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Increased risk of esophageal cancer after breast cancer
Annals of Oncology 16: 1829–1831, 2005 doi:10.1093/annonc/mdi363 Published online 5 August 2005
Original article
Increased risk of esophageal cancer after breast cancer F. Levi1,2,3*, L. Randimbison1,2, V.-C. Te2 & C. La Vecchia1,4,5 1
Unite´ d’Epide´miologie du Cancer, Institut Universitaire de Me´decine Sociale et Pre´ventive, Bugnon 17, 1005 Lausanne; 2Registre Vaudois des Tumeurs, Institut Universitaire de Me´decine Sociale et Pre´ventive, CHUV-Falaises 1, 1011 Lausanne; 3Registre Neuchaˆtelois des Tumeurs, avenue de Cadolles 7, 2000 Neuchaˆtel, Switzerland; 4Istituto di Biometria e Statistica Medica, Universita` degli Studi di Milano, via Venezian 1, 20133 Milan; 5 Istituto di Ricerche Farmacologiche ‘Mario Negri’, via Eritrea 62, 20157 Milan, Italy Received 22 April 2005; revised 14 June 2005; accepted 22 June 2005
Introduction Women treated for breast cancer have excess risk of skin neoplasms [1, 2] and of other neoplasms related to radiation therapy. In a cohort study of 64 782 cases of breast cancer diagnosed between 1961 and 2000 in the Thames Cancer Registry, the incidence of esophageal cancer in 33 763 radiotherapy-treated patients was compared with that in 31 019 patients who had not received this treatment [3]. Overall, 58 cases of esophageal cancer were observed in the non-radiotherapy cohort and 67 in the radiotherapy cohort. The relative risk (RR) for radiotherapy was not elevated for up to 15 years after breast cancer diagnosis, but rose to 2.19 [95% confidence interval (CI), 1.10–4.62] thereafter. The US Surveillance Epidemiology and End Results (SEER) Program also provided estimates of esophageal cancer risk following adjuvant radiation therapy for breast cancer [4, 5]. In the period 1973–2000, 171 cases of squamous cell esophageal cancer were registered, and the RR was 1.04 in the first 4 years after breast cancer diagnosis, 2.86 from 5 to 9 years and 1.81 for ‡10 years after breast cancer [4]. The excess risk was mainly due to cancers in the upper and middle third of the esophagus. No
*Correspondence to: Dr F. Levi, Registre Vaudois des Tumeurs, CHUV-Falaises 1, CH 1011 Lausanne, Switzerland. Tel: +41-21-3147311; Fax: +41-21-3230303; E-mail: [email protected] Ó 2005 European Society for Medical Oncology
excess risk was observed for adenocarcinomas. Other reports of esophageal cancer following radiotherapy for breast cancer are based on case reports, and therefore cannot provide estimates of risk [6–8]. To provide further information on this issue [1], we used the datasets of the Swiss Vaud and Neuchaˆtel Cancer Registries, which include data concerning incident cases of malignant neoplasms in the two cantons.
Materials and methods Population-based incidence data from the French-speaking cantons of Vaud and Neuchaˆtel, Switzerland, have been available since 1974. According to the December 2000 National Census, the total population of the two cantons was 786 000. The registries are tumour based, and multiple primaries in the same person are registered separately [9–11]. The information available comprises the sociodemographic characteristics of the patient (i.e. age, sex), the primary site and histological type of the tumour classified according to the International Classification of Diseases for Oncology (ICD-O) [12] and the date of diagnostic confirmation. Both passive and active (based on active tracing through municipality registries of all cases not known to be dead on 31 December 2002) follow-up are recorded, and each subsequent item of information is used to complete the patient’s record [11]. After exclusion of 20 breast cancer cases detected at autopsy and 21 at death, 181 by death certification alone, and synchronous cancers (i.e. within 2 months after the first primary) (n = 1), the present series comprised 11 130
Downloaded from http://annonc.oxfordjournals.org/ at Purdue University Libraries ADMN on June 30, 2015
