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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, 5164
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:
loredana@marcunet.com).

Accepted 10 July 2013

DOI: 10.1111/ecc.12109
European Journal of Cancer Care, 2014, 23, 5164

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 patients 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
(<50) are more susceptible to develop second cancers
later in life. While in the younger group there were
2013 John Wiley & Sons Ltd

Risk of second primary cancer

Table 1. SIR data extracted from population-based studies evaluating the risk of SPC after primary breast cancer treatment
(all treatments)
Second cancer site
analysis

SIR (95%CI)
A

Comments

Thames Cancer Registry

145 677 patients (1961
1995 treatment period)
(Evans et al. 2001)

Bone
Oesophagus
Connective tissue
Myeloid leukaemia
Stomach
Lung
Corpus uteri
Ovary

2.79 (1.057.43)
2.39 (1.603.57)
2.27 (1.184.37)
2.31 (1.523.51)
1.83 (1.292.59)
1.49 (1.261.78)
1.29 (1.021.64)
1.29 (1.051.59)

0.46 (0.151.44)
1.11 (0.941.30)
0.94 (0.581.53)
1.39 (1.121.71)
0.95 (0.841.07)
0.68 (0.620.74)
1.68 (1.531.85)
0.89 (0.791.01)

Vaud & Neuchtel

Cancer Registries
9729 patients
(19581997 treatment
period)
(Levi et al. 2003)

Soft tissue
Oesophagus
Corpus uteri
Skin melanoma
Mouth/pharynx
Ovary
Multiple myeloma
Salivary glands
Pleura
Bone
Connective tissue
Pharynx
Bladder
Skin melanoma
Ovary
Mouth/pharynx
Colon

6.06 (2.7711.51)
2.35 (1.014.63)
1.64 (1.072.40)
1.57 (0.842.69)
1.50 (0.652.96)
1.44 (0.822.34)
1.38 (0.453.23)
4.6 (1.212.5)
3.5 (0.414.4)
3.2 (0.413.5)
3.2 (1.27.3)
2.0 (0.46.4)
1.9 (1.22.9)
1.8 (1.12.7)
1.7 (1.32.4)
1.7 (0.93.1)
1.5 (1.11.8)

Data analysis includes two

age-stratified groups: patients
diagnosed with breast cancer
at age <50 (A) and at age
5084 (B). Significantly higher
risks were reported in women
<50 years at first diagnosis,
excluding corpus uteri where
the risk was higher in the
older population group.
The reported SIR is based on a
latency period of at least 5
years. For lung cancer and
leukaemia only a modest
excess was reported: 1.10
(0.651.75) and 1.10
(0.402.39) respectively.
Generally, the incidences of
SPC were higher in women
younger than 50 at first
diagnosis, excluding colon
and bladder cancers which
were more common in
women diagnosed with breast
cancer after the age of 50.

Study

Eindhoven Cancer
Registry
9919 patients (1972
2000 treatment
period)
(Soerjomataram et al.
2005)

8.2
5
6.7
1.9

2.2

1.9
1.31

1.81
4.39
1.77
1.24
1.64

SEER Cancer Registry

332 014 patients
(19732000 treatment
period)
(Raymond & Hogue
2006)

Acute leukaemia
Bone
Ovary
Lung
Thyroid

27.3
20.1
16

International Cancer
Registry (13 registries)
525 527 patients
(19432000 treatment
period)
(Mellemkjaer et al.
2006)

Soft tissue
Bone
Myeloid leukaemia
Ovary
Oesophagus
Leukaemia
Lung
Thyroid

13.7 (9.2419.56)
4.04 (2.436.31)
3.02 (2.323.85)
2.84 (2.613.09)
2.22 (1.483.18)
2.16 (1.782.59)
2.12 (1.922.33)
2.00 (1.642.42)

6.27 (4.099.18)
1.95 (1.113.17)
2.60 (2.153.13)
1.64 (1.521.77)
2.17 (1.762.65)
1.82 (1.592.07)
1.53 (1.421.64)
2.11 (1.802.47)

4.55 (3.455.88)
1.10 (0.721.62)
1.86 (1.662.08)
1.12 (1.061.19)
1.27 (1.141.42)
1.38 (1.281.48)
1.05 (1.001.10)
1.27 (1.101.45)

Danish Breast Cancer

Cooperative Group
(DBCG)
31 818 patients
(19772001 treatment
period)
(Andersson et al. 2008)

Bone
Tongue
Soft tissue
Acute leukaemia
Small intestine
Mouth
Lung
Multiple myeloma

3.3 (0.07.9)
2.9 (0.45.5)
2.8 (0.94.7)
1.9 (0.83.1)
1.8 (0.03.9)
1.3 (0.22.5)
1.3 (1.11.6)
1.2 (0.41.9)

SIR shown for the highest risk

age groups at initial
diagnosis:
A: 2029 years
B: 3039 years
C: 4049 years
D: 5059 years
The risk for cervix uteri as SPC
was reduced for all age groups.
SIR shown for different age
groups: A: <45 years; B: 4555
years; C: >56 years. Overall,
it was found that there is a
25% increase in the risk of
developing a non-breast SPC
after breast cancer treatment.
For several sites SPC were
suggested to be due to
previous RT (see also
Table 3).
The reported SIR is based on a
latency period of at least 10
years. Here only the higher
risks sites are presented.
Overall, the risk of SPC was
marginally increased for all
sites: SIR = 1.04.

