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Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries
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Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries Sarah C Darby, Paul McGale, Carolyn W Taylor, Richard Peto
Summary Background Radiotherapy for early breast cancer can decrease breast cancer mortality but increase other mortality, mainly from heart disease and lung cancer. The mean cardiac dose from irradiation of a left-sided breast cancer can be two or three times that for a right-sided breast cancer. The mean ipsilateral (ie, on the same side as the breast cancer) lung dose can also be two or three times the mean contralateral lung dose. Particularly during the 1970s, when typical heart and lung exposures were greater than now, the laterality of an irradiated breast cancer could measurably affect cardiac mortality and mortality from cancer of the right or the left lung decades later. This study aimed to assess the hazards in the general US population from routine cancer-registry and death-certificate data. Methods We analysed data for 308 861 US women with early breast cancer of known laterality (left-sided or rightsided) who were registered in the US Surveillance Epidemiology and End Results (SEER) cancer registries during 1973–2001 and followed prospectively for cause-specific mortality until Jan 1, 2002. Findings 115 165 (37%) received radiotherapy. Among those who did not, tumour laterality was of little relevance to subsequent mortality. For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio (left versus right tumour laterality) was 1·20 (95% CI 1·04–1·38) less than 10 years afterwards, 1·42 (1·11–1·82) 10–14 years afterwards, and 1·58 (1·29–1·95) after 15 years or more (trend: 2p=0·03). For women diagnosed during 1983–92 and irradiated, the cardiac mortality ratio was 1·04 (0·91–1·18) less than 10 years afterwards and 1·27 (0·99–1·63) 10 or more years afterwards. For women diagnosed during 1993–2001 and irradiated the cardiac mortality ratio was 0·96 (0·82–1·12), with none yet followed for 10 years. Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973–82 and irradiated was 1·17 (0·62–2·19), 2·00 (1·00–4·00), and 2·71 (1·65–4·48), respectively, less than 10 years, 10–14 years, and 15 or more years afterwards (trend: 2p=0·04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards.
Lancet Oncol 2005; 6: 557–65 See Reflection and Reaction page 539 Published online July 5, 2005 DOI:10.1016/S1470-2045(05) 70251-5 Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK (Prof S C Darby PhD, P McGale PhD, C W Taylor FRCR, Prof R Peto FRS) Correspondence to: Prof Sarah Darby, CTSU, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, UK [email protected]
Interpretation US breast cancer radiotherapy regimens of the 1970s and early 1980s appreciably increased mortality from heart disease and lung cancer 10–20 years afterwards with, as yet, little direct evidence on the hazards after more than 20 years. Since the early 1980s, improvements in radiotherapy planning should have reduced such risks, but the long-term hazards in the general populations of various countries still need to be monitored directly.
Introduction Although radiotherapy for early breast cancer can reduce the risk of death from the disease several years later, it usually involves some irradiation of the heart or lungs, and some of the breast cancer radiotherapy regimens used during previous decades could increase the risks of heart disease and lung cancer many years after treatment.1–4 Regimens that incidentally irradiate the heart will generally do so to a greater extent when used to treat left-sided breast cancer than when used to treat right-sided breast cancer. Likewise, those that incidentally irradiate the lung will generally affect the ipsilateral lung (ie, on the same side as the breast cancer) more than the contralateral lung. These differences in exposure can be substantial: for example, the mean dose to the heart or to one of the lungs may differ by a factor of two or three, depending on the laterality (ie, left or right) of the breast tumour.5,6 Some indication of the http://oncology.thelancet.com Vol 6 August 2005
extent to which the radiotherapy regimens of the 1970s or early 1980s were causing mortality from heart disease and lung cancer 10–20 years later in the general population of patients with breast cancer can, therefore, be obtained from routine cancer-registry data that recorded the use or otherwise of radiotherapy for any breast cancers, the laterality of those breast cancers and of any subsequent primary lung cancers, and the certified causes of any deaths during the first and, particularly, subsequent decades after treatment. The US Surveillance Epidemiology and End Results (SEER) cancer registries have, since 1973, covered in this way a substantial proportion of the US population. Increases in heart disease7,8 and lung cancer9–11 after radiotherapy for breast cancer have been reported in the SEER data, and the 20-year hazards of the breast cancer radiotherapy regimens used in the 1970s and early 1980s are now becoming clear. However, it is as yet less clear 557
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how much risk there will be from the regimens used since the early 1980s, when the majority of women with early breast cancer started to receive breast-conserving surgery (BCS) plus radiotherapy, often just to the breast. Although cardiac doses and lung doses from radiotherapy have decreased since the 1970s,12,13 some breast cancer radiotherapy techniques used during the 1980s would still have involved mean doses to the heart and ipsilateral lung of several Gray (Gy), so some eventual risk might still be expected. Atomic bomb survivors exposed to single doses of up to 4 Gy had dose-related excess risks decades later of about 17% per Gy for heart disease and 90% per Gy for lung cancer.14,15 Likewise, in patients given fractionated radiotherapy for peptic ulcer disease with mean cardiac doses of up to 4 Gy there was a dose-related increase in late cardiac mortality.16 In atomic bomb survivors and in patients with peptic ulcers, the excess risks did not become clear until more than 10 years after exposure. Thus, a possible explanation for the lack of any definite hazard from the US regimens of the 1980s in previous analyses of SEER data (some of which truncated data after only 12 years to compare the 1980s with the 1970s without bias)8 is that the follow-up is not yet long enough.17 We have therefore reanalysed the risks of heart disease and lung cancer in the latest data from the SEER cancer registries, with Laterality of breast cancer Left-sided Number of women
Right-sided Number given radiotherapy (%)
Number of women
Number given radiotherapy (%)
Localised breast cancer, by year and type of surgery 1973–82 18 101 1983–92, not BCS 21 168 1993–2001, not BCS 19 299 1983–92, BCS 10 753 1993–2001, BCS 30 141
2382 (13%) 1102 (5%) 1298 (7%) 8484 (79%) 23 902 (79%)
16 929 20 137 18 628 10 240 29 177
2239 (13%) 1054 (5%) 1306 (7%) 8019 (78%) 23 154 (79%)
Regional breast cancer, by year and type of surgery 1973–82 15 795 1983–92, not BCS 15 637 1993–2001, not BCS 15 000 1983–92, BCS 3175 1993–2001, BCS 9089
5164 (33%) 2805 (18%) 4512 (30%) 2487 (78%) 6686 (74%)
14 819 14 963 14 179 3069 8562
4823 (33%) 2752 (18%) 4348 (31%) 2410 (79%) 6238 (73%)
78 422 23 158 56 578
29 883 (38%) 10 175 (44%) 18 764 (33%)
75 752 20 941 54 010
28 745 (38%) 9412 (45%) 18 186 (34%)
43 407 38 921 40 773 35 057
17 405 (40%) 15 625 (40%) 14 784 (36%) 11 008 (31%)
42 345 36 849 38 613 32 896
16 948 (40%) 14 887 (40%) 14 119 (37%) 10 389 (32%)
135 079 12 248 10 831 158 158
50 291 (37%) 4350 (36%) 4181 (39%) 58 822 (37%)
128 757 11 410 10 536 150 703
48 097 (37%) 4188 (37%) 4058 (39%) 56 343 (37%)
Location of breast cancer Outer quadrants (including centre and tail) Inner quadrants (upper or lower) Both quadrants (inner and outer) or unknown Age at diagnosis (years) 20–49 50–59 60–69 70–79 Ethnic origin White Black Other, or unknown Overall total
BCS=breast-conserving surgery (recorded only from 1983).
Table 1: Characteristics of study population by laterality of breast cancer
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particular emphasis on the periods 10–14 years and 15 or more years after exposure.
Methods Materials The SEER programme of the US National Cancer Institute began registering cancer incidence for about 10% of the US population in 1973. Since then its coverage has increased,18 and it currently registers cancer incidence and subsequent cause-specific mortality in 26% of the US population. Women were potentially eligible for the present study if they were registered in SEER during 1973–2001 with local or regional breast cancer of known laterality diagnosed at age 20–79 years, and had no previous cancer registered. Women with bilateral breast cancer and those registered only as a result of breast cancer being found at autopsy or mentioned on the death certificate were not included. Since 1973, SEER has recorded tumour laterality and whether radiotherapy was given, but not which sites were irradiated. BCS was uncommon during the 1970s but became common during the early 1980s and, since 1983, SEER has also recorded whether BCS was done. Cause-specific mortality in SEER involves only the routine International Classification of Disease (ICD) coding of the certified underlying cause of death.19 The SEER public-use data set20 subdivides cardiac mortality during 1973–2000 (but not 2001) according to whether the certified cause involved acute myocardial infarction (ICD-9 410), other ischaemic heart disease (ICD-9 411–414), or other heart disease. A study of patients with breast cancer in Sweden21 suggested that all three of these categories of heart disease might be affected by radiotherapy. Although the laterality of a fatal lung cancer is not usually available from the death certificate, laterality is generally available if the lung cancer was also registered in SEER as a histologically confirmed second primary. Our main lung cancer analyses are therefore of cancers thus registered.
Statistical methods Each woman’s contribution to the person-years at risk began from the date of breast cancer diagnosis to Jan 1, 2002, or to the date of death, loss to follow-up, or 85th birthday—whichever was earliest. Mortality ratios were estimated by Poisson regression with stratification by ethnic origin and, in 5-year groups, by age, year of diagnosis, and time since diagnosis. Poisson regression was used to test mortality ratios for departure from one. Tests for trend and heterogeneity used weighted least squares, assuming Poisson variation. Significance tests for differences and trends were two-sided and, for consistency with previous reports,2,3 the corresponding significance levels are referred to as 2p. Significance tests for heterogeneity are one-sided, and the corresponding significance levels are referred to as p. Calculations were done with STATA version 6. http://oncology.thelancet.com Vol 6 August 2005
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Role of the funding source The study sponsors had no role in the study design; in the collection, analysis, and interpretation of data; or in the writing of the report. All the authors had full access to the data in the study and were jointly responsible for the decision to submit for publication.