Background: Adjuvant radiation therapy for breast cancer has been related to excess esophageal cancer risk, but population-based data are scanty. Patients and methods: We considered esophageal cancer risk among 11 130 breast cancer patients diagnosed between 1974 and 2002 in the Swiss cantons of Vaud and Neuchaˆtel, and followed-up to the end of 2002, for a total of 75 900 women-years at risk. Results: Overall, 18 cases were observed compared with 8.9 expected, corresponding to a standardised incidence ratio (SIR) of 2.0 [95% confidence interval (CI) 1.2–3.2]. The SIR was 1.6 in the first 10 years after diagnosis and 3.3 for ‡10 years after diagnosis, 2.3 for cases diagnosed between 1974 and 1988 and 1.5 for those diagnosed after 1988, 2.3 (based on 15 cases) for squamous cell cancer and 1.3 (based on three cases) for adenocarcinomas, and 2.9 for the upper third, 2.3 for the middle third and 1.9 for the lower third of the esophagus. Conclusions: These data confirm an excess esophageal cancer risk following treatment for breast cancer which could not be explained by confounding of tobacco or alcohol alone. The excess risk tended to decrease for cases diagnosed after 1988, leaving open the issue of the risk of modern radiotherapy for breast cancer on esophageal cancer. Key words: breast neoplasms, esophageal neoplasms, radiotherapy, second primary neoplasms
1830 breast cancers diagnosed between 1974 and 2002. These women were followed-up to the end of 2002 for the occurrence of a second primary esophageal neoplasm, emigration outside the registration areas or death, for a total of 75 900 women-years at risk. Calculation of expected numbers of esophageal primaries were based on age-specific and calendar-year-specific incidence rates multiplied by the corresponding number of women-years at risk. The significance of the observed-to-expected ratios [standardized incidence ratio (SIR)] and their corresponding 95% CIs were based on the Poisson distribution [13].
Results
Discussion The present population-based study confirms that esophageal cancer risk is increased after breast cancer [3,5]. This is probably due to radiotherapy following breast cancer, but we had no information on treatment for breast cancer except for the most recent years studied. Thus, since only a proportion of
References Table 1. Observed and expected numbers of esophageal cancers following breast cancer, with corresponding standardised incidence ratio (SIR) and 95% confidence interval (CI), in Vaud and Neuchaˆtel, Switzerland, 1974–2002 Characteristics
No. of esophageal cancer cases
SIR
95% CI
Observed
Expected
18
8.9
2.0
1.2–3.2
<10 years
11
6.8
1.6
0.8–2.9
‡10 years
7
2.1
3.3
1.3–6.9
1974–1988
13
5.6
2.3
1.2–4.0
1989–2002
5
3.3
1.5
0.5–3.6
Total Time since diagnosis
Date of diagnosis
Histology Squamous cell
15
6.7
2.3
1.3–3.8
3
2.3
1.3
0.3–3.8
Upper third
4
1.4
2.9
0.8–7.5
Middle third
7
3.0
2.3
0.9–4.8
Lower third
6
3.1
1.9
0.7–4.2
Adenocarcinoma Sitea
a
Site was unknown for one case.
1. Levi F, Randimbison L, Te VC, La Vecchia C. Second primary cancers in breast cancer patients in Vaud, Switzerland. Cancer Causes Control 1998; 9: 463–465. 2. Volk NV, Pompe-Kirn V. Second primary cancers in breast cancer patients in Slovenia. Cancer Causes Control 1997; 8: 764–770. 3. Roychoudhuri R, Evans H, Robinson D, Moller H. Radiation-induced malignancies following radiotherapy for breast cancer. Br J Cancer 2004; 91: 868–872. 4. Zablotska LB, Chal A, Das A, Neugut AI. Increased risk of squamous cell esophageal cancer after adjuvant radiation therapy for primary breast cancer. Am J Epidemiol 2005; 161: 330–337. 5. Ahsan H, Neugut AI. Radiation therapy for breast cancer and increased risk for esophageal carcinoma. Ann Int Med 1998; 128: 114–117. 6. Goffman TE, McKeen EA, Curtis RE, Schein PS. Esophageal carcinoma following irradiation for breast cancer. Cancer 1983; 52: 1808–1809. 7. Micke O, Schafer U, Glashorster M, et al. Radiation-induced esophageal carcinoma 30 years after mediastinal irradiation: case report and review of the literature. Jpn J Clin Oncol 1999; 29: 164–170. 8. Scholl B, Reis ED, Zouhair A, et al. Esophageal cancer as second primary tumor after breast cancer radiotherapy. Am J Surg 2001; 182: 476–480. 9. Levi F, Te VC, Randimbison L. Statistics from the Registry of the Canton of Vaud, Switzerland, 1993–1996. In: Parkin DM, Whelan S, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents, Vol. 8. IARC Scientific Publication No 155. Lyon: International Agency for Research on Cancer, 2002; 460–461.