RT, radiotherapy; SIR, standardised incidence ratios; SPC, second primary cancer.

2013 John Wiley & Sons Ltd

53

MARCU ET AL.

Figure 1. Standardised incidence ratios for SPC at all sites excluding breast as a function of age decade at primary breast cancer
diagnosis, based on the study of Raymond and Hogue (2006). The
two charts also show the large differences in SIR for each age
group between the two latency periods: SPC diagnosed within the
first 10 years after breast treatment or in the 1019 year period
after primary breast cancer treatment. , <10 years after initial
breast cancer; , 1019 years after initial breast cancer. SIR,
standardised incidence ratios; SPC, second primary cancer.

8 anatomical sites (other than breast) identified with

higher second cancer incidences (see Table 1), in the older
patients group there were only two malignancies with
statistically significant increase in their occurrence:
corpus uteri with SIR = 1.68 (1.53 1.85) and myeloid
leukaemia with SIR = 1.39 (1.121.71). An explanation for
these differences might be linked to the genetic susceptibility of the younger population, given that early occurrence of breast cancer is also attributed to genetic
predisposition. The large incidence of bone tumours
labelled as second primaries might also be a misclassification, as breast tumours are known for their metastatic
preference in bone. However, no increased incidences
were observed in the older patients group. The age-related
risk reported in this study was confirmed by the Danish
Breast Cancer Cooperative Group (DBCG) results
(Andersson et al. 2008) as well as by others, showing that
the risk for SPCs combined for all sites was the highest
among the younger patients (i.e. diagnosed with breast
cancer under the age of 50) (SIR = 1.35 in the Danish
study). Based on the US Surveillance, Epidemiology and
End Results (SEER) Cancer Registry database, Raymond
and Hogue (2006) have reported a detailed SIR for SPC
diagnosis by age decade at risk. Based on their results,
Figure 1 shows the SIR for all SPC sites, excluding second
primary breast cancer. It is to be noted that in the youngest cohort (2029 years at first diagnosis), SIR declines
from 8.90 to 1.46 between the two latency periods
(i.e. less than 10 years and more than 10 years
respectively), illustrating the high susceptibility of
these patients to develop cancer early in life, whether
54

treatment-related or due to genetic/environmental factors. While the risk is highest for the young age group, the
absolute number of radiation induced cancer cases is quite
small because of relative low baseline cancer rate for this
group of patients.
A peak in risk of SPCs is also observed for the 5059 age
group at primary breast diagnosis. These results are in
agreement with the data reported by Fowble et al. (2001)
showing that women of older age at diagnosis are at higher
risk of second non-breast malignancies, while patients
which were young at first diagnosis were more prone to
develop contralateral breast cancers. Similar findings were
reported by Zhang et al. (2011) whereby the 5064 age
group (at time of treatment) was shown to be at higher risk
of non-breast second cancers than women younger than 50
[relative risk (RR) 2.44 versus 1.54]. The higher risk of
second primary malignancies in the older age group was
associated with the menopausal status.
While the above results are in contradiction with the
general trend shown in Table 1 where SIR was observed to
decrease with the age at diagnosis, the conflicting data
could be attributed to variations in data collection by
different cancer registries (or lack of certain data, such as
dosage and schedules), which can thus lead to inconclusive results. It is important to note that while patients
diagnosed with breast cancer before the age of 50 are more
susceptible to develop SPC later in life (as shown in the
previous studies), Figure 1, which is based on SEER cancer
registry, illustrates that the highest risk is actually only in
the 2029 years age group.

Common anatomical sites for SPC

Overall, 12.3% of patients from the SEER registry database previously treated for breast tumours have developed
SPCs. The most common sites, other than breast, as also
shown in Table 1, were bone, ovary, lung, thyroid and
leukaemia. Some of these second cancers, as pointed out
before, could be attributed to genetic mutations which are
shared by the primary (i.e. breast cancer) and the SPC
(Szabo & King 1997; Welcsh & King 2001).
In the study of Levi et al. (2003), the largest excess risk
of second primaries was found for soft tissue sarcomas
which occurred in the shoulder, thorax and pelvis. Considering the extent of the irradiated area during breast
radiotherapy, it was suggested that these sarcomas were
radiation-induced late effects. These results highlighted
the importance of conformal radiotherapy in order to
minimise the exposure of the adjacent normal tissue. The
differences reported in the incidence of soft tissue sarcomas [for instance SIR = 6.06 (Levi et al. 2003) versus
2013 John Wiley & Sons Ltd

Risk of second primary cancer

Table 2. The risks of SPC in terms of SIR for all sites reported by population-based studies over the last decade
Reference
SIR for all SPC sites
95% CI
Reference
SIR for all SPC sites
95% CI

Evans et al. (2001)

1.49
1.421.57
Mellemkjaer et al. (2006)
1.25
1.241.26

Tanaka et al. (2001)

1.3
1.11.6
Brown* et al. (2007)
1.15
1.141.17

Levi et al. (2003)

1.14
1.041.25
Andersson et al. (2008)
1.04

Soerjomataram et al. (2005)

2.4
2.32.5
Schaapveld et al. (2008)
1.22
1.171.27

*Only non-haematological malignancies were included.

SIR, standardised incidence ratios; SPC, second primary cancer.

