Journal of Cancer Therapy, 2012, 3, 768-776
http://dx.doi.org/10.4236/jct.2012.325096 Published Online October 2012 (http://www.SciRP.org/journal/jct)
Region of Treatment in Radiotherapy and Second
Malignancies in Breast Cancer Patients
Wei Zhang1*, Aldo Becciolini2, Annibale Biggeri3,4, P ao lo Pacini5, Colin R. Muirhead6
1Epidemiology Department, Centre for Radiation, Chemical and Environmental Hazards, Health Protection Agency, Didcot, UK;
2Department of Clinical Physiopathology, University of Fl orence, Florence, Italy ; 3Department of Statistics “G. Parenti”, University
of Florence, Florence, Italy; 4Biostatistics Unit, ISPO Cancer Prevention and Research Institute, Florence, Italy; 5Radiotherapy Unit,
General Hospital, Firenze, Italy; 6Institute of Health & Society, University of Newcastle, Newcastle, UK.
Received July 19th, 2012; revised August 21st, 2012; accepted August 31st, 2012
ABSTRACT
A cohort study was conducted based on clinical records for 5248 women treated for breast cancer in Florence (Italy),
with continuous follow up from 1965 to 1994. The subjects were categorised into groups such as no radiation treatment;
breast dose only; and radiation doses in one, two, three or four of the following fields: namely internal mammary chain ,
supraclavicular nodes, axillary lymph nodes and chest wall. The Cox proportional hazards model for ungrouped sur-
vival data was used to estimate the relativ e risk for second cancer after radiotherapy delivered to different regions. The
relative risk for all second cancers combined was statistically significantly raised if the internal mammary chain and
supraclavicular nodes were irradiated. However, we found that the relative risk of the second malignancies could be
reduced if all the locoregional lymph nodes (the internal mammary chain, supraclacicular nodes, axillary nodes) and
chest wall are irradiated at the same time. If this finding can be verified by other large cohort studies or randomized
clinical trials, it may have implication s in clinical practice when deciding upon the targeted areas for radiotherapy; par-
tial radiation treatment of the locoregional lymph nodes could raise the risk of second malignancies and should ideally
be avoided.
Keywords: Second Cancer; Radiotherapy; Breast Cancer
1. Introduction
Many patients are diagnosed with breast cancer each year
and are often treated with surgery followed by adjuvant
radiation therapy [1]. With advances in early diagnosis
and treatment, breast cancer is becoming an increasingly
survivable disease resulting in a large population of
long-term survivors. Recent trials have shown an overall
survival benefit in favour of adjuvant radiotherapy for
breast cancer [2-4]. Nevertheless, there is clear evidence
for the association between radiation exposure and cancer,
especially from epidemiological studies of survivors of
the atomic bombings in Japan [5-6], as well as from
various studies of medically-exposed groups [7]. In par-
ticular, irradiation of surrounding tissues during breast
radiotherapy can cause second malignancies to develop
within these tissues [8-9]. The second malignancy refers
to a new primary cancer in a person who has survived an
earlier cancer. The probability of a radiation induced se-
cond malignancy after radiotherapy is a topic that has
been widely discussed [9-15]. While the benefit of radio-
therapy should outweigh the risks of developing sub-
sequent cancers, it is importan t to evaluate the long-term
consequences of breast cancer treatment.
Our study involved the analysis of clinical records for
female breast cancer patients treated at the University of
Florence (Italy) with radiotherapy and/or chemotherapy
and/or hormonal therapy from 1965 to 1994 and who were
subsequently followed-up [16]. Previous analysis of this
cohort [17] compared the incidence of second primary
cancers in a group of patients treated with radiation
therapy for breast cancer to breast cancer patients not
treated in this way. In that analysis, an increased relative
risk of all second cancers combined following radio-
therapy was found. The increased relative risk appeared
five or more years after radiotherapy and appeared to be
highest among women treated after the menopause. In-
creased relative risks were observed specifically for
leukaemia and other solid cancers that exclude leukaemia
and contralateral breast cancer. For contralateral breast
cancer, no raised relative risk was observed during the
period more than 5 years after radiotherapy.
Recent randomized trials [18] have demonstrated that
*Corresponding a uthor.

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients 769
locoregional nodal irradiation after mastectomy reduces
locoregional recurrence and improves overall survival at
5 years after radiation therapy in women with node
positive breast cancer. However, Obedian et al. [19] re-
ported that the region of radiation treatment may affect
the risk of the second cancer and suggested that this risk
might be higher when the internal mammary nodes were
irradiated. In our cohort, 26% of those patients given
radiotherapy had the mammary chain and supraclavi-
cular nodes or chest wall irradiated. This provides an
opportunity to examine further the relationship between
the region of treatment and second cancers. In this paper,
we evaluate the effect that the region of treatment in
radiotherapy may have had on the subsequent risk of
second malignancies among patients treated in Florence,
based on categorising the patients into the following
groups such as no radiation treatment, breast dose only,
or radiation dose in one, two, three or four of the following
fields: namely, internal mammary chain, supraclavicular
nodes, axillary lymph nodes and chest wall.