Downloaded from http://annonc.oxfordjournals.org/ at Purdue University Libraries ADMN on June 30, 2015
Table 1 gives the observed and expected numbers of esophageal cancers following breast cancer. Overall, 18 cases were observed compared with 8.9 expected, corresponding to a SIR of 2.0 (95% CI 1.2–3.2). The SIR was 1.6 in the first 10 years after diagnosis and 3.3 for ‡10 years, 2.3 for cases diagnosed between 1974 and 1988 and 1.5 for those diagnosed after 1988, 2.3 (based on 15 cases) for squamous cell cancer and 1.3 (based on three cases) for adenocarcinomas, and 2.9 for the upper third, 2.3 for the middle third and 1.9 for the lower third of the esophagus. None of these estimates was significantly heterogeneous.
breast cancer patients receive radiotherapy (50% in the population studied), the real radiation-related risks are probably greater than the SIRs estimated in the present work. These limitations notwithstanding, the present dataset confirms that esophageal cancer risk is increased >2-fold in women treated for breast cancer. Alcohol drinking is associated with both breast [14, 15] and esophageal cancer [16], with a direct dose–risk relation, and may have biased or modified the risk estimates. However, alcohol alone is unlikely to explain a >2-fold excess of esophageal cancer, particularly since the risk of other alcohol-related neoplasms (oral cavity and pharynx, larynx and liver) were not elevated in the same dataset [1]. Tobacco, in contrast, is unlikely to have introduced any material bias, since smoking is not related to breast cancer [15, 17], and lung cancer incidence was not increased after breast cancer in the same dataset [1]. Similarly, it is unlikely that surveillance bias has played any material role on these estimates, given the serious and almost invariably fatal prognosis of esophageal cancer [18]. This study also suggests that the excess risk is not significantly different for adenocarcinomas and squamous cell cancers, or for various esophageal subsites, although the numbers are inadequate for any conclusion. The esophageal cancer risk tended to decrease for cases diagnosed after 1988 compared with those diagnosed earlier, but this study has inadequate statistical power to address the issue of change in risk over time. Consequently, available data are unable to address the risk, if any, of modern radiotherapy [19] for breast cancer on esophageal carcinogenesis.
1831 15. Collaborative Group on Hormonal Factors in Breast Cancer. Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58 515 women with breast cancer and 95 067 women without the disease. Br J Cancer 2002; 87: 1234–1245. 16. Polesel J, Dal Maso L, Bagnardi V et al. Estimating dose-response relationship between ethanol and risk of cancer using regression spline models. Int J Cancer 2005; 114: 836–841. 17. Evaluation of carcinogenic risk to humans: tobacco smoke and involuntary smoking. IARC Monograph No. 83. Lyon: International Agency for Research on Cancer, 2004. 18. Levi F, Randimbison L, Te VC, La Vecchia C. Second primary cancers in patients with lung carcinoma. Cancer 1999; 86: 186–190. 19. Bucci MK, Bevan A, Roach III M. Advances in radiation therapy: Conventional to 3D, to 4D, and beyond. CA Cancer J Clin 2005; 55: 117–134.
Downloaded from http://annonc.oxfordjournals.org/ at Purdue University Libraries ADMN on June 30, 2015
10. Levi F, Erler G, Choffat R et al. Statistics from the Registry of the Canton of Neuchaˆtel, Switzerland, 1993–1996. In: Parkin DM, Whelan S, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents, Vol. 8. IARC Scientific Publication No 155. Lyon: International Agency for Research on Cancer, 2002; 452–453. 11. Levi F, Randimbison L, Te VC et al. Multiple primary cancers in the Vaud Cancer Registry, Switzerland, 1974–89. Br J Cancer 1993; 67: 391–395. 12. World Health Organization. International Classification of Diseases for Oncology (ICD-O). Geneva: World Health Organization, 1976. 13. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol. II, The Design and Analysis of Cohort Studies. IARC Scientific Publication No 82. Geneva: World Health Organization, 1987. 14. Levi F, Pasche C, Lucchini F, La Vecchia C. Alcohol and breast cancer in the Swiss Canton of Vaud. Eur J Cancer 1996; 32: 2108–2113.