SIR = 2.8 (Andersson et al. 2008)] could be attributed

to different irradiation techniques encompassing different
treatment areas and also to variations in dose and doserate delivered.
Similarly, the increased SPC risk for connective
tissue, salivary gland and bone in the Dutch study of
Soerjomataram et al. (2005) was suggested to be due to
previous irradiation for primary breast cancer. The excess
risk of developing bladder cancer as SPC was speculated to
be due to the out-of-field, i.e. scattered radiation, as also
suggested by others (Mattsson et al. 1997; Hall 2006).
While the higher occurrence of melanoma among breast
cancer survivors was previously shown to be linked to
BRCA2 mutations (Goggins et al. 2004) relatively high
skin dose during radiotherapy could also be a determinant.
The risks of SPC in terms of total SIR for all sites
reported by population-based studies after year 2000 are
summarised in Table 2. Given that majority of the epidemiological studies also include second primary breast
cancers when reporting SIR for all SPC sites, the data
presented in Table 2 reflect the overall status of SPC. The
incidence of second breast cancers was proven to be considerably higher than SPC in other anatomical sites, thus
the risk of developing second primaries other than breast
and/or in the out-of-field organs is smaller than the values
presented in the table. For instance, Evans et al. (2001)
reported a SIR of 1.21 (1.131.31) for all sites excluding
breast cancer, as compared with 1.49 (1.421.57) for all sites
(including breast). Similarly, Raymond and Hogue (2006)
showed that the SIR for a SPC diagnosis by age decade is
significantly higher for breast as a second primary compared with all other sites. The most dramatic difference
was shown for the 2029 age group, with SIR = 478.5 for
breast versus SIR = 17.3 for all other sites (95% CI).

RADIOTHERAPY-RELATED SECOND
PRIMARY CANCERS
Radiotherapy versus non-radiotherapy studies
Since radiotherapy is considered a risk-factor in the
development of SPCs, it is important to evaluate the
2013 John Wiley & Sons Ltd

available patient data on a comparative basis: patient

receiving radiotherapy for the primary breast cancers
versus patients who have not received radiotherapy. Some
of the aforementioned studies have also stratified the
patients according to this criterion. In addition, radiation
therapy was attributable to the excess SPC for certain
anatomical sites among studies that did not separate the
two cohorts. Table 3 aims to present the SIR results for
such cohorts from some large population-based studies.
The epidemiological study of breast cancer patients
from the Thames Cancer Registry database analysed the
risk of SPCs after treatment involving either surgery (the
control cohort of 31 019 patients) or surgery followed by
radiotherapy (the radiotherapy cohort of 33 763 patients)
(Schaapveld et al. 2008). Relative risks were calculated for
various anatomical sites by comparing the SIR in the two
cohorts with 95% confidence intervals. It was found that
for lung and oesophagus there were elevated risks of developing second primaries 15 years after breast radiotherapy
(RR = 1.49 and RR = 2.19 respectively). Similarly, the
incidence of myeloid leukaemia was elevated in the radiotherapy group, with a RR of 2.99 at 5 years after the
primary treatment. These results were confirmed by the
Early Breast Trialists Collaborative Group (Clarke et al.
2005) after reviewing 78 randomised trials comprising of
42 000 breast cancer patients. On the other hand, in the
study of Roychoudhuri et al. (2004) no reportable differences in risk between the two cohorts were observed for
colon, thyroid or malignant skin melanomas.
Levi et al. (2006) conducted a similar study, whereby
a radiotherapy cohort (1549 patients) versus a nonradiotherapy cohort (4570 patients) of breast cancer
patients from the Vaud Cancer Registry were assessed for
their risks of second primaries. Their data showed that the
risk was increased among women who received radiotherapy for their primary breast cancer, with an overall
excess risk of 30% for all neoplasms.
The SIR data reported by Mellemkjaer et al. (2006)
covered several patient classifications, based on age at
initial diagnosis (see Tables 1 and 3), time to diagnosis of
SPC, as well as calendar year for the treatment of first
primary breast cancer. They found that patients treated
55

MARCU ET AL.

Table 3. SIR data extracted from population-based studies evaluating the risk of SPC after primary breast cancer treatment for RT versus
non-RT cohorts
Study
Thames Cancer Registry
64 782 patients (1961
2000 treatment period)
(Roychoudhuri et al 2004
Vaud Cancer Registry
6119 patients (19781998
treatment period)
(Levi et al. 2006)

Second cancer
site analysis
Oesophagus
Myeloid
leukaemia
Lung
Lung
All second
primaries

RT cohort

Non-RT cohort

SIR (95%CI)

SIR (95%CI)

Comments

2.80 (1.864.05)
2.09 (0.953.96)

1.28 (0.682.18)
0.45 (0.051.62)

1.47 (1.161.83)
1.40 (0.702.51)
1.54 (1.321.78)

0.98 (0.741.28)
0.76 (0.441.22)
1.13 (1.021.25)

The reported SIR is based on a

latency period of 15+ years.
No significant excess for
other sites was reported.
After 15 years, 20% of RT vs.
16% of non-RT patients
developed a SPC.

