Beruflich Dokumente
Kultur Dokumente
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).
MARCU ET AL.
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.
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
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)
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)
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
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)
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)
RT, radiotherapy; SIR, standardised incidence ratios; SPC, second primary cancer.
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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.
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.
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
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
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)
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
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)
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
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
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
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MARCU ET AL.
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
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MARCU ET AL.
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
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.
MARCU ET AL.
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