Original article
Increased risk of esophageal cancer after breast cancer F. Levi1,2,3*, L. Randimbison1,2, V.-C. Te2 & C. La Vecchia1,4,5 1
Unite´ d’Epide´miologie du Cancer, Institut Universitaire de Me´decine Sociale et Pre´ventive, Bugnon 17, 1005 Lausanne; 2Registre Vaudois des Tumeurs, Institut Universitaire de Me´decine Sociale et Pre´ventive, CHUV-Falaises 1, 1011 Lausanne; 3Registre Neuchaˆtelois des Tumeurs, avenue de Cadolles 7, 2000 Neuchaˆtel, Switzerland; 4Istituto di Biometria e Statistica Medica, Universita` degli Studi di Milano, via Venezian 1, 20133 Milan; 5 Istituto di Ricerche Farmacologiche ‘Mario Negri’, via Eritrea 62, 20157 Milan, Italy Received 22 April 2005; revised 14 June 2005; accepted 22 June 2005
Introduction Women treated for breast cancer have excess risk of skin neoplasms [1, 2] and of other neoplasms related to radiation therapy. In a cohort study of 64 782 cases of breast cancer diagnosed between 1961 and 2000 in the Thames Cancer Registry, the incidence of esophageal cancer in 33 763 radiotherapy-treated patients was compared with that in 31 019 patients who had not received this treatment [3]. Overall, 58 cases of esophageal cancer were observed in the non-radiotherapy cohort and 67 in the radiotherapy cohort. The relative risk (RR) for radiotherapy was not elevated for up to 15 years after breast cancer diagnosis, but rose to 2.19 [95% confidence interval (CI), 1.10–4.62] thereafter. The US Surveillance Epidemiology and End Results (SEER) Program also provided estimates of esophageal cancer risk following adjuvant radiation therapy for breast cancer [4, 5]. In the period 1973–2000, 171 cases of squamous cell esophageal cancer were registered, and the RR was 1.04 in the first 4 years after breast cancer diagnosis, 2.86 from 5 to 9 years and 1.81 for ‡10 years after breast cancer [4]. The excess risk was mainly due to cancers in the upper and middle third of the esophagus. No
*Correspondence to: Dr F. Levi, Registre Vaudois des Tumeurs, CHUV-Falaises 1, CH 1011 Lausanne, Switzerland. Tel: +41-21-3147311; Fax: +41-21-3230303; E-mail: [email protected] Ó 2005 European Society for Medical Oncology
excess risk was observed for adenocarcinomas. Other reports of esophageal cancer following radiotherapy for breast cancer are based on case reports, and therefore cannot provide estimates of risk [6–8]. To provide further information on this issue [1], we used the datasets of the Swiss Vaud and Neuchaˆtel Cancer Registries, which include data concerning incident cases of malignant neoplasms in the two cantons.
Materials and methods Population-based incidence data from the French-speaking cantons of Vaud and Neuchaˆtel, Switzerland, have been available since 1974. According to the December 2000 National Census, the total population of the two cantons was 786 000. The registries are tumour based, and multiple primaries in the same person are registered separately [9–11]. The information available comprises the sociodemographic characteristics of the patient (i.e. age, sex), the primary site and histological type of the tumour classified according to the International Classification of Diseases for Oncology (ICD-O) [12] and the date of diagnostic confirmation. Both passive and active (based on active tracing through municipality registries of all cases not known to be dead on 31 December 2002) follow-up are recorded, and each subsequent item of information is used to complete the patient’s record [11]. After exclusion of 20 breast cancer cases detected at autopsy and 21 at death, 181 by death certification alone, and synchronous cancers (i.e. within 2 months after the first primary) (n = 1), the present series comprised 11 130
Downloaded from http://annonc.oxfordjournals.org/ at Purdue University Libraries ADMN on June 30, 2015