Results Of 318 293 potentially eligible women, 6859 (2%) had radiotherapy status unknown, 654 (1%) had received only brachytherapy implants or radiation of unknown type, 1919 (1%) had no information on survival, and 308 861 (97%) were included. Of the included women, 115 165 (37%) were recorded as having received external-beam radiotherapy as part of the initial treatment for breast cancer. Of those known to have died before 2002, the certified cause was available for 26 216 (96%) of the 27 400 irradiated women and 65 033 (95%) of the 68 302 unirradiated women. The proportion of women who were irradiated varied substantially with age, stage, calendar year, tumour location, and type of surgery, being particularly common after BCS (table 1). Within every particular category of any of these characteristics, however, the proportion of women irradiated was virtually identical in those with left-sided and those with right-sided breast cancer, indicating that in this population tumour laterality had little effect on whether or not radiotherapy was given (table 1). Hence, the relationship among irradiated women between tumour laterality and subsequent cardiac mortality can be used to help assess the cardiotoxicity of previous radiotherapy regimens. Likewise, the relationship between breast cancer laterality and the laterality of any subsequent lung cancers can be used to help assess the
extent to which previous radiotherapy regimens could cause lung cancer.
Breast cancer laterality versus subsequent cardiac mortality Among women who had not been irradiated, when the cardiac mortality in those with left-sided breast cancer was compared with the cardiac mortality in those with rightsided breast cancer, the cardiac mortality ratio, left versus right tumour laterality, was close to one (1·03 [95% CI 0·99–1·07]), and there was no significant trend in this ratio with time since diagnosis (2p=0·83). By contrast, among irradiated women the cardiac mortality ratio, left versus right tumour laterality, was significantly greater than one (1·16 [1·08–1·24], 2p=0·00004). The ratio increased steeply with time since diagnosis of breast cancer, which is effectively time since irradiation (trend: 2p=0·0001), and was highly significantly greater than one during the periods 10–14 years and 15 years or more after diagnosis (figure 1). When different categories of heart disease were analysed separately, the mortality ratios, left versus right tumour laterality, among irradiated women during the period 10 years or more after diagnosis of breast cancer for acute myocardial infarction, for other ischaemic heart disease, and for other heart disease (table 2) did not differ significantly from each other. Furthermore, the distinction between these different types of heart disease on death certificates is often somewhat arbitrary, so subsequent analyses are of overall cardiac mortality. During the period 10 years or more after diagnosis, the cardiac mortality ratio, left versus right tumour laterality, among irradiated women did not vary significantly by: stage of breast cancer (either overall or among women diagnosed during 1973–82); stage and type of surgery
No radiotherapy Years since breast cancer diagnosis
Number of deaths left/right
Radiotherapy Mortality ratio, left-sided vs right-sided (95% Cl)
Number of deaths left/right
Mortality ratio, left-sided vs right-sided (95% Cl)
Death from heart disease 5 years
2164/1972
1·03 (0·97–1·09)
700/633
1·04 (0·93–1·15)
5–9
1632/1479
1·05 (0·98–1·13)
521/442
1·10 (0·97–1·25)
10–14
806/758
1·01 (0·91–1·11)
281/197
1·37 (1·14–1·64)
15
568/524
1·02 (0·91–1·15)
254/162
1·53 (1·25–1·86)
14 775/13 522
1·04 (1·01–1·06)
6911/6516
1·01 (0·98–1·05)
5–9
8009/7863
0·97 (0·94–1·00)
3178/2990
1·01 (0·96–1·06)
10–14
3472/3343
0·99 (0·94–1·04)
1165/1095
1·01 (0·93–1·10)
15
2106/2040
0·98 (0·92–1·04)
611/560
1·04 (0·93–1·17)
Death from all other known causes 5 years
0
0·5
1·0
1·5
2·0
0
0·5
1·0
1·5
2·0
Figure 1: Left-sided versus right-sided breast cancer: subsequent mortality ratios by radiotherapy status, cause, and years since diagnosis
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Cause of death (ICD-9 code)
Number of deaths (left/right)
Heart disease* Total Acute myocardial infarction (410) Other ischaemic heart disease (411–414) Other (390–8, 402, 404, 415–29) Lung cancer (162, excluding 162.0 trachea)† Total Right-sided Left-sided Unspecified, bilateral, or without histological confirmation in SEER All other known causes Total Breast cancer (174) Other known causes Circulatory (390–448), excluding heart* Haemorrhagic stroke (430–432) Ischaemic stroke (433–435) Unspecified stroke (436–438) All other circulatory disease Pneumonia or chronic lung disease (480–496) Cancer of corpus uteri (182) Alzheimer’s disease (331·0) 88 other causes, all with 2p0·10
Mortality ratio, left-sided vs right sided (95% CI)
Significance (2p)
535/359 135/91 185/113 157/119
1·44 (1·26–1·65) 1·43 (1·10–1·87) 1·60 (1·26–2·02) 1·26 (0·99–1·60)
0·00001 0·008 0·0001 0·06
130/127 39/67 55/26 36/34
0·98 (0·76–1·25) 0·55 (0·37–0·82) 2·08 (1·30–3·33) 0·99 (0·62–1·58)
0·86 0·003 0·002 0·96
1646/1528 850/871 796/657 118/95 12/16 13/6 58/33 25/28 129/110 13/3 29/14 507/435
1·02 (0·95–1·10) 0·92 (0·84–1·01) 1·16 (1·04–1·28) 1·19 (0·91–1·56) 0·71 (0·33–1·50) 2·05 (0·78–5·41) 1·68 (1·09–2·58) 0·87 (0·51–1·50) 1·12 (0·87–1·45) 4·08 (1·16–14·32) 1·98 (1·04–3·75) 1·11 (0·98–1·26)
0·52 0·10 0·006 0·20 0·37 0·15 0·02 0·62 0·37 0·03 0·04 0·11
hazard compared with women diagnosed during 1973–82 (trend across three periods of diagnosis: 2p=0·04). For women diagnosed during 1983–92 and irradiated, however, there was only a limited amount of follow-up during the second decade after diagnosis, and the cardiac mortality ratio, left versus right tumour laterality, during this second decade was 1·27 (0·99–1·63). This ratio is based mainly on deaths 10–14 years after diagnosis, and its confidence limits are so wide that it is uninformative. Therefore, it is not yet possible to determine directly just from these data how much excess cardiac mortality will eventually occur among women irradiated during 1983–92, a period when much of the radiotherapy given was after BCS and when improvements in radiotherapy planning would have tended to result in progressively lower cardiac doses.12,13 The women diagnosed during 1993–2001 have not yet been followed for 10 years, so no direct information on their late cardiac mortality is yet available, although there is other evidence that mean cardiac doses had been continuing to decrease.22–24
Mortality from ipsilateral lung cancer *Subdivisions of heart disease and of other circulatory diseases available up to 2000, but not for available for 2001. †Lung-cancer mortality: 122 ipsilateral (55 left-sided breast tumour, 67 right-sided breast tumour) versus 65 contralateral (39 left-sided breast tumour, 26 right-sided breast tumour); ratio 1·88 (1·39–2·54), 2p=0·00004.
Table 2: Relevance of breast cancer laterality to cause-specific mortality among irradiated women 10 years or longer after breast cancer diagnosis and irradiation
among women diagnosed during 1983–92; tumour location (ie, outer or inner breast quadrants); age at breast cancer diagnosis; or ethnic origin (table 3). Such analyses are, however, not particularly powerful, and some real variation in these mortality ratios cannot be ruled out.
Cardiac mortality ratios by period of breast cancer diagnosis and years since diagnosis Even if radiotherapy after mastectomy and after BCS are considered separately, there are substantial differences between the US radiotherapy regimens of the 1970s and those of the 1990s. Hence the relevance of time since radiotherapy must be studied separately among women treated in different time periods. For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio, left versus right tumour laterality, was 1·20 (1·04–1·38, 2p=0·01) during the first decade after diagnosis, 1·42 (1·11–1·82, 2p=0·005) during years 10–14, and 1·58 (1·29–1·95, 2p0·0001) after 15 or more years (trend: 2p=0·03, figure 2). Thus there is clear evidence of substantial hazard, particularly in the second decade after irradiation. For women diagnosed during 1983–92 or 1993–2001, and irradiated, the cardiac mortality ratios, left versus right tumour laterality, during only the first decade after diagnosis were 1·04 (0·91–1·18) and 0·96 (0·82–1·12), respectively, indicating a reduction in any early cardiac 560
Our main analyses of lung cancer mortality (figure 3) involve only those deaths where the disease was recorded by the SEER cancer registries as a unilateral primary lung cancer of known laterality with histological confirmation. Other deaths attributed on the death certificate to lung cancer (particularly during the first decade) could include a substantial proportion of miscertified deaths that were actually due to pulmonary metastases from the previous breast cancer. Among unirradiated women the lung cancer mortality ratio, ipsilateral versus contralateral, was 0·96 (0·85–1·08), and there was no significant trend in this ratio with time since diagnosis of breast cancer (trend: 2p=0·18). Among irradiated women, however, the lung cancer mortality ratio, ipsilateral versus contralateral, was 1·42 (1·19–1·70, 2p=0·0001, based on 283 ipsilateral versus 199 contralateral unilateral lung cancers). Among women diagnosed during 1973–82 and then irradiated, the lung cancer mortality ratio, ipsilateral versus contralateral, increased with time since diagnosis of breast cancer (trend: 2p=0·04), with no significant excess during the first decade but with a substantial and highly significant excess during the second decade after diagnosis. Among those diagnosed 15 or more years earlier and irradiated the mortality ratio, ipsilateral versus contralateral, was 2·71 (57 vs 21 lung cancer deaths), but with a wide 95% CI (1·65–4·48, figure 3). For women diagnosed during 1983–92 and irradiated there was for lung cancer, as for heart disease, only limited information on mortality rates during the second decade after diagnosis, and for women diagnosed during 1993–2001 there was none. Overall, the lung cancer mortality ratio, ipsilateral versus contralateral, 10 or more years after irradiation did not vary significantly by: http://oncology.thelancet.com Vol 6 August 2005
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stage of breast cancer (either overall, or among women diagnosed during 1973–82); stage and type of surgery among women diagnosed during 1983–92; tumour location in the breast (ie, outer or inner quadrants); age at breast cancer diagnosis; or ethnic origin (table 3).
