UK Medical Research Council.

The dose-response relationship for radiation-induced leukemia was examined in a pooled analysis of three exposed populations: Japanese atomic bomb survivors, women treated for cervical cancer, and patients irradiated for ankylosing spondylitis. A total of 383 leukemias were observed among 283,139 study subjects. Considering all leukemias apart from chronic lymphocytic leukemia, the optimal relative risk model had a dose response with a purely quadratic term representing induction and an exponential term consistent with cell sterilization at high doses; the addition of a linear induction term did not improve the fit of the model. The relative risk decreased with increasing time since exposure and increasing attained age, and there were significant (P < 0.00001) differences in the parameters of the model between datasets. These differences were related in part to the significant differences (P = 0.003) between the models fitted to the three main radiogenic leukemia subtypes (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia). When the three datasets were considered together but the analysis was repeated separately for the three leukemia subtypes, for each subtype the optimal model included quadratic and exponential terms in dose. For acute myeloid leukemia and chronic myeloid leukemia, there were reductions of relative risk with increasing time after exposure, whereas for acute lymphocytic leukemia the relative risk decreased with increasing attained age. For each leukemia subtype considered separately, there was no indication of a difference between the studies in the relative risk and its distribution as a function of dose, age and time (P > 0.10 for all three subtypes). The nonsignificant indications of differences between the three datasets when leukemia subtypes were considered separately may be explained by random variation, although a contribution from differences in exposure dose-rate regimens, inhomogeneous dose distribution within the bone marrow, inadequate adjustment for cell sterilization effects, or errors in dosimetry could have played a role.

The "Gardner hypothesis" suggests that an excess of childhood leukaemia near a nuclear reprocessing plant is caused by paternal exposure to ionizing radiation. But the evidence shows that this explanation is wrong.

This thesis considers parallel line bioassay from a Bayesian point of view along the lines laid about Lindley (1972) and de Finetti (1975). The mathematical model used for the analysis is a non-linear one in which the log potency appears explicitly as a parameter. This enables prior knowledge about the log potency ratio to be incorporated straightforwardly in the analysis. The method of analysis follows closely the ideas of Lindley and Smith (1972) for the linear model. Extended models in which experimental design features such as randomized blocks and Latin squares are accounted for are also considered, and a method for the use of prior information to design an assay is given. In addition to the analysis of a single essay the problem of combining information from several assays is considered and two different models which combine such information are discussed.

The Chernobyl accident, which occurred April 26, 1986, resulted in a large release of radionuclides, which were deposited over a very wide area, particularly in Europe. Although an increased risk of thyroid cancer in exposed children has been clearly demonstrated in the most contaminated regions, the impact of the accident on the risk of other cancers as well as elsewhere in Europe is less clear. The objective of the present study was to evaluate the human cancer burden in Europe as a whole from radioactive fallout from the accident. Average country- and region-specific whole-body and thyroid doses from Chernobyl were estimated using new dosimetric models and radiological data. Numbers of cancer cases and deaths possibly attributable to radiation from Chernobyl were estimated, applying state-of-the-art risk models derived from studies of other irradiated populations. Simultaneously, trends in cancer incidence and mortality were examined over time and by dose level. The risk projections suggest that by now Chernobyl may have caused about 1,000 cases of thyroid cancer and 4,000 cases of other cancers in Europe, representing about 0.01% of all incident cancers since the accident. Models predict that by 2065 about 16,000 (95% UI 3,400-72,000) cases of thyroid cancer and 25,000 (95% UI 11,000-59,000) cases of other cancers may be expected due to radiation from the accident, whereas several hundred million cancer cases are expected from other causes. Although these estimates are subject to considerable uncertainty, they provide an indication of the order of magnitude of the possible impact of the Chernobyl accident. It is unlikely that the cancer burden from the largest radiological accident to date could be detected by monitoring national cancer statistics. Indeed, results of analyses of time trends in cancer incidence and mortality in Europe do not, at present, indicate any increase in cancer rates -- other than of thyroid cancer in the most contaminated regions -- that can be clearly attributed to radiation from the Chernobyl accident.

Summary Background Diagnostic X-rays are the largest man-made source of radiation exposure to the general population, contributing about 14% of the total annual exposure worldwide from all sources. Although diagnostic X-rays provide great benefits, that their use involves some small risk of developing cancer is generally accepted. Our aim was to estimate the extent of this risk on the basis of the annual number of diagnostic X-rays undertaken in the UK and in 14 other developed countries. Methods We combined data on the frequency of diagnostic X-ray use, estimated radiation doses from X-rays to individual body organs, and risk models, based mainly on the Japanese atomic bomb survivors, with population-based cancer incidence rates and mortality rates for all causes of death, using life table methods. Findings Our results indicate that in the UK about 0·6% of the cumulative risk of cancer to age 75 years could be attributable to diagnostic X-rays. This percentage is equivalent to about 700 cases of cancer per year. In 13 other developed countries, estimates of the attributable risk ranged from 0·6% to 1·8%, whereas in Japan, which had the highest estimated annual exposure frequency in the world, it was more than 3%. Interpretation We provide detailed estimates of the cancer risk from diagnostic X-rays. The calculations involved a number of assumptions and so are inevitably subject to considerable uncertainty. The possibility that we have overestimated the risks cannot be ruled out, but that we have underestimated them substantially seems unlikely.