Background: Adjuvant radiation therapy for breast cancer has been related to excess esophageal cancer risk, but population-based data are scanty. Patients and methods: We considered esophageal cancer risk among 11 130 breast cancer patients diagnosed between 1974 and 2002 in the Swiss cantons of Vaud and Neuchaˆtel, and followed-up to the end of 2002, for a total of 75 900 women-years at risk. Results: Overall, 18 cases were observed compared with 8.9 expected, corresponding to a standardised incidence ratio (SIR) of 2.0 [95% confidence interval (CI) 1.2–3.2]. The SIR was 1.6 in the first 10 years after diagnosis and 3.3 for ‡10 years after diagnosis, 2.3 for cases diagnosed between 1974 and 1988 and 1.5 for those diagnosed after 1988, 2.3 (based on 15 cases) for squamous cell cancer and 1.3 (based on three cases) for adenocarcinomas, and 2.9 for the upper third, 2.3 for the middle third and 1.9 for the lower third of the esophagus. Conclusions: These data confirm an excess esophageal cancer risk following treatment for breast cancer which could not be explained by confounding of tobacco or alcohol alone. The excess risk tended to decrease for cases diagnosed after 1988, leaving open the issue of the risk of modern radiotherapy for breast cancer on esophageal cancer. Key words: breast neoplasms, esophageal neoplasms, radiotherapy, second primary neoplasms
1830 breast cancers diagnosed between 1974 and 2002. These women were followed-up to the end of 2002 for the occurrence of a second primary esophageal neoplasm, emigration outside the registration areas or death, for a total of 75 900 women-years at risk. Calculation of expected numbers of esophageal primaries were based on age-specific and calendar-year-specific incidence rates multiplied by the corresponding number of women-years at risk. The significance of the observed-to-expected ratios [standardized incidence ratio (SIR)] and their corresponding 95% CIs were based on the Poisson distribution [13].
Results
Discussion The present population-based study confirms that esophageal cancer risk is increased after breast cancer [3,5]. This is probably due to radiotherapy following breast cancer, but we had no information on treatment for breast cancer except for the most recent years studied. Thus, since only a proportion of
References Table 1. Observed and expected numbers of esophageal cancers following breast cancer, with corresponding standardised incidence ratio (SIR) and 95% confidence interval (CI), in Vaud and Neuchaˆtel, Switzerland, 1974–2002 Characteristics
No. of esophageal cancer cases
SIR
95% CI
Observed
Expected
18
8.9
2.0
1.2–3.2
<10 years
11
6.8
1.6
0.8–2.9
‡10 years
7
2.1
3.3
1.3–6.9
1974–1988
13
5.6
2.3
1.2–4.0
1989–2002
5
3.3
1.5
0.5–3.6
Total Time since diagnosis
Date of diagnosis
Histology Squamous cell
15
6.7
2.3
1.3–3.8
3
2.3
1.3
0.3–3.8
Upper third
4
1.4
2.9
0.8–7.5
Middle third
7
3.0
2.3
0.9–4.8
Lower third
6
3.1
1.9
0.7–4.2
Adenocarcinoma Sitea
a
Site was unknown for one case.
1. Levi F, Randimbison L, Te VC, La Vecchia C. Second primary cancers in breast cancer patients in Vaud, Switzerland. Cancer Causes Control 1998; 9: 463–465. 2. Volk NV, Pompe-Kirn V. Second primary cancers in breast cancer patients in Slovenia. Cancer Causes Control 1997; 8: 764–770. 3. Roychoudhuri R, Evans H, Robinson D, Moller H. Radiation-induced malignancies following radiotherapy for breast cancer. Br J Cancer 2004; 91: 868–872. 4. Zablotska LB, Chal A, Das A, Neugut AI. Increased risk of squamous cell esophageal cancer after adjuvant radiation therapy for primary breast cancer. Am J Epidemiol 2005; 161: 330–337. 5. Ahsan H, Neugut AI. Radiation therapy for breast cancer and increased risk for esophageal carcinoma. Ann Int Med 1998; 128: 114–117. 6. Goffman TE, McKeen EA, Curtis RE, Schein PS. Esophageal carcinoma following irradiation for breast cancer. Cancer 1983; 52: 1808–1809. 7. Micke O, Schafer U, Glashorster M, et al. Radiation-induced esophageal carcinoma 30 years after mediastinal irradiation: case report and review of the literature. Jpn J Clin Oncol 1999; 29: 164–170. 8. Scholl B, Reis ED, Zouhair A, et al. Esophageal cancer as second primary tumor after breast cancer radiotherapy. Am J Surg 2001; 182: 476–480. 9. Levi F, Te VC, Randimbison L. Statistics from the Registry of the Canton of Vaud, Switzerland, 1993–1996. In: Parkin DM, Whelan S, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents, Vol. 8. IARC Scientific Publication No 155. Lyon: International Agency for Research on Cancer, 2002; 460–461.