Mortality from other causes The mortality ratio, left versus right breast cancer laterality, was close to one for the aggregate of all causes of death other than heart disease or lung cancer both in unirradiated women and in irradiated women (mortality ratios 1·01 (0·99–1·02) based on 27 402 versus 25 858 deaths in unirradiated women, and 1·02 (0·99–1·04) based on 11 487 versus 10 778 deaths in irradiated women, respectively). The biggest contributor to these deaths was, of course, breast cancer, even 10 or more years after diagnosis (table 2). Taking all time periods together, the breast cancer mortality ratio, left versus right tumour laterality, was close to one both in unirradiated and in irradiated women (unirradiated: 1·01 [0·99–1·03] based on 18 239 versus 17 191 deaths; irradiated: 1·00 [0·97–1·03] based on 8477 versus 8087 deaths). There was a slight tendency for the breast cancer mortality ratio, left versus right tumour laterality, to decrease with time since diagnosis, and this trend was similar in unirradiated and in irradiated women (trends: 2p=0·02 and 2p=0·03, respectively, considering time periods 5, 5–9, 10–14, and 15 years after
diagnosis) so it might, if real, reflect some slight physiological differences between left and right. The mortality ratio, left versus right tumour laterality, among unirradiated women for deaths attributed to all known causes other than heart disease, lung cancer, or breast cancer was 1·00 (0·97–1·03). In the irradiated group this mortality ratio was 1·03 (0·97–1·09) less than 10 years after diagnosis and 1·16 (1·04–1·28, 2p=0·006) 10 or more years after diagnosis. If, however, due allowance is made for multiple-hypothesis testing, for the cardioembolic origin of some ischaemic strokes, and for the possible misclassification of some cardiac deaths (eg, as fatal stroke of unspecified aetiology, or as respiratory disease), there was no clear evidence that breast cancer laterality was associated with any particular cause of death other than heart disease, lung cancer, or breast cancer (table 2).
Discussion We have shown that, in women recorded in the US SEER cancer registries as having been diagnosed with breast cancer during 1973–82 and irradiated, mortality from heart disease was increased among women with left-sided breast tumours compared with women with right-sided breast tumours. In these same women, mortality from cancer of the ipsilateral lung was increased compared with mortality from cancer of the contralateral lung. For both heart disease and ipsilateral
Heart disease
Lung cancer
Number of deaths (left/right)
Mortality ratio, left-sided vs right-sided (95% CI)
Number of deaths (ipsilateral/contralateral)
Mortality ratio, ipsilateral vs contralateral (95% CI)
Diagnosed 1973–82 Localised Regional 2p for difference
131/90 260/161
1·44 (1·10–1·88) 1·59 (1·30–1·94) 0.55
42/15 39/18
2·80 (1·55–5·05) 2·17 (1·24–3·79) 0·54
Diagnosed 1983–92 Localised, BCS Localised, not BCS Regional, BCS Regional, not BCS p for heterogeneity
75/60 21/11 26/13 22/24
1·18 (0·84–1·66) 2·14 (1·01–4·52) 1·93 (0·98–3·79) 0·89 (0·50–1·60) 0·18
26/17 3/6 8/4 4/5
1·53 (0·83–2·82) 0·50 (0·13–2·00) 2·00 (0·60–6·64) 0·80 (0·21–2·98) 0·37
Location of breast cancer Outer quadrants (including centre and tail) Inner quadrants (upper or lower) Other or unknown p for heterogeneity
206/138 110/68 219/153
1·48 (1·19–1·84) 1·58 (1·16–2·16) 1·36 (1·11–1·68) 0·71
47/25 21/17 54/23
1·88 (1·16–3·05) 1·24 (0·65–2·34) 2·35 (1·44–3·82) 0·29
Age at breast-cancer diagnosis (years) 20–49 50–59 60–69 70–79 2p for trend
82/50 154/97 241/167 58/45
1·54 (1·08–2·19) 1·53 (1·19–1·98) 1·40 (1·15–1·70) 1·28 (0·87–1·90) 0·40
49/18 38/33 35/13 0/1
2·72 (1·59–4·67) 1·15 (0·72–1·84) 2·69 (1·42–5·09) ·· 0·75
Ethnic origin White Black Other/unknown p for heterogeneity
461/315 50/23 24/21
1·39 (1·21–1·61) 2·25 (1·36–3·72) 1·30 (0·71–2·39) 0·19
110/51 9/11 3/3
2·16 (1·55–3·01) 0·82 (0·34–1·97) 1·00 (0·20–4·95) 0·10
BCS=breast-conserving surgery.
Table 3: Relevance of breast cancer laterality to mortality from heart disease and lung cancer 10 years or longer after breast cancer diagnosis and irradiation
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Years from breast cancer diagnosis to cardiac death
No radiotherapy
Radiotherapy
Cardiac deaths left/right
Cardiac mortality ratio, left-sided vs right-sided (95% Cl)
Cardiac deaths left/right
Cardiac mortality ratio, left-sided vs right-sided (95% Cl)
5 years
717/679
0·98 (0·89–1·09)
230/180
1·19 (0·98–1·45)
5–9
673/614
1·04 (0·93–1·15)
189/145
1·21 (0·97–1·50)
10–14
469/441
1·00 (0·87–1·13)
157/106
1·42 (1·11–1·82)
15
515/480
1·01 (0·89–1·15)
234/145
1·58 (1·29–1·95)
5 years
880/785
1·06 (0·96–1·16)
245/227
1·00 (0·84–1·20)
5–9
815/729
1·07 (0·97–1·18)
249/218
1·08 (0·90–1·29)
10
390/361
1·04 (0·90–1·20)
144/108
1·27 (0·99–1·63)
5 years
567/508
1·05 (0·93–1·18)
225/226
0·95 (0·79–1·14)
5–9
144/136
1·02 (0·81–1·29)
83/79
0·99 (0·73–1·35)
Diagnosed 1973–82
Diagnosed 1983–92
Diagnosed 1993–2001
0
0·5
1·0
1·5
2·0
0
0·5
1·0
1·5
2·0
Figure 2: Left-sided versus right-sided breast cancer: subsequent cardiac mortality ratios by radiotherapy status, period of diagnosis, and years from breast cancer diagnosis to cardiac death
lung cancer these increases, which are likely to be caused by radiation, were larger during the second decade after the diagnosis of the breast cancer than during the first decade. As yet, there is little information on the magnitude of any hazard in these women more than 20 years after irradiation. For women recorded in SEER as diagnosed with breast cancer more recently— ie, since the early 1980s—there is, as yet, little information on mortality during the period 10 or more years after the diagnosis of breast cancer.
Assessment of late mortality risks in the general population In the randomised trials of radiotherapy for breast cancer that began before the 1980s there is an appreciable late hazard of heart disease1,2 and lung cancer.4 Outside trials, patients may have been selected for irradiation not only according to their age and the nature of their breast cancer, but also according to factors that are correlated with their prognosis. Therefore, simple comparisons of the subsequent mortality of irradiated and unirradiated patients cannot be used to assess reliably the real benefits and hazards of treatment. In the SEER data, however, the similarity of the proportions of women with left-sided and with rightsided breast cancer who received radiotherapy within many particular categories of stage, calendar year, tumour location, age, and ethnic origin (table 1) suggests that breast cancer laterality played little part in determining who should be given radiotherapy. Also, in unirradiated women, who formed the majority of the 562
population, breast cancer laterality was not associated with mortality from heart disease (figure 2), and mortality from ipsilateral lung cancer was close to that for contralateral lung cancer (figure 3). Hence, the relevance of breast cancer laterality in irradiated women to subsequent mortality from heart disease and from unilateral lung cancer can be used to help assess the long-term hazards of the radiotherapy regimens actually given in this large, and approximately representative, sample of the US population. In the entire female population of the USA, the commonest cause of death is heart disease and the commonest cause of neoplastic death is lung cancer; and the unirradiated women in the SEER population who did not die from breast cancer are no exception (data not shown). Hence, if radiotherapy causes an appreciable proportionate increase in either of these diseases during the period 10 years or longer after breast cancer diagnosis, and particularly if the increase were to persist for some decades, it could well be of greater absolute importance to long-term survival than any other adverse (or even, for some patients, beneficial) effects of the radiotherapy regimens of the 1970s. Fatal ischaemic heart disease commonly originates in the anterior coronary arteries, and the effects of radiotherapy on these arteries may be one of the main reasons for the subsequent increase in cardiac mortality rates. But, deaths caused directly or indirectly by coronary artery disease include not only those attributed to acute myocardial infarction (ICD-9 410) or other ischaemic heart disease (ICD-9 411–414) on the death certificate, http://oncology.thelancet.com Vol 6 August 2005
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Radiotherapy
No radiotherapy Years from breast cancer diagnosis to lung cancer death
Lung cancer deaths (ipsilateral/ contralateral)
Lung cancer deaths Lung cancer mortality ratio, (ipsilateral/ ipsilateral vs contralateral contralateral) (95% Cl)
Lung cancer mortality ratio, ipsilateral vs contralateral (95% Cl)
Diagnosed 1973–82 10 years
77/94
0·82 (0·61–1·11)
21/18
1·17 (0·62–2·19)
10–14
53/60
0·88 (0·61–1·28)
24/12
2·00 (1·00–4·00)
15
98/81
1·21 (0·90–1·62)
57/21
2·71 (1·65–4·48)
152/181
0·84 (0·68–1·04)
74/67
1·10 (0·79–1·54)
65/53
1·23 (0·85–1·76)
41/32
1·28 (0·81–2·03)
67/65
1·03 (0·73–1·45)
66/49
1·35 (0·93–1·95)
Diagnosed 1983–92 10 years 10 Diagnosed 1993–2001 10 years
0
1·0
2·0
0
1·0
2·0
3·0
4·0
Figure 3: Unilateral breast cancer: subsequent ipsilateral versus contralateral lung cancer mortality ratios by radiotherapy status, period of breast cancer diagnosis, and years from breast cancer diagnosis to lung cancer death
but also many of those attributed to other cardiac disease. Hence, the absolute cardiac hazard would be somewhat underestimated by analyses restricted to ICD 410–414,8 and would be substantially underestimated by analyses restricted only to ICD 410 (table 2).7
Cardiac risks from US radiotherapy regimens of the 1970s and early 1980s Among women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio, left versus right tumour laterality, after 10 or more years was about 1·5 (figure 2). If there were no cardiac risk at all from irradiation for right-sided tumours, this finding would indicate that the proportionate increase in risk produced by irradiation for left-sided tumours was about 50%. Irradiation for right-sided tumours can, however, also involve some cardiac exposure, so it may also have led to some cardiac hazard. If, for example, radiotherapy for right-sided tumours led to an increase in the cardiac hazard one third as great as that from radiotherapy for left-sided tumours, then a cardiac mortality ratio, left versus right tumour laterality, of 1·5 during the second decade after irradiation would indicate a doubling of cardiac risk for irradiation versus no irradiation for leftsided tumours, and an increase of one third for irradiation versus no irradiation for right-sided tumours. In atomic bomb survivors and in patients with peptic ulcers, the radiation-related excess of heart disease was not apparent until more than a decade after exposure.14,16 Likewise, in the SEER data the excess cardiac risk occurs chiefly after the first decade. The present evidence of http://oncology.thelancet.com Vol 6 August 2005
hazard relates chiefly to the 20-year risks of the postmastectomy radiotherapy regimens used in the USA during the 1970s (when BCS was still uncommon), and to the 15-year risks of the regimens used in the USA during the early 1980s, when BCS was first becoming common. At that time it was still usual to irradiate the ipsilateral internal mammary chain (IMC) of lymph nodes after BCS,22 which can lead to relatively high cardiac doses, especially for left-sided tumours.25–27 It will, however, be 2010 or 2020 before there can be direct evidence of the 30-year and 40-year risks and benefits from the radiotherapy regimens used during the 1970s in various populations. Likewise, direct evidence of the 20-year risks and benefits from the regimens used more recently will not become available until about 2010 (for the regimens of the late 1980s) or 2020 (for those of the 1990s).
