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Feature and review paper
Risk of second primary cancer after breast cancer treatment L.G. MARCU, PHD, Department of Medical Physics, Royal Adelaide Hospital, Adelaide, SA, School of Chemistry and Physics, University of Adelaide, Adelaide, SA, Australia, and Faculty of Science, University of Oradea, Oradea, Romania, A. SANTOS, PHD STUDENT, Department of Medical Physics, Royal Adelaide Hospital, Adelaide, SA, and School of Chemistry and Physics, University of Adelaide, Adelaide, SA, & E. BEZAK, PHD, Department of Medical Physics, Royal Adelaide Hospital, Adelaide, SA, and School of Chemistry and Physics, University of Adelaide, Adelaide, SA, Australia MARCU L.G., SANTOS A. & BEZAK E. (2014) European Journal of Cancer Care 23, 51–64 Risk of second primary cancer after breast cancer treatment Technological advances in both diagnosis and treatment of breast cancer lead to early detection and better treatment management. Consequently, the population of long-term survivors is on the rise. The risk of developing second cancers among breast cancer survivors was shown to be higher than that for the general population. The aim of this work was to review the literature on the risk of second primary cancer (SPC) after breast irradiation. Pubmed search of population-based studies on SPC after breast irradiation was conducted and the findings (in terms of Standardised Incidence Ratio) were collated and discussed. Several studies confirmed the link between breast tumour irradiation and risk of SPC, showing a small, but valid risk. There are, however, confounding factors that can either underestimate or overestimate risks: misclassification of tumour status, genetic inheritance, smoking, environmental factors, and the lack of accurate data in cancer registries. While isolating these potential triggers might be difficult, this approach would allow better discernability between radiotherapy-related risks and those generated by other factors. It is also important to evaluate the current status of treatment-related late effects and to lower such risks by minimising the dose delivered to normal tissues.
Keywords: breast cancer, radiotherapy, risk factors, standardised incidence ratio, second primary cancer, cancer registry.
INTRODUCTION Breast cancer is the most common malignancy among women worldwide. Recent technological advances in both diagnosis and treatment of this disease have lead to early detection of breast cancer and better treatment management. Therefore, the population of long-term survivors of breast cancer is on the rise (Darby et al. 2011).
Correspondence address: Loredana G. Marcu, Royal Adelaide Hospital, Department of Medical Physics, North Terrace, SA 5000, Australia (e-mail: [email protected]).
Accepted 10 July 2013 DOI: 10.1111/ecc.12109 European Journal of Cancer Care, 2014, 23, 51–64
© 2013 John Wiley & Sons Ltd
Most commonly, breast cancers are treated with surgery, radiotherapy and chemotherapy, often with a combination of all the above. Majority of patients diagnosed with breast cancer undergo radiotherapy (Tubiana 2009). The cure, following radiation therapy, though comes sometimes at a price as the risk of developing a second cancer among breast cancer survivors was shown to be higher than that for the general population (Rubino et al. 2000, 2003; Raymond & Hogue 2006; Brown et al. 2007; Zhang et al. 2011). Several population-based studies have confirmed the link between primary breast tumour irradiation and risk of second cancer, either within the treated area or outside the treatment field (Neugut et al. 1999; Mellemkjaer et al. 2006; Raymond & Hogue 2006; Brown et al. 2007).
MARCU ET AL.
Furthermore, a large number of studies from the 1980s and 1990s strengthen the evidence showing that women with previous breast cancer are more susceptible to develop second primary malignancies, either due to treatment-related causes or other factors (Adami et al. 1984; Ewertz & Mouridsen 1985; Harvey & Brinton 1985; Murakami et al. 1987; Brenner et al. 1993; Volk & Pompe-Kirn 1997). The aim of the current work was to review the scientific literature of the more recent data on the risk of second primary cancer (SPC) after breast cancer treatment in general, with emphasis on irradiation, and to collate the findings in a comprehensive manner, which allows assessing the current status.
METHODS The current review was based on clinical papers collated, as a result of a Pubmed search on SPCs after breast irradiation, as follows: 1 Pubmed results after the following keywords search were considered: second cancer AND breast radiotherapy AND population registry; 2 The Reference lists of the relevant articles were also studied and articles of interest further selected; 3 The clinical reports must have been published after 2000, in order to include the more recent findings; 4 The articles must have reported on the risk of SPC, other-than-breast, after primary breast irradiation; 5 Mainly population-based studies were included (for a sizeable number of subjects) to identify even small risks of second primary malignancies; 6 Reports on male breast cancers were excluded.