RT cohort
International Cancer
Registry (13 registries)
525 527 patients
(19432000 treatment
period)
(Mellemkjaer et al. 2006)

Soft tissue
Oesophagus
Lung
Stomach
Thyroid
Leukaemia

17.7 (10.328.4)
2.3 (1.53.5)
2.2 (1.92.5)
1.8 (1.42.2)
1.7 (1.22.4)
1.6 (1.22.1)

9.3 (5.315.1)
2.5 (1.93.2)
1.8 (1.61.9)
1.7 (1.41.9)
2.3 (1.82.9)
1.5 (1.21.8)

9.2 (5.913.6)
1.9 (1.52.3)
1.4 (1.31.5)
1.4 (1.21.5)
1.6 (1.22.1)
1.4 (1.21.6)

2.32
2.81
2.94
1.85
1.78
2.35
1.27

1.05
1.94
1.96
1.17
1.52
1.57
1.74

1.03
1.02
1.09
0.88
1.06
1.14
1.00

Scandinavian Cancer
Registries
(4 registries)
376 825 patients
(19432002 treatment
period)
(Brown et al. 2007)

Pleura
Bone
Connective tissue
Lung
Thyroid
Oesophagus
Salivary gland

8.56
5.71
3.19
2.78
2.74
2.42
1.81
RT cohort

Non-RT cohort

Danish Breast Cancer

Cooperative Group
(DBCG)
31 818 patients
(19772001 treatment
period)
(Andersson et al. 2008)

Soft tissue
Acute leukaemia
Pharynx
Uterus
Pleura
Larynx
Oesophagus
Stomach
Colon
Kidney
Bone
Lung
Thyroid

3.9 (1.76.0)
2.4 (1.23.6)
2.0 (0.53.6)
2.0 (0.03.9)
1.9 (0.04.6)
1.8 (0.43.3)
1.6 (0.62.7)
1.4 (0.82.0)
1.3 (1.01.6)
1.3 (0.71.9)
1.3 (0.03.9)
1.2 (1.01.4)
1.2 (0.22.3)

1.5 (0.62.5)
1.9 (1.22.6)
0.9 (0.21.6)
1.1 (0.12.0)
1.2 (0.02.6)
0.5 (0.01.1)
0.8 (0.31.3)
1.2 (0.81.6)
0.9 (0.81.1)
0.8 (0.51.1)
0.6 (0.01.8)
0.9 (0.81.1)
0.7 (0.11.3)

The data show SPC SIRs

suggested to be induced by
RT. Patients are categorised
by age group: A: <45 years;
B: 4555 years; C: 56+ years.
Non-RT cohort was not clearly
specified.
The data show SPC SIRs
suggested to be induced by
RT. Patients are categorised
by age group: A: <40 years;
B: 4049 years; C: 5059
years; D: 65+ years. Non-RT
cohort was not clearly
specified.
35% of all patients received RT
after surgery. Significantly
increased risks for SPC were
observed in the RT group for
all sites, with combined
SIR = 1.2 (1.11.2)

RT, radiotherapy; SIR, standardised incidence ratios; SPC, second primary cancer.

before 1974 showed a higher excess risk for all SPC sites
(SIR =1.32) than those treated after 1984 (SIR = 1.23) or
after 1991 (SIR = 1.18). The advances in technology
over the last few decades, which provide better dose
conformality to target, thus better sparing of the adjacent
normal tissue, are possible reasons for lower SPC risks
among the radiotherapy-related sites. This decrease in
incidence of potentially radiotherapy-related SPC for
patients treated after the 1980s (SIR = 1.08) as compared
with those treated before (SIR = 1.61) was confirmed by
Brown et al. (2007) based on patient data originating from
four Scandinavian Cancer Registries. In addition, out of all
56

SPC sites, the most elevated risk was found among those
sites which were associated with radiation induction (SIR
= 1.34) compared with those SPC sites linked to other
determinants (SIR = 1.09). The group also found that the
excess risk of SPC (including the radiotherapy-related
second cancers) continues to be present even 30+ years
after the initial breast cancer diagnosis.
Similarly, the Danish Breast Cancer Cooperative
Groups analysis (Andersson et al. 2008) showed that
patients undergoing post-operative radiotherapy for their
primary breast cancers presented with significantly higher
risks of SPC in the radiotherapy-related sites (soft tissue,
2013 John Wiley & Sons Ltd