Cardiac doses and risks from current radiotherapy regimens Contemporary radiotherapy techniques can involve substantially lower cardiac exposures than those used previously. This situation has been achieved partly by omitting irradiation of the IMC in most patients. When an ipsilateral IMC field is used, however, an estimate dating from 2000 suggests that the mean cardiac dose could still be around 4–8 Gy for tumours of the left breast (with part of the heart receiving more than 20 Gy in some patients), and 2–4 Gy for tumours of the right breast.5 Although irradiation of the IMC in axillary node-negative breast cancer is now uncommon in the USA,23 a survey carried out in 2001 indicated that about 20% of US and 563
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6% of UK radiation oncologists would still generally have irradiated the IMC in women with axillary node-positive disease following either BCS or mastectomy,28 and in some other countries the proportion was still over 50%.28 Also, even if an IMC field is not used, other radiotherapy fields can deliver appreciable doses to parts of the heart. Indeed, studies from the 1990s showed that some patients with left-sided tumours who were irradiated with a tangential opposed pair of megavoltage beams would still receive doses of more than 20 Gy to at least a small proportion of the cardiac volume, probably including part of the left anterior descending coronary artery, which is one of the most important sites of origin of fatal ischaemic heart disease.12,13
Lung cancer risks and doses Radiation-induced lung cancer after radiotherapy for breast cancer has already been found to have a long natural history, with much less hazard during the first decade than later.6,9,10 In the present analysis, among women diagnosed with breast cancer during 1973–82 and then irradiated, there were 81 deaths from ipsilateral lung cancer 10 years or more after breast cancer diagnosis and 33 deaths from contralateral lung cancer, indicating a mortality ratio (irradiated versus unirradiated) of about 2, but with wide confidence limits. If there were no effect at all on contralateral lung cancer, such a two-fold ratio would correspond to a doubling of ipsilateral lung cancer (ie, a 50% increase in lung cancer as a whole) during the second decade after irradiation. Mean lung doses to women irradiated for breast cancer during this period could well, however, have been around 15 Gy for the ipsilateral lung and about a third of this dose for the contralateral lung.6 If the excess risk is about three times as great in the ipsilateral as in the contralateral lung, then a two-fold mortality ratio (ipsilateral versus contralateral) would correspond to a quadrupling of ipsilateral lung cancer and a doubling of contralateral lung cancer (ie, a tripling of lung cancer as a whole). As with the heart, irradiated lung volumes and mean doses to the entire lung, have probably decreased appreciably in recent years, but estimates based on radiotherapy techniques dating from about 2000 suggest that the mean ipsilateral lung dose was still around 10 Gy.29,30 Such exposures would probably carry an appreciable absolute risk of lung cancer, particularly among smokers.9,31
Conclusion For both cardiac mortality and lung cancer mortality, the absolute hazards depend on the background hazards (ie, heart disease and lung cancer death rates that would have occurred anyway in future decades), on how the relative risks will evolve during the second, third, and even fourth decade of follow-up, and on how likely the patient is to survive long enough to incur those risks. The experience of atomic bomb survivors suggests that, after the first decade, the radiation-induced relative risks 564
of heart disease and lung cancer remain approximately constant for some decades.14,15 If the same is true for breast cancer radiotherapy, then the long-term hazards of regimens that were commonly used 20 or more years ago in the USA will eventually substantially offset the definite reduction2 that radiotherapy produces in late mortality from breast cancer. Since then, improvements in radiotherapy planning should have reduced such risks, but the long-term population hazards still need monitoring directly in various different populations. In the USA, the periodic national surveys22,23 of the characteristics of radiotherapy given after BCS show substantial changes in practice that reduce, but do not eliminate, exposure to the heart and lungs. Such changes must also have happened, to varying extents, in other countries. Nationally representative periodic surveys of routine practice in breast cancer radiotherapy could monitor such changes and accelerate the worldwide dissemination of appropriate practice in deciding which patients with breast cancer to irradiate and how best to irradiate them. For the foreseeable future, however, there is likely to be some unwanted exposure, involving potential hazards of heart disease and lung cancer. In many populations both these hazards could be monitored from routine cancer registration and mortality records if, as with SEER, cancer registries routinely record tumour laterality and whether or not radiotherapy was given, and if routine follow-up to ascertain vital status and cause of death is possible. Over the next few decades, such monitoring would eventually provide direct evidence of the main lifelong hazards (after three or four decades of follow-up) of the radiotherapy of a few decades ago and direct evidence of the main 20-year hazards of the radiotherapy that is being used now in various different countries. Contributors All authors contributed substantially to this study. Conflict of interest We declare no conflicts of interest. Acknowledgments The SEER cancer registries are funded by the US National Cancer Institute, and many thousands of medical staff, over several decades, have consistently registered new patients. This study was funded by the long-term support to the CTSU from Cancer Research UK, the UK Medical Research Council, and the British Heart Foundation. References 1 Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994; 12: 447–53. 2 Early Breast Cancer Trialists Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000; 355: 1757–70. 3 Early Breast Cancer Trialists Collaborative Group. Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials. N Engl J Med 1995; 333: 1444–55. 4 Deutsch M, Land SR, Begovic M, et al. The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Cancer 2003; 98: 1362–68.