It is to be noted that only second primary tumours were included in the study (i.e. tumours developing at different anatomical sites and being of different histological type from the first tumour), whereas recurrences of the initial tumour (i.e. tumours developing within the treated area) were outside the scope of this work. Furthermore, a second primary tumour can be considered to be caused by radiation if the latency period is around 5 years for leukaemias and 10 years for solid tumours (Boice et al. 1996). A tumour detected within 1 year after the primary cancer treatment is most certainly unrelated to radiotherapy and is due to the patient’s genetic susceptibility, lifestyle, environmental exposures or other factors. 52
POPULATION-BASED STUDIES SUPPORTING THE EVIDENCE OF SECOND PRIMARY CANCER RISK AFTER BREAST CANCER TREATMENT This section is a review of population-based studies on SPCs after breast cancer management including all available treatment modalities. There is a vast amount of scientific literature dealing with the risk of second primary tumours after breast cancer treatment, with divided opinions regarding the excess risk of neoplasms other than breast. A number of studies report on findings where second cancers, which were attributed to the treatment of the primary, were identified in several anatomical sites (Evans et al. 2001; Levi et al. 2003; Andersson et al. 2008). On the other hand, there are studies showing no appreciable risk in developing SPCs after breast radiotherapy, outside the treatment field (Berrington de Gonzalez et al. 2010, 2011). The results of the most relevant epidemiological studies undertaken over the last decade are shown in Table 1. Risk measures for these cohort studies were usually estimated in the form of standardised incidence ratios (SIR). Standardised incidence ratios are defined as (Breslow & Day 1987):
SIR = ( Total number of events observed in the cohort ) (Total number of expected events) The anatomical sites for SPCs listed for each study are reported in decreasing order of SIR, thus the sites with the largest excess risks are reported first. As observed from Table 1, the risk of developing second cancers in various anatomical locations after primary breast treatment differs significantly from study to study. This might be due to the limitations of each data registry and possible bias factors which make the overall assessment more difficult. These factors include: the different calendar periods assessed (thus differences in treatment devices and techniques), variations among populations (such as lifestyle, smoking habits, and race), age groups, etc.
Correlation between age and SPC An epidemiological study which has included 145 677 patients from the Thames Cancer Registry examined the incidence of second primary malignancies after primary breast cancers treated, with any available modality, between 1961 and 1995 (Evans et al. 2001). The results reported by Evans et al. confirm the knowledge that patients diagnosed with breast cancer at an earlier age (
Feature and review paper
Risk of second primary cancer after breast cancer treatment L.G. MARCU, PHD, Department of Medical Physics, Royal Adelaide Hospital, Adelaide, SA, School of Chemistry and Physics, University of Adelaide, Adelaide, SA, Australia, and Faculty of Science, University of Oradea, Oradea, Romania, A. SANTOS, PHD STUDENT, Department of Medical Physics, Royal Adelaide Hospital, Adelaide, SA, and School of Chemistry and Physics, University of Adelaide, Adelaide, SA, & E. BEZAK, PHD, Department of Medical Physics, Royal Adelaide Hospital, Adelaide, SA, and School of Chemistry and Physics, University of Adelaide, Adelaide, SA, Australia MARCU L.G., SANTOS A. & BEZAK E. (2014) European Journal of Cancer Care 23, 51–64 Risk of second primary cancer after breast cancer treatment Technological advances in both diagnosis and treatment of breast cancer lead to early detection and better treatment management. Consequently, the population of long-term survivors is on the rise. The risk of developing second cancers among breast cancer survivors was shown to be higher than that for the general population. The aim of this work was to review the literature on the risk of second primary cancer (SPC) after breast irradiation. Pubmed search of population-based studies on SPC after breast irradiation was conducted and the findings (in terms of Standardised Incidence Ratio) were collated and discussed. Several studies confirmed the link between breast tumour irradiation and risk of SPC, showing a small, but valid risk. There are, however, confounding factors that can either underestimate or overestimate risks: misclassification of tumour status, genetic inheritance, smoking, environmental factors, and the lack of accurate data in cancer registries. While isolating these potential triggers might be difficult, this approach would allow better discernability between radiotherapy-related risks and those generated by other factors. It is also important to evaluate the current status of treatment-related late effects and to lower such risks by minimising the dose delivered to normal tissues.
Keywords: breast cancer, radiotherapy, risk factors, standardised incidence ratio, second primary cancer, cancer registry.
INTRODUCTION Breast cancer is the most common malignancy among women worldwide. Recent technological advances in both diagnosis and treatment of this disease have lead to early detection of breast cancer and better treatment management. Therefore, the population of long-term survivors of breast cancer is on the rise (Darby et al. 2011).
Correspondence address: Loredana G. Marcu, Royal Adelaide Hospital, Department of Medical Physics, North Terrace, SA 5000, Australia (e-mail: [email protected]).