Risk of second primary cancer

pleura, oesophagus, stomach, bone, thyroid, lung, and leukaemia) than those patients who had not been irradiated
(SIR = 1.35 versus 1.0) (see Table 3). Most important is
the risk of second lung cancers, which was 33% higher
for the radiotherapy cohort as compared with the nonradiotherapy one. This observation is in accordance with
several other reports on high incidences of lung cancer in
previously irradiated breast cancer patients, with some
studies showing even higher risks (Deutsch et al. 2003;
Roychoudhuri et al. 2004; Levi et al. 2006). A critical
review on the incidence of SPC after radiotherapy showed
that the occurrence of second malignancies was common
in tissue exposed to accumulated doses above 2 Gy
(Tubiana 2009); however, for lung cancers the cut-off dose
was much less (0.5 Gy). The lower threshold might also be
the result of the synergistic effect of the interaction
between radiation and smoking.
Another reason for concern among the radiotherapycohort is the high incidence of oesophageal cancers
(Roychoudhuri et al. 2004; Mellemkjaer et al. 2006;
Brown et al. 2007). Similarly to lung, some oesophageal
cancers were attributed to smoking, however, given the
anatomical vicinity to the treated area (i.e. breast), SPCs of
the oesophagus are also suggested to be radiation-induced
(Levi et al. 2005; Zablotska et al. 2005). A populationbased SEER study conducted by Zablotska et al. (2005)
revealed that squamous cell carcinomas rather than
adenocarcinomas of the oesophagus are more common
after breast irradiation. Thus tumours which are located
in the upper-middle parts of the oesophagus (squamous
cell carcinomas) and are closer to the radiation field have
higher occurrence than those originating from the lower
end of the organ which is a site for adenocarcinomas.
These findings confirm the carcinogenic potential of
radiotherapy, close to the irradiation field, among breast
cancer survivors.
A closer analysis of the radiotherapy-related anatomical sites, as reported by various studies, confirm the SIR
values for the incidence risk of several second primary
tumours. As shown in Figure 2, both solid tumours
(such as lung, oesophagus, bone, and thyroid) as well
as leukaemias have comparable SIR values among the
reports, while the widest variation is observed for the soft
tissue sarcomas, where SIR varies from 1.6 (Virtanen et al.
2006) to 11.7 (weighted average) (Mellemkjaer et al. 2006).
In the study of Mellemkjaer et al. (2006) the soft tissue
sarcoma incorporates the soft tissue of the thorax and
upper limb (including shoulder), which are clearly in the
vicinity of the radiation field. The Finnish study of
Virtanen et al. (2006) had sole focus on the incidence
of sarcomas after radiotherapy and their result is consider 2013 John Wiley & Sons Ltd

Figure 2. Standardised incidence ratios for radiotherapy-related

sites collated from cancer registry data (Roychoudhuri et al. 2004;
Levi et al. 2006; Mellemkjaer et al. 2006; Virtanen et al. 2006;
Brown et al. 2007; Andersson et al. 2008). Error bars are shown for
studies where such data was available. , Levi; , Roychoudhuri;
, Andersson; , Mellemkjaer*; , Brown*; , Virtanen. *SIR
data in these studies are categorised by age group; weighted
averages were calculated for comparison with the other studies.

ably lower than the one reported by Mellemkjaer et al.

However, the Finnish study has included all sarcomas in
their report, irrespective of the anatomical site, which
biases the final evaluation on breast irradiation-related
sarcoma risk. Nevertheless, the published studies confirm
that patient previously undergoing radiotherapy for
primary breast cancers are at higher risks of developing soft
tissue sarcomas than those not receiving radiotherapy.

Radiotherapy-related parameters
Population-based studies from cancer registries often lack
valuable information related to radiotherapy such as fractionation regimen, dose-rate, radiation quality, treatment
technique, use of wedges, etc (Kumar 2012). All these
factors would influence treatment outcome thus SPC risk
assessment analysis. Older treatment techniques as well
as older apparatus (such as kilovoltage X-ray and cobalt-60
units) were prone to increase the risk of SPC due to less
tumour conformity. Furthermore, before the 1970s, scattered radiation was not considered to play an important
role in patients dosimetry (Keller et al. 1974) leading to an
underestimation of the dose received by critical organs.
While new technology allows better tumour control and
sparing of adjacent tissues, there is yet a debate regarding
techniques such as IMRT (Intensity Modulated Radiation
Therapy) and their role in SPC incidence. Despite IMRTs
tumour conformity, the scatter radiation from the treatment head could possibly increase the dose to non-target
organs (Hall 2006). Also, IMRT delivers a larger number of
monitor units than conventional treatment and involves
57

MARCU ET AL.

more radiation fields, which increases both the total dose

delivered to the patient and the extent of normal tissue
exposed to low doses.
An additional source of radiation employed lately in
clinics is image guidance, which became an important tool
in tumour localisation and is nowadays an integral part of
radiotherapy. Image guided radiotherapy (IGRT) can contribute to significant out-of-field doses, which can further
increase the risk of SPC (Newhauser & Durante 2011).
The above-presented treatment characteristics are
usually missing from cancer registry data, though the possible effects of the new technology will only show up in
the years to come.
Another important factor when assessing the risk of
SPC after radiotherapy of primary breast cancer is the
extent of irradiation, or the number of regions irradiated.
In a recent report Zhang et al. (2012) showed that partial
irradiation of the locoregional lymph nodes in breast
cancer patients can increase the risk of second malignancies (including leukaemia, contralateral breast cancer and
other second cancers). They showed a correlation between
the treatment regions and the risk of second malignancies
in women treated for primary breast cancer indicating that
patients irradiated in one or two fields (only internal
mammary/supraclavicular nodes) were at higher risk of
SPC than those irradiated in four fields (i.e. including the
chest wall and axillary lymph nodes). Their recommendation was to include all fields in one treatment in order to
decrease the risk of second cancers.
Similar findings were reported by Obedian et al. (2000)
who also suggested a correlation between the irradiated
region and the risk of second cancer. They showed that
irradiation of internal mammary nodes can increase the
risk of second malignancies.
From all the above studies it can be concluded that the
most commonly developed second solid cancers after
primary breast treatment are lung, oesophagus, soft tissue
sarcoma, and second breast cancers (the latter is not discussed in the current paper), as these anatomical locations
are situated within the irradiation field. Other reported
sites, such as thyroid, ovary or colon receive much lower
doses, thus cancers arising from these sites might not be
radiation-induced. However, without the knowledge of
treatment-related details regarding dosage and scattered
radiation, it is difficult to derive a definitive conclusion.
Furthermore, there are population-based studies which
report on small, but existing risks of developing second
primaries in these sites. While some of the studies are
conflicting, hence no conclusive results can be derived,
there is need for awareness and precaution when treating
breast cancers with radiation, as follow-up data from the
58