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Sautter-Bihl M, Hultenschmidt B, Melcher U, Ulmer HU. Radiotherapy of internal mammary lymph nodes in breast cancer. Strahlenther Onkol 2002; 178: 18–24. Inskip PD, Stovall M, Flannery JT. Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 1994; 86: 983–88. Paszat LF, Mackillop WJ, Groome PA, et al. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 1998; 16: 2625–31. Giordano SH, Kuo Y-F, Freeman JL, et al. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 2005; 97: 419–24. Neugut AI, Murray T, Santos J, et al. Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer 1994; 73: 1615–20. Travis LB, Curtis RE, Inskip PD, Hankey BF. Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 1995; 87: 60–61. Zablotska LB, Neugut AI. Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma. Cancer 2003; 97: 1404–11. Fuller SA, Haybittle JL, Smith RE, Dobbs HJ. Cardiac doses in post-operative breast irradiation. Radiother Oncol 1992; 25: 19–24. Gyenes G, Gagliardi G, Lax I, et al. Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy. J Clin Oncol 1997; 15: 1348–53. Preston DL, Shimizu Y, Pierce DA, et al. Studies of mortality of atomic bomb survivors. Report 13: solid cancer and non-cancer disease mortality, 1950–1997. Radiat Res 2003; 160: 381–407. Pierce DA, Sharp GB, Mabuchi K. Joint effects of radiation and smoking on lung cancer risk among atomic bomb survivors. Radiat Res 2003; 159: 511–20. Carr ZA, Land CE, Kleinerman RA, et al. Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys 2005; 61: 842–50. Cuzick J. Radiotherapy for breast cancer. J Natl Cancer Inst 2005; 97: 406–07. Hankey BF, Ries LA, Edwards BK. The Surveillance, Epidemiology, and End Results Program: a national resource. Cancer Epidemiol, Biomarkers Prev 1999; 8: 1117–21. World Health Organisation. Manual of the international statistical classification of diseases, injuries and causes of death, 9th revision. Geneva: World Health Organisation, 1975. Surveillance, Epidemiology, and End Results (SEER) Program. Public-use data (1973–2001), National Cancer Institute, DCCPS,
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Surveillance Research Program, Cancer Statistics Branch. www.seer.cancer.gov (released April, 2004, based on November, 2003, submission, and accessed June 24, 2004). Public-use data (1973–2000), released April, 2003, based on November, 2002, submission, accessed Nov 21, 2003. Darby S, McGale P, Peto R, et al. Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90 000 Swedish women. BMJ 2003; 326: 256–57. Solin LJ, Fowble BL, Martz KL, et al. Results of the 1983 patterns of care process survey for definitive breast irradiation. Int J Radiat Oncol Biol Phys 1991; 20: 105–11. Shank B, Moughan J, Owen J, et al. The 1993–94 patterns of care process survey for breast irradiation after breast-conserving surgery—comparison with the 1992 standard for breast conservation treatment. Int J Radiat Oncol Biol Phys 2000; 48: 1291–99. Hurkmans CW, Borger JH, Bos LJ, et al. Cardiac and lung complication probabilities after breast cancer irradiation. Radiother Oncol 2000; 55: 145–51. Krueger EA, Schipper MJ, Koelling T, et al. Cardiac chamber and coronary artery doses associated with postmastectomy radiotherapy techniques to the chest wall and regional nodes. Int J Radiat Oncol Biol Phys 2004; 60: 1195–203. Janjan NA, Gillin MT, Prows J, et al. Dose to the cardiac vascular and conduction systems in primary breast irradiation. Med Dosimetry 1989; 14: 81–87. Pierce LJ, Butler JB, Martel MK, et al. Postmastectomy radiotherapy of the chest wall: dosimetric comparison of common techniques. Int J Radiat Oncol Biol Phys 2002; 52: 1220–30. Taghian A, Jagsi R, Makris A, et al. Results of a survey regarding irradiation of internal mammary chain in patients with breast cancer: practice is culture driven rather than evidence based. Int J Radiat Oncol Biol Phys 2004; 60: 706–14. Kong FM, Klein EE, Bradley JD, et al. The impact of central lung distance, maximal heart distance, and radiation technique on the volumetric dose of the lung and heart for intact breast radiation. Int J Radiat Oncol Biol Phys 2002; 54: 963–71. Lind P, Wennberg B, Gagliardi G, Fornander T. Pulmonary complications following different radiotherapy techniques for breast cancer, and the association to irradiated lung volume and dose. Breast Cancer Res Treat 2001; 68: 199–210. Ford MB, Sigurdson AJ, Petrulis ES, et al. Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer 2003; 98: 1457–64.
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Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries Sarah C Darby, Paul McGale, Carolyn W Taylor, Richard Peto
Summary Background Radiotherapy for early breast cancer can decrease breast cancer mortality but increase other mortality, mainly from heart disease and lung cancer. The mean cardiac dose from irradiation of a left-sided breast cancer can be two or three times that for a right-sided breast cancer. The mean ipsilateral (ie, on the same side as the breast cancer) lung dose can also be two or three times the mean contralateral lung dose. Particularly during the 1970s, when typical heart and lung exposures were greater than now, the laterality of an irradiated breast cancer could measurably affect cardiac mortality and mortality from cancer of the right or the left lung decades later. This study aimed to assess the hazards in the general US population from routine cancer-registry and death-certificate data. Methods We analysed data for 308 861 US women with early breast cancer of known laterality (left-sided or rightsided) who were registered in the US Surveillance Epidemiology and End Results (SEER) cancer registries during 1973–2001 and followed prospectively for cause-specific mortality until Jan 1, 2002. Findings 115 165 (37%) received radiotherapy. Among those who did not, tumour laterality was of little relevance to subsequent mortality. For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio (left versus right tumour laterality) was 1·20 (95% CI 1·04–1·38) less than 10 years afterwards, 1·42 (1·11–1·82) 10–14 years afterwards, and 1·58 (1·29–1·95) after 15 years or more (trend: 2p=0·03). For women diagnosed during 1983–92 and irradiated, the cardiac mortality ratio was 1·04 (0·91–1·18) less than 10 years afterwards and 1·27 (0·99–1·63) 10 or more years afterwards. For women diagnosed during 1993–2001 and irradiated the cardiac mortality ratio was 0·96 (0·82–1·12), with none yet followed for 10 years. Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973–82 and irradiated was 1·17 (0·62–2·19), 2·00 (1·00–4·00), and 2·71 (1·65–4·48), respectively, less than 10 years, 10–14 years, and 15 or more years afterwards (trend: 2p=0·04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards.
Lancet Oncol 2005; 6: 557–65 See Reflection and Reaction page 539 Published online July 5, 2005 DOI:10.1016/S1470-2045(05) 70251-5 Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK (Prof S C Darby PhD, P McGale PhD, C W Taylor FRCR, Prof R Peto FRS) Correspondence to: Prof Sarah Darby, CTSU, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, UK [email protected]
Interpretation US breast cancer radiotherapy regimens of the 1970s and early 1980s appreciably increased mortality from heart disease and lung cancer 10–20 years afterwards with, as yet, little direct evidence on the hazards after more than 20 years. Since the early 1980s, improvements in radiotherapy planning should have reduced such risks, but the long-term hazards in the general populations of various countries still need to be monitored directly.
Introduction Although radiotherapy for early breast cancer can reduce the risk of death from the disease several years later, it usually involves some irradiation of the heart or lungs, and some of the breast cancer radiotherapy regimens used during previous decades could increase the risks of heart disease and lung cancer many years after treatment.1–4 Regimens that incidentally irradiate the heart will generally do so to a greater extent when used to treat left-sided breast cancer than when used to treat right-sided breast cancer. Likewise, those that incidentally irradiate the lung will generally affect the ipsilateral lung (ie, on the same side as the breast cancer) more than the contralateral lung. These differences in exposure can be substantial: for example, the mean dose to the heart or to one of the lungs may differ by a factor of two or three, depending on the laterality (ie, left or right) of the breast tumour.5,6 Some indication of the http://oncology.thelancet.com Vol 6 August 2005
extent to which the radiotherapy regimens of the 1970s or early 1980s were causing mortality from heart disease and lung cancer 10–20 years later in the general population of patients with breast cancer can, therefore, be obtained from routine cancer-registry data that recorded the use or otherwise of radiotherapy for any breast cancers, the laterality of those breast cancers and of any subsequent primary lung cancers, and the certified causes of any deaths during the first and, particularly, subsequent decades after treatment. The US Surveillance Epidemiology and End Results (SEER) cancer registries have, since 1973, covered in this way a substantial proportion of the US population. Increases in heart disease7,8 and lung cancer9–11 after radiotherapy for breast cancer have been reported in the SEER data, and the 20-year hazards of the breast cancer radiotherapy regimens used in the 1970s and early 1980s are now becoming clear. However, it is as yet less clear 557
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how much risk there will be from the regimens used since the early 1980s, when the majority of women with early breast cancer started to receive breast-conserving surgery (BCS) plus radiotherapy, often just to the breast. Although cardiac doses and lung doses from radiotherapy have decreased since the 1970s,12,13 some breast cancer radiotherapy techniques used during the 1980s would still have involved mean doses to the heart and ipsilateral lung of several Gray (Gy), so some eventual risk might still be expected. Atomic bomb survivors exposed to single doses of up to 4 Gy had dose-related excess risks decades later of about 17% per Gy for heart disease and 90% per Gy for lung cancer.14,15 Likewise, in patients given fractionated radiotherapy for peptic ulcer disease with mean cardiac doses of up to 4 Gy there was a dose-related increase in late cardiac mortality.16 In atomic bomb survivors and in patients with peptic ulcers, the excess risks did not become clear until more than 10 years after exposure. Thus, a possible explanation for the lack of any definite hazard from the US regimens of the 1980s in previous analyses of SEER data (some of which truncated data after only 12 years to compare the 1980s with the 1970s without bias)8 is that the follow-up is not yet long enough.17 We have therefore reanalysed the risks of heart disease and lung cancer in the latest data from the SEER cancer registries, with Laterality of breast cancer Left-sided Number of women
Right-sided Number given radiotherapy (%)
Number of women
Number given radiotherapy (%)
Localised breast cancer, by year and type of surgery 1973–82 18 101 1983–92, not BCS 21 168 1993–2001, not BCS 19 299 1983–92, BCS 10 753 1993–2001, BCS 30 141
2382 (13%) 1102 (5%) 1298 (7%) 8484 (79%) 23 902 (79%)
16 929 20 137 18 628 10 240 29 177
2239 (13%) 1054 (5%) 1306 (7%) 8019 (78%) 23 154 (79%)
Regional breast cancer, by year and type of surgery 1973–82 15 795 1983–92, not BCS 15 637 1993–2001, not BCS 15 000 1983–92, BCS 3175 1993–2001, BCS 9089
5164 (33%) 2805 (18%) 4512 (30%) 2487 (78%) 6686 (74%)
14 819 14 963 14 179 3069 8562
4823 (33%) 2752 (18%) 4348 (31%) 2410 (79%) 6238 (73%)
78 422 23 158 56 578
29 883 (38%) 10 175 (44%) 18 764 (33%)
75 752 20 941 54 010
28 745 (38%) 9412 (45%) 18 186 (34%)
43 407 38 921 40 773 35 057
17 405 (40%) 15 625 (40%) 14 784 (36%) 11 008 (31%)
42 345 36 849 38 613 32 896
16 948 (40%) 14 887 (40%) 14 119 (37%) 10 389 (32%)
135 079 12 248 10 831 158 158
50 291 (37%) 4350 (36%) 4181 (39%) 58 822 (37%)
128 757 11 410 10 536 150 703
48 097 (37%) 4188 (37%) 4058 (39%) 56 343 (37%)
Location of breast cancer Outer quadrants (including centre and tail) Inner quadrants (upper or lower) Both quadrants (inner and outer) or unknown Age at diagnosis (years) 20–49 50–59 60–69 70–79 Ethnic origin White Black Other, or unknown Overall total
BCS=breast-conserving surgery (recorded only from 1983).
Table 1: Characteristics of study population by laterality of breast cancer
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particular emphasis on the periods 10–14 years and 15 or more years after exposure.