Downloaded from http://annonc.oxfordjournals.org/ at Purdue University Libraries ADMN on June 30, 2015
Table 1 gives the observed and expected numbers of esophageal cancers following breast cancer. Overall, 18 cases were observed compared with 8.9 expected, corresponding to a SIR of 2.0 (95% CI 1.2–3.2). The SIR was 1.6 in the first 10 years after diagnosis and 3.3 for ‡10 years, 2.3 for cases diagnosed between 1974 and 1988 and 1.5 for those diagnosed after 1988, 2.3 (based on 15 cases) for squamous cell cancer and 1.3 (based on three cases) for adenocarcinomas, and 2.9 for the upper third, 2.3 for the middle third and 1.9 for the lower third of the esophagus. None of these estimates was significantly heterogeneous.
breast cancer patients receive radiotherapy (50% in the population studied), the real radiation-related risks are probably greater than the SIRs estimated in the present work. These limitations notwithstanding, the present dataset confirms that esophageal cancer risk is increased >2-fold in women treated for breast cancer. Alcohol drinking is associated with both breast [14, 15] and esophageal cancer [16], with a direct dose–risk relation, and may have biased or modified the risk estimates. However, alcohol alone is unlikely to explain a >2-fold excess of esophageal cancer, particularly since the risk of other alcohol-related neoplasms (oral cavity and pharynx, larynx and liver) were not elevated in the same dataset [1]. Tobacco, in contrast, is unlikely to have introduced any material bias, since smoking is not related to breast cancer [15, 17], and lung cancer incidence was not increased after breast cancer in the same dataset [1]. Similarly, it is unlikely that surveillance bias has played any material role on these estimates, given the serious and almost invariably fatal prognosis of esophageal cancer [18]. This study also suggests that the excess risk is not significantly different for adenocarcinomas and squamous cell cancers, or for various esophageal subsites, although the numbers are inadequate for any conclusion. The esophageal cancer risk tended to decrease for cases diagnosed after 1988 compared with those diagnosed earlier, but this study has inadequate statistical power to address the issue of change in risk over time. Consequently, available data are unable to address the risk, if any, of modern radiotherapy [19] for breast cancer on esophageal carcinogenesis.
1831 15. Collaborative Group on Hormonal Factors in Breast Cancer. Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58 515 women with breast cancer and 95 067 women without the disease. Br J Cancer 2002; 87: 1234–1245. 16. Polesel J, Dal Maso L, Bagnardi V et al. Estimating dose-response relationship between ethanol and risk of cancer using regression spline models. Int J Cancer 2005; 114: 836–841. 17. Evaluation of carcinogenic risk to humans: tobacco smoke and involuntary smoking. IARC Monograph No. 83. Lyon: International Agency for Research on Cancer, 2004. 18. Levi F, Randimbison L, Te VC, La Vecchia C. Second primary cancers in patients with lung carcinoma. Cancer 1999; 86: 186–190. 19. Bucci MK, Bevan A, Roach III M. Advances in radiation therapy: Conventional to 3D, to 4D, and beyond. CA Cancer J Clin 2005; 55: 117–134.
Downloaded from http://annonc.oxfordjournals.org/ at Purdue University Libraries ADMN on June 30, 2015
10. Levi F, Erler G, Choffat R et al. Statistics from the Registry of the Canton of Neuchaˆtel, Switzerland, 1993–1996. In: Parkin DM, Whelan S, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents, Vol. 8. IARC Scientific Publication No 155. Lyon: International Agency for Research on Cancer, 2002; 452–453. 11. Levi F, Randimbison L, Te VC et al. Multiple primary cancers in the Vaud Cancer Registry, Switzerland, 1974–89. Br J Cancer 1993; 67: 391–395. 12. World Health Organization. International Classification of Diseases for Oncology (ICD-O). Geneva: World Health Organization, 1976. 13. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol. II, The Design and Analysis of Cohort Studies. IARC Scientific Publication No 82. Geneva: World Health Organization, 1987. 14. Levi F, Pasche C, Lucchini F, La Vecchia C. Alcohol and breast cancer in the Swiss Canton of Vaud. Eur J Cancer 1996; 32: 2108–2113.