This review gives a general account of how and why epidemiological studies of UK participants in the nuclear weapons test programme were set up. There is a short description of the circumstances in which the tests were planned and executed and a discussion of the general considerations involved in designing studies to show whether the health of test participants suffered as a result of the tests. The companion review article summarises the results of the epidemiological studies.

Recent analyses of mortality among atomic bomb survivors have suggested a linear dose-response relationship between ionizing radiation and diseases of the circulatory system for exposures in the range 0-4 Sv. If confirmed, this has substantial implications. We have therefore reviewed the published literature to see if other epidemiological data support this finding. Other studies allowing a comparison of the rates of circulatory disease in individuals drawn from the same population but exposed to ionizing radiation at different levels within the range 0-5 Gy or 0-5 Sv were identified through systematic literature searches. Twenty-six studies were identified. In some, disease rates among those exposed at different levels may have differed for reasons unrelated to radiation exposure, while many had low power to detect effects of the relevant magnitude. Among the remainder, one study found appreciable evidence that exposure to low-dose radiation was associated with circulatory diseases, but five others, all with appreciable power, did not. We conclude that the other epidemiological data do not at present provide clear evidence of a risk of circulatory diseases at doses of ionizing radiation in the range 0-4 Sv, as suggested by the atomic bomb survivors. Further evidence is needed to characterize the possible risk.

The National Radiological Protection Board has recently carried out a reappraisal of the annual genetically significant dose (GSD) to the population of Great Britain arising from the practice of diagnostic radiology. The current value of 120 muGy (12 mrad) is indistinguishable from the value determined 20 years ago despite a 48% increase in the number of X-ray examinations performed per head of the population. This is mostly due to a large decrease in the contribution from obstetric radiology and to a marked reduction in the gonadal doses delivered to children for nearly all types of examination. The GSD and the frequency of X-ray examinations in Great Britain would appear to be considerably lower than those found in other industrialized countries and seem unlikely to result in more than 100 cases of serious hereditary ill-health per year at genetic equilibrium. On the other hand, diagnostic radiology is responsible for 87% of the GSD from all man-made sources of population exposure in Great Britain and there is evidence from the data collected for this reappraisal that radiological protection measures could be improved so as to reduce significantly this large contribution without detriment to patient care.

Data are presented on the risks of cancers other than lung cancer in a cohort of iron miners from northern Sweden occupationally exposed to elevated levels of the radioactive gas radon. Compared with rates for the four northernmost counties of Sweden, mortality was increased for all cancers other than lung cancer (ratio of observed to expected deaths 1.21, 95% confidence interval 1.03-1.41), stomach cancer (ratio of observed to expected deaths 1.45, 95% confidence interval 1.04-1.98), and rectal cancer (ratio of observed to expected deaths 1.94, 95% confidence interval 1.03-3.31). Despite these overall increases, mortality was not significantly associated with cumulative exposure to radon, either for all cancers other than lung cancer or for any site of cancer other than lung cancer individually. However, the data from this cohort on its own have limited power; and for several sites of cancer the data in this study would be consistent with a radon-related increase. Further study of cancers other than lung cancer in populations exposed to radon is required.

BACKGROUND AND PURPOSE: We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002.MATERIAL AND METHODS: Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left-sided patients, mean heart dose was related to maximum heart distance in the medial field.RESULTS: For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from 8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always CONCLUSIONS: The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT-scans.

OBJECTIVE: To investigate the impact of smoking on overall mortality and life expectancy in a large Japanese population, including some who smoked throughout adult life. DESIGN: The Life Span Study, a population-based prospective study, initiated in 1950. SETTING: Hiroshima and Nagasaki, Japan. PARTICIPANTS: Smoking status for 27,311 men and 40,662 women was obtained during 1963-92. Mortality from one year after first ascertainment of smoking status until 1 January 2008 has been analysed. MAIN OUTCOME MEASURES: Mortality from all causes in current, former, and never smokers. RESULTS: Smokers born in later decades tended to smoke more cigarettes per day than those born earlier, and to have started smoking at a younger age. Among those born during 1920-45 (median 1933) and who started smoking before age 20 years, men smoked on average 23 cigarettes/day, while women smoked 17 cigarettes/day, and, for those who continued smoking, overall mortality was more than doubled in both sexes (rate ratios versus never smokers: men 2.21 (95% confidence interval 1.97 to 2.48), women 2.61 (1.98 to 3.44)) and life expectancy was reduced by almost a decade (8 years for men, 10 years for women). Those who stopped smoking before age 35 avoided almost all of the excess risk among continuing smokers, while those who stopped smoking before age 45 avoided most of it. CONCLUSIONS: The lower smoking related hazards reported previously in Japan may have been due to earlier birth cohorts starting to smoke when older and smoking fewer cigarettes per day. In Japan, as elsewhere, those who start smoking in early adult life and continue smoking lose on average about a decade of life. Much of the risk can, however, be avoided by giving up smoking before age 35, and preferably well before age 35.