Methods Materials The SEER programme of the US National Cancer Institute began registering cancer incidence for about 10% of the US population in 1973. Since then its coverage has increased,18 and it currently registers cancer incidence and subsequent cause-specific mortality in 26% of the US population. Women were potentially eligible for the present study if they were registered in SEER during 1973–2001 with local or regional breast cancer of known laterality diagnosed at age 20–79 years, and had no previous cancer registered. Women with bilateral breast cancer and those registered only as a result of breast cancer being found at autopsy or mentioned on the death certificate were not included. Since 1973, SEER has recorded tumour laterality and whether radiotherapy was given, but not which sites were irradiated. BCS was uncommon during the 1970s but became common during the early 1980s and, since 1983, SEER has also recorded whether BCS was done. Cause-specific mortality in SEER involves only the routine International Classification of Disease (ICD) coding of the certified underlying cause of death.19 The SEER public-use data set20 subdivides cardiac mortality during 1973–2000 (but not 2001) according to whether the certified cause involved acute myocardial infarction (ICD-9 410), other ischaemic heart disease (ICD-9 411–414), or other heart disease. A study of patients with breast cancer in Sweden21 suggested that all three of these categories of heart disease might be affected by radiotherapy. Although the laterality of a fatal lung cancer is not usually available from the death certificate, laterality is generally available if the lung cancer was also registered in SEER as a histologically confirmed second primary. Our main lung cancer analyses are therefore of cancers thus registered.
Statistical methods Each woman’s contribution to the person-years at risk began from the date of breast cancer diagnosis to Jan 1, 2002, or to the date of death, loss to follow-up, or 85th birthday—whichever was earliest. Mortality ratios were estimated by Poisson regression with stratification by ethnic origin and, in 5-year groups, by age, year of diagnosis, and time since diagnosis. Poisson regression was used to test mortality ratios for departure from one. Tests for trend and heterogeneity used weighted least squares, assuming Poisson variation. Significance tests for differences and trends were two-sided and, for consistency with previous reports,2,3 the corresponding significance levels are referred to as 2p. Significance tests for heterogeneity are one-sided, and the corresponding significance levels are referred to as p. Calculations were done with STATA version 6. http://oncology.thelancet.com Vol 6 August 2005
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Role of the funding source The study sponsors had no role in the study design; in the collection, analysis, and interpretation of data; or in the writing of the report. All the authors had full access to the data in the study and were jointly responsible for the decision to submit for publication.
Results Of 318 293 potentially eligible women, 6859 (2%) had radiotherapy status unknown, 654 (1%) had received only brachytherapy implants or radiation of unknown type, 1919 (1%) had no information on survival, and 308 861 (97%) were included. Of the included women, 115 165 (37%) were recorded as having received external-beam radiotherapy as part of the initial treatment for breast cancer. Of those known to have died before 2002, the certified cause was available for 26 216 (96%) of the 27 400 irradiated women and 65 033 (95%) of the 68 302 unirradiated women. The proportion of women who were irradiated varied substantially with age, stage, calendar year, tumour location, and type of surgery, being particularly common after BCS (table 1). Within every particular category of any of these characteristics, however, the proportion of women irradiated was virtually identical in those with left-sided and those with right-sided breast cancer, indicating that in this population tumour laterality had little effect on whether or not radiotherapy was given (table 1). Hence, the relationship among irradiated women between tumour laterality and subsequent cardiac mortality can be used to help assess the cardiotoxicity of previous radiotherapy regimens. Likewise, the relationship between breast cancer laterality and the laterality of any subsequent lung cancers can be used to help assess the
extent to which previous radiotherapy regimens could cause lung cancer.
Breast cancer laterality versus subsequent cardiac mortality Among women who had not been irradiated, when the cardiac mortality in those with left-sided breast cancer was compared with the cardiac mortality in those with rightsided breast cancer, the cardiac mortality ratio, left versus right tumour laterality, was close to one (1·03 [95% CI 0·99–1·07]), and there was no significant trend in this ratio with time since diagnosis (2p=0·83). By contrast, among irradiated women the cardiac mortality ratio, left versus right tumour laterality, was significantly greater than one (1·16 [1·08–1·24], 2p=0·00004). The ratio increased steeply with time since diagnosis of breast cancer, which is effectively time since irradiation (trend: 2p=0·0001), and was highly significantly greater than one during the periods 10–14 years and 15 years or more after diagnosis (figure 1). When different categories of heart disease were analysed separately, the mortality ratios, left versus right tumour laterality, among irradiated women during the period 10 years or more after diagnosis of breast cancer for acute myocardial infarction, for other ischaemic heart disease, and for other heart disease (table 2) did not differ significantly from each other. Furthermore, the distinction between these different types of heart disease on death certificates is often somewhat arbitrary, so subsequent analyses are of overall cardiac mortality. During the period 10 years or more after diagnosis, the cardiac mortality ratio, left versus right tumour laterality, among irradiated women did not vary significantly by: stage of breast cancer (either overall or among women diagnosed during 1973–82); stage and type of surgery
No radiotherapy Years since breast cancer diagnosis
Number of deaths left/right
Radiotherapy Mortality ratio, left-sided vs right-sided (95% Cl)
Number of deaths left/right
Mortality ratio, left-sided vs right-sided (95% Cl)
Death from heart disease 5 years
2164/1972
1·03 (0·97–1·09)
700/633
1·04 (0·93–1·15)
5–9
1632/1479
1·05 (0·98–1·13)
521/442
1·10 (0·97–1·25)
10–14
806/758
1·01 (0·91–1·11)
281/197
1·37 (1·14–1·64)
15
568/524
1·02 (0·91–1·15)
254/162
1·53 (1·25–1·86)
14 775/13 522
1·04 (1·01–1·06)
6911/6516
1·01 (0·98–1·05)
5–9
8009/7863
0·97 (0·94–1·00)
3178/2990
1·01 (0·96–1·06)
10–14
3472/3343
0·99 (0·94–1·04)
1165/1095
1·01 (0·93–1·10)
15
2106/2040
0·98 (0·92–1·04)
611/560
1·04 (0·93–1·17)
Death from all other known causes 5 years
0
0·5
1·0
1·5
2·0
0
0·5
1·0
1·5
2·0
Figure 1: Left-sided versus right-sided breast cancer: subsequent mortality ratios by radiotherapy status, cause, and years since diagnosis
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Cause of death (ICD-9 code)
Number of deaths (left/right)
Heart disease* Total Acute myocardial infarction (410) Other ischaemic heart disease (411–414) Other (390–8, 402, 404, 415–29) Lung cancer (162, excluding 162.0 trachea)† Total Right-sided Left-sided Unspecified, bilateral, or without histological confirmation in SEER All other known causes Total Breast cancer (174) Other known causes Circulatory (390–448), excluding heart* Haemorrhagic stroke (430–432) Ischaemic stroke (433–435) Unspecified stroke (436–438) All other circulatory disease Pneumonia or chronic lung disease (480–496) Cancer of corpus uteri (182) Alzheimer’s disease (331·0) 88 other causes, all with 2p0·10
Mortality ratio, left-sided vs right sided (95% CI)
Significance (2p)
535/359 135/91 185/113 157/119
1·44 (1·26–1·65) 1·43 (1·10–1·87) 1·60 (1·26–2·02) 1·26 (0·99–1·60)
0·00001 0·008 0·0001 0·06
130/127 39/67 55/26 36/34
0·98 (0·76–1·25) 0·55 (0·37–0·82) 2·08 (1·30–3·33) 0·99 (0·62–1·58)
0·86 0·003 0·002 0·96
1646/1528 850/871 796/657 118/95 12/16 13/6 58/33 25/28 129/110 13/3 29/14 507/435
1·02 (0·95–1·10) 0·92 (0·84–1·01) 1·16 (1·04–1·28) 1·19 (0·91–1·56) 0·71 (0·33–1·50) 2·05 (0·78–5·41) 1·68 (1·09–2·58) 0·87 (0·51–1·50) 1·12 (0·87–1·45) 4·08 (1·16–14·32) 1·98 (1·04–3·75) 1·11 (0·98–1·26)
0·52 0·10 0·006 0·20 0·37 0·15 0·02 0·62 0·37 0·03 0·04 0·11
hazard compared with women diagnosed during 1973–82 (trend across three periods of diagnosis: 2p=0·04). For women diagnosed during 1983–92 and irradiated, however, there was only a limited amount of follow-up during the second decade after diagnosis, and the cardiac mortality ratio, left versus right tumour laterality, during this second decade was 1·27 (0·99–1·63). This ratio is based mainly on deaths 10–14 years after diagnosis, and its confidence limits are so wide that it is uninformative. Therefore, it is not yet possible to determine directly just from these data how much excess cardiac mortality will eventually occur among women irradiated during 1983–92, a period when much of the radiotherapy given was after BCS and when improvements in radiotherapy planning would have tended to result in progressively lower cardiac doses.12,13 The women diagnosed during 1993–2001 have not yet been followed for 10 years, so no direct information on their late cardiac mortality is yet available, although there is other evidence that mean cardiac doses had been continuing to decrease.22–24
Mortality from ipsilateral lung cancer *Subdivisions of heart disease and of other circulatory diseases available up to 2000, but not for available for 2001. †Lung-cancer mortality: 122 ipsilateral (55 left-sided breast tumour, 67 right-sided breast tumour) versus 65 contralateral (39 left-sided breast tumour, 26 right-sided breast tumour); ratio 1·88 (1·39–2·54), 2p=0·00004.
Table 2: Relevance of breast cancer laterality to cause-specific mortality among irradiated women 10 years or longer after breast cancer diagnosis and irradiation
among women diagnosed during 1983–92; tumour location (ie, outer or inner breast quadrants); age at breast cancer diagnosis; or ethnic origin (table 3). Such analyses are, however, not particularly powerful, and some real variation in these mortality ratios cannot be ruled out.