latest technology are still scarce and it might be expected

that more conformal, but also more prolonged treatments
such as IMRT, that result in higher integrated dose, could
possibly increase the aforementioned risks (Hall & Wuu
2003).
One of the most recent population-based studies was
reported by Grantzau et al. (2013) based on a cohort of
46 176 breast cancer patients treated between 1982 and
2007 under the guidelines of the Danish Breast Cancer
Cooperative Group. The study found no increased risk
in SPC for the non-radiotherapy associated sites, whereas
for the radiotherapy-related sites the risk was translated
into 1 radiation-caused second cancer in every 200
women treated with radiotherapy for their primary breast
malignancy.
Radiotherapy + chemotherapy/hormonal therapy
It is necessary to mention that other treatment modalities
and/or combination of techniques present their own risk
of SPC. For example, Kirova et al. (2008) reported on a
retrospective study undertaken on 16 705 consecutive
breast cancer patients treated with various modalities,
including radiotherapy. They showed that adjuvant
treatment, such as chemotherapy or hormonal therapy,
increases the risk of SPC to a higher extent than radiotherapy. For example, the risk of leukaemia was found to
be much higher in the chemotherapy group (SIR = 13.3)
than in the radiotherapy group (1.86). Similarly, the higher
risk of gynaecological cancers was attributed to hormonal
therapy (SIR = 2.9).
An interesting, although contradicting finding of
Zhang et al.s study (2011) was the lower risk of second
cancers among women receiving combined therapy for
their breast cancer (radiotherapy plus chemotherapy
and/or hormonal therapy) as compared with the cohort
receiving radiotherapy-only (RR of 0.47 versus 1.14, 95%
CI). Since the authors did not have detailed information
about the staging of primary breast cancers, it is difficult
to explain these findings. One might hypothesise that the
total dose delivered during radiotherapy as a sole treatment was higher and therefore lead to increased late
tissue effects and higher risks of developing second primaries than the combined effect of lower doses of
radiation and chemotherapy/hormonal treatment. There
are also studies, which disconfirm any chemotherapyinduced second malignant neoplasm after primary breast
cancer treatment (Rubino et al. 2003). Rubino et al.
showed in their case-control study of 281 patients
(small cohort) with histologically confirmed SPCs that
chemotherapy, irrespective of the type of the drug used,
2013 John Wiley & Sons Ltd

Risk of second primary cancer

was not associated with second primary malignancy

[odds ratio (OR) 0.8, 95% CI], while tamoxifen, used as
hormonal therapy, was found to have an overall OR of
1.2 (95% CI) (Rubino et al. 2003).
Radiotherapy + surgery
Patients undergoing lumpectomy and radiotherapy versus
mastectomy were analysed for their risk in developing
SPCs in a study reported by Obedian et al. (2000). A
number of 1029 patients undergoing lumpectomy and
radiotherapy were compared with a control group consisting of 1387 breast cancer patients treated with surgeryonly (mastectomy). The 15-year risk of SPC other-thanbreast was very similar in the two cohorts: 11% (surgery +
radiotherapy) versus 10% (surgery-only). As the risk of
SPC is usually higher in the younger population, an age
stratification assessment was completed within the study.
The findings showed no increase in the risk of SPC in
those women who were younger than 45 years of age at
the time of treatment: 5% (surgery + radiotherapy) versus
4% (surgery-only).
Findings were also reported based on data from 182 057
patients with locoregional breast cancer from the SEER
cancer registries (Berrington de Gonzalez et al. 2010). The
study analysed previous breast cancer patients treated
with surgery-alone or surgery plus radiotherapy and
investigated the incidence of second solid cancers
among this patient group. A percentage of 8.5% of patients
were found with SPCs with a RR for the radiotherapy
group of 1.45 (95% CI = 1.331.58) for the sites previously
exposed to high doses of radiation. There was no elevated
risk found for the sites receiving medium and low doses
for their primary cancer, thus outside the radiation field.
The rates of second malignancies after breastconserving therapy was analysed in a cohort of 256 patients
treated with surgery + radiotherapy when compared with
a surgery-alone cohort of 2788 women (Shaitelman et al.
2011). The risk of SPC, other than breast, 15 years following the original treatment was 14.2% for the surgery +
radiotherapy cohort and 13.4% for the surgery-only cohort.
The study concluded that radiotherapy does not increase
the risk of second malignancy when combined with surgical intervention as compared with surgery-alone, not
even inside the radiation field (i.e. lung, head and neck,
gastrointestinal system, central nervous system).
The benefits of radiotherapy in primary breast
cancer treatment
While a number of epidemiological studies show a small,
but valid risk of SPC development after breast radio 2013 John Wiley & Sons Ltd