A cohort of 4320 uranium miners in West Bohemia who started work at the mines during 1948 to 1959 and worked there for at least four years were followed up to the end of 1990 to determine cause specific mortality risks in relation to exposures in the mines. The miners had experienced high radon exposures, on average 219 working level months during their uranium mining careers, for which detailed measurements were available. They had also been exposed to high arsenic levels in one of the two major mines, and to dust. New follow up methods, not previously used for occupational cohorts in Czechoslovakia, were utilised. By the end of follow up 2415 (56%) of the cohort were known to have died. Overall mortality was significantly raised compared with that in the general population (relative risk (RR) = 1.56, 95% confidence interval (95% CI) 1.50-1.63), with significantly raised risks of lung cancer (RR = 5.08, 95% CI 4.71-5.47), accidents (RR = 1.59, 95% CI 1.34-1.87), homicide (RR = 5.57, 95% CI 2.66-10.21), mental disorders (RR = 5.18, 95% CI 2.83-8.70), cirrhosis (RR = 1.51, 95% CI 1.16-1.94), and non-rheumatic circulatory diseases (RR = 1.16, 95% CI 1.08-1.25). The relative risk of lung cancer was greatest four to 14 years after entry to the mines. Relative risks for homicide and accidents were raised up to 25 years from entry but not after this. Substantial significantly raised risks at 15 to 24 years after entry occurred for cirrhosis, non-rheumatic circulatory diseases,a nd pneumonia and other respiratory infections. Sizeable significantly raised risks at 25 and more years after entry, but not earlier, were present for mental disorders, tuberculosis, and non-malignant non-infectious respiratory conditions. No specific causes showed risks significantly related to age at entry to mining. Risk of lung cancer was significantly positively related to radon exposure, estimated arsenic exposure, and duration of work in the mines, but no other cause was significantly positively related to these variables. The raised risk of lung cancer in uranium miners, which is well established, is related aetiologically to radon exposure, and in the present cohort it may also in part have been due to exposure to arsenic. The raised risks of accidents, tuberculosis, and non-infectious respiratory diseases have also been seen in other uranium mining cohorts, and are likely to reflect the dangerous and dusty working conditions and the confined spaces in which work occurred. The cirrhosis and homicide deaths probably related to the lifestyle associated with mining. The raised risk of circulatory diseases does not seem to be related to radon or arsenic exposure; its causes are unclear. The use of multiple follow up methods was found to be mortality in the cohort.

The hazards of exposure to some types of ionising radiation were recognized shortly after the discovery of the X-ray in 1895: by 1902 the first radiation-associated cancer was reported in a skin sore and, within a few years, a large number of such skin cancers had been observed. The first report of leukaemia in radiation workers appeared in 1911. Since then there have been many reviews of the health effects of ionising radiation, most notably in the reports of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) (see, for example, UNSCEAR, 2006). The International Agency for Research on Cancer's Monographs on the Carcinogenic Risk to Humans also reviewed the effects of ionising radiation, both in the form of exposure to external γ or X-rays (IARC, 2000) and as α and β particles from internalised radionuclides (IARC, 2001), and all these types of radiation were classified as carcinogenic to humans.

A brief description is given of the study of West Bohemian uranium miners, and recent and ongoing efforts to improve the quality of the data are summarized. Three recent analyses of the data from the cohort have led to rather different estimates of the excess relative risk of mortality from lung cancer per working-level month. The reasons for these different estimates are described, and it is concluded that estimates of lung cancer risk are strongly influenced by the quality of the exposure estimates, especially by the omission of some exposures accumulated during employment at other uranium mines, following the closure of most of the shafts at the original two mines. The most recent analysis has shown that, in common with other cohorts of radon-exposed miners, the excess relative risk of lung cancer per working-level month is modified by age and time since exposure. An inverse effect of exposure rate was also demonstrated, but it affected only men at very high concentrations and appears to be related to the time pattern of exposure. In addition, the risk was found to differ between the two main mines, possibly due to the influence of arsenic in the dust of the mines.

SummaryAlthough it has been widely accepted since the 1960s that smoking cigarettes carries a substantial health risk, worldwide mortality from tobacco-related diseases is increasing rapidly at the beginning of the 21st century. To provide the motivation to control this epidemic there is a continuing and pressing need for information on the risks of tobacco consumption that is accurate, up to date, locally relevant and imaginatively presented.