Cardiac mortality ratios by period of breast cancer diagnosis and years since diagnosis Even if radiotherapy after mastectomy and after BCS are considered separately, there are substantial differences between the US radiotherapy regimens of the 1970s and those of the 1990s. Hence the relevance of time since radiotherapy must be studied separately among women treated in different time periods. For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio, left versus right tumour laterality, was 1·20 (1·04–1·38, 2p=0·01) during the first decade after diagnosis, 1·42 (1·11–1·82, 2p=0·005) during years 10–14, and 1·58 (1·29–1·95, 2p0·0001) after 15 or more years (trend: 2p=0·03, figure 2). Thus there is clear evidence of substantial hazard, particularly in the second decade after irradiation. For women diagnosed during 1983–92 or 1993–2001, and irradiated, the cardiac mortality ratios, left versus right tumour laterality, during only the first decade after diagnosis were 1·04 (0·91–1·18) and 0·96 (0·82–1·12), respectively, indicating a reduction in any early cardiac 560
Our main analyses of lung cancer mortality (figure 3) involve only those deaths where the disease was recorded by the SEER cancer registries as a unilateral primary lung cancer of known laterality with histological confirmation. Other deaths attributed on the death certificate to lung cancer (particularly during the first decade) could include a substantial proportion of miscertified deaths that were actually due to pulmonary metastases from the previous breast cancer. Among unirradiated women the lung cancer mortality ratio, ipsilateral versus contralateral, was 0·96 (0·85–1·08), and there was no significant trend in this ratio with time since diagnosis of breast cancer (trend: 2p=0·18). Among irradiated women, however, the lung cancer mortality ratio, ipsilateral versus contralateral, was 1·42 (1·19–1·70, 2p=0·0001, based on 283 ipsilateral versus 199 contralateral unilateral lung cancers). Among women diagnosed during 1973–82 and then irradiated, the lung cancer mortality ratio, ipsilateral versus contralateral, increased with time since diagnosis of breast cancer (trend: 2p=0·04), with no significant excess during the first decade but with a substantial and highly significant excess during the second decade after diagnosis. Among those diagnosed 15 or more years earlier and irradiated the mortality ratio, ipsilateral versus contralateral, was 2·71 (57 vs 21 lung cancer deaths), but with a wide 95% CI (1·65–4·48, figure 3). For women diagnosed during 1983–92 and irradiated there was for lung cancer, as for heart disease, only limited information on mortality rates during the second decade after diagnosis, and for women diagnosed during 1993–2001 there was none. Overall, the lung cancer mortality ratio, ipsilateral versus contralateral, 10 or more years after irradiation did not vary significantly by: http://oncology.thelancet.com Vol 6 August 2005
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stage of breast cancer (either overall, or among women diagnosed during 1973–82); stage and type of surgery among women diagnosed during 1983–92; tumour location in the breast (ie, outer or inner quadrants); age at breast cancer diagnosis; or ethnic origin (table 3).
Mortality from other causes The mortality ratio, left versus right breast cancer laterality, was close to one for the aggregate of all causes of death other than heart disease or lung cancer both in unirradiated women and in irradiated women (mortality ratios 1·01 (0·99–1·02) based on 27 402 versus 25 858 deaths in unirradiated women, and 1·02 (0·99–1·04) based on 11 487 versus 10 778 deaths in irradiated women, respectively). The biggest contributor to these deaths was, of course, breast cancer, even 10 or more years after diagnosis (table 2). Taking all time periods together, the breast cancer mortality ratio, left versus right tumour laterality, was close to one both in unirradiated and in irradiated women (unirradiated: 1·01 [0·99–1·03] based on 18 239 versus 17 191 deaths; irradiated: 1·00 [0·97–1·03] based on 8477 versus 8087 deaths). There was a slight tendency for the breast cancer mortality ratio, left versus right tumour laterality, to decrease with time since diagnosis, and this trend was similar in unirradiated and in irradiated women (trends: 2p=0·02 and 2p=0·03, respectively, considering time periods 5, 5–9, 10–14, and 15 years after
diagnosis) so it might, if real, reflect some slight physiological differences between left and right. The mortality ratio, left versus right tumour laterality, among unirradiated women for deaths attributed to all known causes other than heart disease, lung cancer, or breast cancer was 1·00 (0·97–1·03). In the irradiated group this mortality ratio was 1·03 (0·97–1·09) less than 10 years after diagnosis and 1·16 (1·04–1·28, 2p=0·006) 10 or more years after diagnosis. If, however, due allowance is made for multiple-hypothesis testing, for the cardioembolic origin of some ischaemic strokes, and for the possible misclassification of some cardiac deaths (eg, as fatal stroke of unspecified aetiology, or as respiratory disease), there was no clear evidence that breast cancer laterality was associated with any particular cause of death other than heart disease, lung cancer, or breast cancer (table 2).
Discussion We have shown that, in women recorded in the US SEER cancer registries as having been diagnosed with breast cancer during 1973–82 and irradiated, mortality from heart disease was increased among women with left-sided breast tumours compared with women with right-sided breast tumours. In these same women, mortality from cancer of the ipsilateral lung was increased compared with mortality from cancer of the contralateral lung. For both heart disease and ipsilateral
Heart disease
Lung cancer
Number of deaths (left/right)
Mortality ratio, left-sided vs right-sided (95% CI)
Number of deaths (ipsilateral/contralateral)
Mortality ratio, ipsilateral vs contralateral (95% CI)
Diagnosed 1973–82 Localised Regional 2p for difference
131/90 260/161
1·44 (1·10–1·88) 1·59 (1·30–1·94) 0.55
42/15 39/18
2·80 (1·55–5·05) 2·17 (1·24–3·79) 0·54
Diagnosed 1983–92 Localised, BCS Localised, not BCS Regional, BCS Regional, not BCS p for heterogeneity
75/60 21/11 26/13 22/24
1·18 (0·84–1·66) 2·14 (1·01–4·52) 1·93 (0·98–3·79) 0·89 (0·50–1·60) 0·18
26/17 3/6 8/4 4/5
1·53 (0·83–2·82) 0·50 (0·13–2·00) 2·00 (0·60–6·64) 0·80 (0·21–2·98) 0·37
Location of breast cancer Outer quadrants (including centre and tail) Inner quadrants (upper or lower) Other or unknown p for heterogeneity
206/138 110/68 219/153
1·48 (1·19–1·84) 1·58 (1·16–2·16) 1·36 (1·11–1·68) 0·71
47/25 21/17 54/23
1·88 (1·16–3·05) 1·24 (0·65–2·34) 2·35 (1·44–3·82) 0·29
Age at breast-cancer diagnosis (years) 20–49 50–59 60–69 70–79 2p for trend
82/50 154/97 241/167 58/45
1·54 (1·08–2·19) 1·53 (1·19–1·98) 1·40 (1·15–1·70) 1·28 (0·87–1·90) 0·40
49/18 38/33 35/13 0/1
2·72 (1·59–4·67) 1·15 (0·72–1·84) 2·69 (1·42–5·09) ·· 0·75
Ethnic origin White Black Other/unknown p for heterogeneity
461/315 50/23 24/21
1·39 (1·21–1·61) 2·25 (1·36–3·72) 1·30 (0·71–2·39) 0·19
110/51 9/11 3/3
2·16 (1·55–3·01) 0·82 (0·34–1·97) 1·00 (0·20–4·95) 0·10
BCS=breast-conserving surgery.
Table 3: Relevance of breast cancer laterality to mortality from heart disease and lung cancer 10 years or longer after breast cancer diagnosis and irradiation
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Years from breast cancer diagnosis to cardiac death
No radiotherapy
Radiotherapy
Cardiac deaths left/right
Cardiac mortality ratio, left-sided vs right-sided (95% Cl)
Cardiac deaths left/right
Cardiac mortality ratio, left-sided vs right-sided (95% Cl)
5 years
717/679
0·98 (0·89–1·09)
230/180
1·19 (0·98–1·45)
5–9
673/614
1·04 (0·93–1·15)
189/145
1·21 (0·97–1·50)
10–14
469/441
1·00 (0·87–1·13)
157/106
1·42 (1·11–1·82)
15
515/480
1·01 (0·89–1·15)
234/145
1·58 (1·29–1·95)
5 years
880/785
1·06 (0·96–1·16)
245/227
1·00 (0·84–1·20)
5–9
815/729
1·07 (0·97–1·18)
249/218
1·08 (0·90–1·29)
10
390/361
1·04 (0·90–1·20)
144/108
1·27 (0·99–1·63)
5 years
567/508
1·05 (0·93–1·18)
225/226
0·95 (0·79–1·14)
5–9
144/136
1·02 (0·81–1·29)
83/79
0·99 (0·73–1·35)
Diagnosed 1973–82
Diagnosed 1983–92
Diagnosed 1993–2001
0
0·5
1·0
1·5
2·0
0
0·5
1·0
1·5
2·0
Figure 2: Left-sided versus right-sided breast cancer: subsequent cardiac mortality ratios by radiotherapy status, period of diagnosis, and years from breast cancer diagnosis to cardiac death
lung cancer these increases, which are likely to be caused by radiation, were larger during the second decade after the diagnosis of the breast cancer than during the first decade. As yet, there is little information on the magnitude of any hazard in these women more than 20 years after irradiation. For women recorded in SEER as diagnosed with breast cancer more recently— ie, since the early 1980s—there is, as yet, little information on mortality during the period 10 or more years after the diagnosis of breast cancer.