therapy, the role of radiation therapy in decreasing the risk

of recurrence and breast cancer death it is well established
(Ragaz et al. 1997, 2005; Vallis & Tannock 2004). These
results were recently confirmed by The Early Breast
Cancer Trialists Collaborative Group through a report
based on 17 randomised trials which included 10 801
women, showing that radiotherapy given after breastconserving surgery halves the rate of recurrence in the
long term (10+ years) and reduces breast cancer-related
death by one-sixth (Darby et al. 2011). Furthermore, a trial
of regional nodal irradiation in early breast cancer (Whelan
et al. 2011) showed that additional regional nodal irradiation after whole breast irradiation (WBI) in women with
node positive breast cancer reduces the risk of recurrence
and increases overall survival. In their trial, a number of
1832 women treated between 2000 and 2007 were randomly assigned to either the WBI (50 Gy over 25 fractions)
group or the WBI + regional nodal irradiation (45 Gy delivered in 25 fractions). After a median follow-up of 62
months, an increase in both local and distant disease-free
survival (DFS) was observed in the WBI + nodal irradiation
group compared with WBI-only (DFS 5-year risk 89.7%
versus 84.0%).

LIMITATIONS OF THE CURRENT STUDIES

Cancer registries are a valuable source of population-based
information for risk analysis of SPCs; however, the data
are usually limited, sometimes imprecise and rather
general, without treatment-related details such as radiotherapy protocol, radiation field size, number of fields,
chemotherapy dosage and administration, family history,
etc (Travis 2006). On the other hand, case-control studies
offer accurate information, with the drawback of short
follow-up time and limited number of patients included in
data analysis (Andersson et al. 2008).

Patient-related limitations
There are several confounding factors that intervene when
analysing the risks of SPCs after primary breast cancer
treatment in irradiated versus non-irradiated patients.
Among these one can list genetic abnormalities, family
history (genetic susceptibility), various risk factors (such
as smoking), previous irradiation, menopausal status, etc.
Several studies show that patients with a family history
of breast cancer are at higher risks in developing SPCs
(ovary, oesophagus, stomach, leukaemia, non-Hodgkins
lymphoma) due to genetic susceptibility (Welcsh & King
2001; Prochazka et al. 2006; Lynch et al. 2008; Ruijs
et al. 2010; Lee et al. 2012; Silva et al. 2012). It is well
59

MARCU ET AL.

documented in the literature that women with BRCA1

and BRCA2 genes are more susceptible to develop breast
cancers than women lacking these genes. Additionally,
both genes were associated with ovarian cancers (Szabo &
King 1997; Welcsh & King 2001), and possibly with lung
cancers (Lee et al. 2007).
The high incidence of leukaemia among the younger age
group could be linked either to treatment (radiotherapy or
chemotherapy) or to genetic mutations in the tumour
suppressor genes CHEK2 and TP53 known as LiFraumeni
syndrome, with the affected women being susceptible to
develop multiple primary tumours early in life, such as
breast cancer, acute adult leukaemia and soft tissue sarcomas. Several recent reports confirm this genetic linkage
(Lynch et al. 2008; Ruijs et al. 2010; Lee et al. 2012; Silva
et al. 2012).
Additionally, a comprehensive study looking into the
geneenvironment interactions in the aetiology of breast
cancer (WECARE study) (Bernstein et al. 2004) has confirmed the link between the carriers of mutant allele
in any of the BRCA1, BRCA2 or ATM genes and the
susceptibility to radiation-induced breast cancer, thus
of second primary breast cancers in the contralateral
breast.
Among the risk factors that bias the findings are the
smoking habits. An additive effect between breast radiotherapy and smoking and the increased risk of second
primary lung cancer was found and the results supported
by several studies (Ford et al. 2003; Prochazka et al. 2005;
Kaufman et al. 2008).
Menopausal status can be another bias-inducing factor.
Breast cancer patients who were pre-menopausal at diagnosis show an excess risk for second non-breast cancers
(ovarian, endometrial) related to other-than-treatment
factors (Evans et al. 2001; Raymond & Hogue 2006;
Langballe et al. 2011).

Database-related limitations
As presented above, several epidemiological studies
showed that women previously treated for primary breast
cancers are at increased risk of developing a SPC in the
lung. However, often cancer registries made no differentiation between metastatic cancers and second primary
lung cancers. Since around 1020% of breast cancers lead
to lung metastases, for an accurate risk assessment it is
important to discern between these two tumour categories (Tennis et al. 2010). The first pathological confirmation of primary lung cancer following breast treatment
was reported by Tennis et al. (2010) and they suggest that
the latency period, which is usually considered an indica60

tor for the origins of second cancers, is not a reliable

measure for primary or metastatic status. Nevertheless,
metastatic disease could generally be included if the
latency period was not defined in the analyses.
Beside lung, breast cancer cells have metastatic predilection towards bone, liver and brain (Evans et al. 2001).
Therefore, part of these sites, which were reported as SPC
in cancer registries, might actually be primary tumour
metastasis.
To distinguish between second primary and metastatic
tumours some studies did carefully take into consideration the histology, site, date of diagnosis, laterality (for
paired organs), and behaviour of the second tumour
(Raymond & Hogue 2006). Obviously, for an accurate distinction between tumour status, there is need for correct
data collection and update in the cancer registries, which
could not have been achieved by all studies.