Accepted 10 July 2013 DOI: 10.1111/ecc.12109 European Journal of Cancer Care, 2014, 23, 51–64
© 2013 John Wiley & Sons Ltd
Most commonly, breast cancers are treated with surgery, radiotherapy and chemotherapy, often with a combination of all the above. Majority of patients diagnosed with breast cancer undergo radiotherapy (Tubiana 2009). The cure, following radiation therapy, though comes sometimes at a price as the risk of developing a second cancer among breast cancer survivors was shown to be higher than that for the general population (Rubino et al. 2000, 2003; Raymond & Hogue 2006; Brown et al. 2007; Zhang et al. 2011). Several population-based studies have confirmed the link between primary breast tumour irradiation and risk of second cancer, either within the treated area or outside the treatment field (Neugut et al. 1999; Mellemkjaer et al. 2006; Raymond & Hogue 2006; Brown et al. 2007).
MARCU ET AL.
Furthermore, a large number of studies from the 1980s and 1990s strengthen the evidence showing that women with previous breast cancer are more susceptible to develop second primary malignancies, either due to treatment-related causes or other factors (Adami et al. 1984; Ewertz & Mouridsen 1985; Harvey & Brinton 1985; Murakami et al. 1987; Brenner et al. 1993; Volk & Pompe-Kirn 1997). The aim of the current work was to review the scientific literature of the more recent data on the risk of second primary cancer (SPC) after breast cancer treatment in general, with emphasis on irradiation, and to collate the findings in a comprehensive manner, which allows assessing the current status.
METHODS The current review was based on clinical papers collated, as a result of a Pubmed search on SPCs after breast irradiation, as follows: 1 Pubmed results after the following keywords search were considered: second cancer AND breast radiotherapy AND population registry; 2 The Reference lists of the relevant articles were also studied and articles of interest further selected; 3 The clinical reports must have been published after 2000, in order to include the more recent findings; 4 The articles must have reported on the risk of SPC, other-than-breast, after primary breast irradiation; 5 Mainly population-based studies were included (for a sizeable number of subjects) to identify even small risks of second primary malignancies; 6 Reports on male breast cancers were excluded.
It is to be noted that only second primary tumours were included in the study (i.e. tumours developing at different anatomical sites and being of different histological type from the first tumour), whereas recurrences of the initial tumour (i.e. tumours developing within the treated area) were outside the scope of this work. Furthermore, a second primary tumour can be considered to be caused by radiation if the latency period is around 5 years for leukaemias and 10 years for solid tumours (Boice et al. 1996). A tumour detected within 1 year after the primary cancer treatment is most certainly unrelated to radiotherapy and is due to the patient’s genetic susceptibility, lifestyle, environmental exposures or other factors. 52
POPULATION-BASED STUDIES SUPPORTING THE EVIDENCE OF SECOND PRIMARY CANCER RISK AFTER BREAST CANCER TREATMENT This section is a review of population-based studies on SPCs after breast cancer management including all available treatment modalities. There is a vast amount of scientific literature dealing with the risk of second primary tumours after breast cancer treatment, with divided opinions regarding the excess risk of neoplasms other than breast. A number of studies report on findings where second cancers, which were attributed to the treatment of the primary, were identified in several anatomical sites (Evans et al. 2001; Levi et al. 2003; Andersson et al. 2008). On the other hand, there are studies showing no appreciable risk in developing SPCs after breast radiotherapy, outside the treatment field (Berrington de Gonzalez et al. 2010, 2011). The results of the most relevant epidemiological studies undertaken over the last decade are shown in Table 1. Risk measures for these cohort studies were usually estimated in the form of standardised incidence ratios (SIR). Standardised incidence ratios are defined as (Breslow & Day 1987):
SIR = ( Total number of events observed in the cohort ) (Total number of expected events) The anatomical sites for SPCs listed for each study are reported in decreasing order of SIR, thus the sites with the largest excess risks are reported first. As observed from Table 1, the risk of developing second cancers in various anatomical locations after primary breast treatment differs significantly from study to study. This might be due to the limitations of each data registry and possible bias factors which make the overall assessment more difficult. These factors include: the different calendar periods assessed (thus differences in treatment devices and techniques), variations among populations (such as lifestyle, smoking habits, and race), age groups, etc.
Correlation between age and SPC An epidemiological study which has included 145 677 patients from the Thames Cancer Registry examined the incidence of second primary malignancies after primary breast cancers treated, with any available modality, between 1961 and 1995 (Evans et al. 2001). The results reported by Evans et al. confirm the knowledge that patients diagnosed with breast cancer at an earlier age (