Assessment of late mortality risks in the general population In the randomised trials of radiotherapy for breast cancer that began before the 1980s there is an appreciable late hazard of heart disease1,2 and lung cancer.4 Outside trials, patients may have been selected for irradiation not only according to their age and the nature of their breast cancer, but also according to factors that are correlated with their prognosis. Therefore, simple comparisons of the subsequent mortality of irradiated and unirradiated patients cannot be used to assess reliably the real benefits and hazards of treatment. In the SEER data, however, the similarity of the proportions of women with left-sided and with rightsided breast cancer who received radiotherapy within many particular categories of stage, calendar year, tumour location, age, and ethnic origin (table 1) suggests that breast cancer laterality played little part in determining who should be given radiotherapy. Also, in unirradiated women, who formed the majority of the 562
population, breast cancer laterality was not associated with mortality from heart disease (figure 2), and mortality from ipsilateral lung cancer was close to that for contralateral lung cancer (figure 3). Hence, the relevance of breast cancer laterality in irradiated women to subsequent mortality from heart disease and from unilateral lung cancer can be used to help assess the long-term hazards of the radiotherapy regimens actually given in this large, and approximately representative, sample of the US population. In the entire female population of the USA, the commonest cause of death is heart disease and the commonest cause of neoplastic death is lung cancer; and the unirradiated women in the SEER population who did not die from breast cancer are no exception (data not shown). Hence, if radiotherapy causes an appreciable proportionate increase in either of these diseases during the period 10 years or longer after breast cancer diagnosis, and particularly if the increase were to persist for some decades, it could well be of greater absolute importance to long-term survival than any other adverse (or even, for some patients, beneficial) effects of the radiotherapy regimens of the 1970s. Fatal ischaemic heart disease commonly originates in the anterior coronary arteries, and the effects of radiotherapy on these arteries may be one of the main reasons for the subsequent increase in cardiac mortality rates. But, deaths caused directly or indirectly by coronary artery disease include not only those attributed to acute myocardial infarction (ICD-9 410) or other ischaemic heart disease (ICD-9 411–414) on the death certificate, http://oncology.thelancet.com Vol 6 August 2005
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Radiotherapy
No radiotherapy Years from breast cancer diagnosis to lung cancer death
Lung cancer deaths (ipsilateral/ contralateral)
Lung cancer deaths Lung cancer mortality ratio, (ipsilateral/ ipsilateral vs contralateral contralateral) (95% Cl)
Lung cancer mortality ratio, ipsilateral vs contralateral (95% Cl)
Diagnosed 1973–82 10 years
77/94
0·82 (0·61–1·11)
21/18
1·17 (0·62–2·19)
10–14
53/60
0·88 (0·61–1·28)
24/12
2·00 (1·00–4·00)
15
98/81
1·21 (0·90–1·62)
57/21
2·71 (1·65–4·48)
152/181
0·84 (0·68–1·04)
74/67
1·10 (0·79–1·54)
65/53
1·23 (0·85–1·76)
41/32
1·28 (0·81–2·03)
67/65
1·03 (0·73–1·45)
66/49
1·35 (0·93–1·95)
Diagnosed 1983–92 10 years 10 Diagnosed 1993–2001 10 years
0
1·0
2·0
0
1·0
2·0
3·0
4·0
Figure 3: Unilateral breast cancer: subsequent ipsilateral versus contralateral lung cancer mortality ratios by radiotherapy status, period of breast cancer diagnosis, and years from breast cancer diagnosis to lung cancer death
but also many of those attributed to other cardiac disease. Hence, the absolute cardiac hazard would be somewhat underestimated by analyses restricted to ICD 410–414,8 and would be substantially underestimated by analyses restricted only to ICD 410 (table 2).7
Cardiac risks from US radiotherapy regimens of the 1970s and early 1980s Among women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio, left versus right tumour laterality, after 10 or more years was about 1·5 (figure 2). If there were no cardiac risk at all from irradiation for right-sided tumours, this finding would indicate that the proportionate increase in risk produced by irradiation for left-sided tumours was about 50%. Irradiation for right-sided tumours can, however, also involve some cardiac exposure, so it may also have led to some cardiac hazard. If, for example, radiotherapy for right-sided tumours led to an increase in the cardiac hazard one third as great as that from radiotherapy for left-sided tumours, then a cardiac mortality ratio, left versus right tumour laterality, of 1·5 during the second decade after irradiation would indicate a doubling of cardiac risk for irradiation versus no irradiation for leftsided tumours, and an increase of one third for irradiation versus no irradiation for right-sided tumours. In atomic bomb survivors and in patients with peptic ulcers, the radiation-related excess of heart disease was not apparent until more than a decade after exposure.14,16 Likewise, in the SEER data the excess cardiac risk occurs chiefly after the first decade. The present evidence of http://oncology.thelancet.com Vol 6 August 2005
hazard relates chiefly to the 20-year risks of the postmastectomy radiotherapy regimens used in the USA during the 1970s (when BCS was still uncommon), and to the 15-year risks of the regimens used in the USA during the early 1980s, when BCS was first becoming common. At that time it was still usual to irradiate the ipsilateral internal mammary chain (IMC) of lymph nodes after BCS,22 which can lead to relatively high cardiac doses, especially for left-sided tumours.25–27 It will, however, be 2010 or 2020 before there can be direct evidence of the 30-year and 40-year risks and benefits from the radiotherapy regimens used during the 1970s in various populations. Likewise, direct evidence of the 20-year risks and benefits from the regimens used more recently will not become available until about 2010 (for the regimens of the late 1980s) or 2020 (for those of the 1990s).
Cardiac doses and risks from current radiotherapy regimens Contemporary radiotherapy techniques can involve substantially lower cardiac exposures than those used previously. This situation has been achieved partly by omitting irradiation of the IMC in most patients. When an ipsilateral IMC field is used, however, an estimate dating from 2000 suggests that the mean cardiac dose could still be around 4–8 Gy for tumours of the left breast (with part of the heart receiving more than 20 Gy in some patients), and 2–4 Gy for tumours of the right breast.5 Although irradiation of the IMC in axillary node-negative breast cancer is now uncommon in the USA,23 a survey carried out in 2001 indicated that about 20% of US and 563
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6% of UK radiation oncologists would still generally have irradiated the IMC in women with axillary node-positive disease following either BCS or mastectomy,28 and in some other countries the proportion was still over 50%.28 Also, even if an IMC field is not used, other radiotherapy fields can deliver appreciable doses to parts of the heart. Indeed, studies from the 1990s showed that some patients with left-sided tumours who were irradiated with a tangential opposed pair of megavoltage beams would still receive doses of more than 20 Gy to at least a small proportion of the cardiac volume, probably including part of the left anterior descending coronary artery, which is one of the most important sites of origin of fatal ischaemic heart disease.12,13
Lung cancer risks and doses Radiation-induced lung cancer after radiotherapy for breast cancer has already been found to have a long natural history, with much less hazard during the first decade than later.6,9,10 In the present analysis, among women diagnosed with breast cancer during 1973–82 and then irradiated, there were 81 deaths from ipsilateral lung cancer 10 years or more after breast cancer diagnosis and 33 deaths from contralateral lung cancer, indicating a mortality ratio (irradiated versus unirradiated) of about 2, but with wide confidence limits. If there were no effect at all on contralateral lung cancer, such a two-fold ratio would correspond to a doubling of ipsilateral lung cancer (ie, a 50% increase in lung cancer as a whole) during the second decade after irradiation. Mean lung doses to women irradiated for breast cancer during this period could well, however, have been around 15 Gy for the ipsilateral lung and about a third of this dose for the contralateral lung.6 If the excess risk is about three times as great in the ipsilateral as in the contralateral lung, then a two-fold mortality ratio (ipsilateral versus contralateral) would correspond to a quadrupling of ipsilateral lung cancer and a doubling of contralateral lung cancer (ie, a tripling of lung cancer as a whole). As with the heart, irradiated lung volumes and mean doses to the entire lung, have probably decreased appreciably in recent years, but estimates based on radiotherapy techniques dating from about 2000 suggest that the mean ipsilateral lung dose was still around 10 Gy.29,30 Such exposures would probably carry an appreciable absolute risk of lung cancer, particularly among smokers.9,31
Conclusion For both cardiac mortality and lung cancer mortality, the absolute hazards depend on the background hazards (ie, heart disease and lung cancer death rates that would have occurred anyway in future decades), on how the relative risks will evolve during the second, third, and even fourth decade of follow-up, and on how likely the patient is to survive long enough to incur those risks. The experience of atomic bomb survivors suggests that, after the first decade, the radiation-induced relative risks 564
of heart disease and lung cancer remain approximately constant for some decades.14,15 If the same is true for breast cancer radiotherapy, then the long-term hazards of regimens that were commonly used 20 or more years ago in the USA will eventually substantially offset the definite reduction2 that radiotherapy produces in late mortality from breast cancer. Since then, improvements in radiotherapy planning should have reduced such risks, but the long-term population hazards still need monitoring directly in various different populations. In the USA, the periodic national surveys22,23 of the characteristics of radiotherapy given after BCS show substantial changes in practice that reduce, but do not eliminate, exposure to the heart and lungs. Such changes must also have happened, to varying extents, in other countries. Nationally representative periodic surveys of routine practice in breast cancer radiotherapy could monitor such changes and accelerate the worldwide dissemination of appropriate practice in deciding which patients with breast cancer to irradiate and how best to irradiate them. For the foreseeable future, however, there is likely to be some unwanted exposure, involving potential hazards of heart disease and lung cancer. In many populations both these hazards could be monitored from routine cancer registration and mortality records if, as with SEER, cancer registries routinely record tumour laterality and whether or not radiotherapy was given, and if routine follow-up to ascertain vital status and cause of death is possible. Over the next few decades, such monitoring would eventually provide direct evidence of the main lifelong hazards (after three or four decades of follow-up) of the radiotherapy of a few decades ago and direct evidence of the main 20-year hazards of the radiotherapy that is being used now in various different countries. Contributors All authors contributed substantially to this study. Conflict of interest We declare no conflicts of interest. Acknowledgments The SEER cancer registries are funded by the US National Cancer Institute, and many thousands of medical staff, over several decades, have consistently registered new patients. This study was funded by the long-term support to the CTSU from Cancer Research UK, the UK Medical Research Council, and the British Heart Foundation. References 1 Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994; 12: 447–53. 2 Early Breast Cancer Trialists Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000; 355: 1757–70. 3 Early Breast Cancer Trialists Collaborative Group. Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials. N Engl J Med 1995; 333: 1444–55. 4 Deutsch M, Land SR, Begovic M, et al. The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Cancer 2003; 98: 1362–68.
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