Treatment-related limitations
There are reports in the literature comparing the risk of
SPC in surgery-only cohort versus surgery + radiotherapy
cohort. The findings can often be biased, as surgery-only
treatment for primary breast cancer is usually the treatment choice for early stage cancers. Patients undergoing
post-surgery radiotherapy have often more advanced
disease, which can affect long-term outcome resulting,
also, in higher incidences of second cancers (Zhang et al.
2011).
The treatment time period as indicated in Tables 1 and
3 can also be considered a limiting factor when comparing
studies to assess the risk of SPC due to radiotherapy. The
techniques employed in radiotherapy towards the end of
the 20th century are significantly different from the ones
used in the 19401970 time period when kilovoltage X-ray
and cobalt-60 units were widely used.
Even among modern treatment techniques there are
identifiable differences, which can lead to various clinical outcomes. While IMRT is more conformal that
standard radiotherapy, the larger number of monitor
units as well as the increased number of fields employed
by IMRT, deliver higher total doses to the adjacent
organs than standard irradiation techniques thus possibly
increasing the risk of SPC (Hall 2006). The use of image
guidance during radiotherapy also adds to the out-of-field
dose.

SUMMARY AND CONCLUSIONS

The risk of second primary malignancies after breast
cancer treatment is a highly debated topic. Several
2013 John Wiley & Sons Ltd

Risk of second primary cancer

population- and hospital-based studies were undertaken in

order to ascertain these risks. As mentioned before, among
these studies, certain common sites with increased second
cancer occurrence were identified (such as lung, oesophagus, myeloid leukaemia and soft tissue). However, for
several other anatomical locations the results are inconclusive. Given the large number of genetic, environmental
and life-style factors, it would be erroneous to assume that
radiotherapy is solely responsible for the incidence of
SPCs. Thus the excess risk in ovarian cancers could be due
to the same predisposing genes as the primary breast
cancer, the excess risk in uterine cancer can be attributed
to shared hormonal risk factors, whereas the excess in
blood/lymphatic cancers could be due to chemotherapyrelated toxicities.
One of the most comprehensive reports which included
all primary sites to assess the extent of second cancers
attributable to radiotherapy shows that only 8% of SPC are
related to radiotherapy (Berrington de Gonzalez et al.
2010), while the vast majority are linked to other factors.
The findings of the above-presented studies can be summarised as follows:
Technological advances in both imaging and treatment
resulted in better outcome among women diagnosed
with breast cancer, thus increasing their life expectancy. This, however, can have as a consequence an
elevated risk of developing second primary tumours.
The risk of second primary tumours after breast cancer
treatment is a valid concern, though certain studies
show no statistically significant risk of second cancers
in anatomical locations outside the treatment area. This
might be explained by genetic association between the
first and SPC, but also by the small amount of radiation
dose received by the out-of-field organs. However, for
more conclusive results, there is a need for better
designed population studies, which should take into
account radiotherapy-related technical details such as:
treatment technique, radiation field, planning target
volume, relevant dose volume histograms, total dose
delivered and dose-rate, as the current data collation
does not contain sufficient information.
There are studies showing an increased risk of SPC due
to radiotherapy (Table 3) with the highest incidence of
SPC, other than breast, being found in the oesophagus,
soft tissue, lung, pharynx, and larynx, and also with
high prevalence of myeloid leukaemia.
Age at first diagnosis of cancer plays a crucial role in the
development of SPC. Several studies confirmed the findings whereby patients diagnosed with breast cancer
before the age of 50 are more susceptible to develop SPC
2013 John Wiley & Sons Ltd

later in life. However, these results might only apply for

contralateral breast cancer.
When analysing population-based data for risk assessment, there are several confounding factors which can
either underestimate or overestimate risks. Such factors
are: misclassification of tumour status, genetic inheritance, smoking, environmental factors, and also the lack
of accurate data in the cancer registry databases regarding patient- and treatment-related details. While isolating these potential triggers might be a difficult task,
perhaps this approach would allow better discernability
between radiotherapy-related risks and those which are
generated by other factors.
Though biases cannot be sometimes avoided, the
similar findings reported by several studies confirm the
fact that there is a group of breast cancer survivors who
are at higher risk of developing SPCs than others. These
risks, however, decrease with increasing age at first
diagnosis and also with the increase in years since diagnosis of the first primary.
The benefits of radiotherapy for breast cancer management outweigh the risks of developing SPC. Furthermore, post-surgery irradiation significantly decreases
the risk of recurrence.
Conclusive results regarding the link between radiotherapy and the risk of second malignancies can only be
achieved by isolating those factors, which have been identified as possible contributors to the development of SPC. A
radiotherapy quality assurance platform such as the newly
initiated VodcaRT (Visualisation and Organization of Data
for Cancer Analysis) (from Medical Software Solutions,
http://mss-medical-software-solutions-gmbh.software
.informer.com/) employed by EORTC (European Organisation for Research and Treatment of Cancer) is an encouraging step towards collecting comprehensive digital
radiotherapy data which can assist in 3D dose distribution
analysis. The software package was developed to assist
with multicentre clinical trial organisation and analysis. It
allows for the complete data set (including 3D dose data) to
be saved, anonymised and evaluated in a systematic
manner across all sites.
While the benefits of radiotherapy for breast cancer
management outweigh the risk of developing SPCs, it is
of high importance to evaluate the current status of
treatment-related late effects and to lower such risks by
minimising the dose delivered to the surrounding normal
tissues. As underlined in a critical review by Tubiana
(2009), the future aim of radiotherapy should be to deliver
the minimal effective radiation therapy rather than the
maximal tolerable dose.
61

MARCU ET AL.

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