2. Materials and Methods
Data were collected on 5248 patients w ith breast cancer
who were submitted to radiotherapy, chemotherapy, hor-
monal therapy or no additional therapy at the University
of Florence from June 1965 to December 1994 [17]. All
of the patients had received surgery for breast cancer.
A treatment schedule of 2 Gy/day, 5 days/week, for a
total dose up to 60 Gy was used. However, the regions
treated with radiation differed from patient to patient.
The exposed volume for a large number of patients was
the breast only, while other patients had also other
regions irradiated, such as internal mammary chain,
supraclavicular nodes, axillary lymph nodes and chest
wall.
Details of the method of follow-up and collection of
data on second malignancies have been presented pre-
viously [17]. The end of follow-up for the subjects was
chosen to be the earliest of: date of second cancer in-
cidence, date of loss to follow-up, date of death and 31
December 1994. The follow-up time among surviving
patients ranged from a minimum of 1 year to a maximum
of 30 years, with a mean of 8 years. The overall average
age at treatment was 54.7 years. The researchers carrying
out the study had no identifiable details of patients for-
warded to them and therefore ethical approval was not
required under Italian laws when the proj ect was initiated
in 1996.
The Cox proportional hazards model for ungrouped
survival data [20] was used to estimate the relative risk
of second cancers after radiotherapy treatment and to
evaluate how the risk varied according to other factors.
Parameter estimation and significance testing were car-
ried out using the Epicure software [21]. Since some
patients also received chemotherapy and/or hormonal
therapy, the relative risks of second cancers due to
radiotherapy were reported both unadjusted and adjusted
for che motherapy an d hormonal the rapy to chec k if there
were any confounding effects from these therapies. The
analyses are stratified by age-at-treatment and age at
outcome categories.
As well as all second cancers combined, leukaemia,
contralateral breast cancer (i.e. cancer in the opposite
breast to that in which cancer had previously been diag-
nosed) and all other cancers combined were considered.
For leukaemia, the follow up period was chosen to be
two years or more following treatment, in view of the
evidence from other studies showing a short latency
period for radiation-induced leukaemia [7]. For other
cancers and for all second cancers combined, the follow-
up period was chosen to be five years, in line with the
pattern reported by Zhang et al. [17].
3. Results
As shown in Table 1, among the 5248 patients in the
cohort, 261 patients (5%) developed contralateral breast
cancer, 8 patients (0.15%) developed leukaemia and a
total of 118 patients (2.25%) developed other types of
second cancers during the period of follow-up. The de-
tails of other second cancer types were presented previ-
ously by Zhang et al. [17]. The median time to develop-
ment of a second malignancy was 3 years for contralat-
eral breast cancer, 4.5 years for leukaemia and 4.4 years
for other cancers combined.
Table 2 summarises the number of subjects based on
the region of radiation treatment. Among the 3080
subjects who had a follow-up of 5 or more years, 1813
subjects had no radiation treatment and 804 subjects
received breast dose only. 14 subjects were irradiated in
only one of the four following fields: internal mammary
chain, supraclavicular nodes, axillary lymph nodes and
chest wall, 138 subjects were irradiated in only two of
the above fields (87% were internal mammary chain and
supraclavicular nodes), 190 subjects received doses in
three of the above fields (97% were internal mammary
chain, supraclavicular nodes and axillary nodes) and 114
subjects received doses in all four fields. A very small
number of subjects received breast doses in addition to
doses in “other fields”, as indicated by + in Table 2 and
Table 1. Sites of second malignancies.
Second cancer typeNumbers of total
second cancer patients
Numbers of second
cancer patients with
radiotherapy
Contralateral breast
cancer 261 103
Leukaemia 8 7
Other type of
cancers combined118 54

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients
770
they are grouped together with patients who only re-
ceived doses to “other fields” in the analyses. Seven
subjects had radiation treatment but without information
on the field of treatment, therefore they are included in
the any radiation tr eatment group but are ex cluded in the
field-specific treatment groups in the analyses.
Table 3 shows the relative risks of all second cancer
combined amongst patients given radiotherapy according
to the region of radiation treatment, based on a follow-
up of 5 or more years and both unadjusted and adjusted
for chemotherapy and hormonal therapy. The reference
category consists of unirradiated patients. The relative
risk was below one for radiation treatment of the breast
only and greater than one for patients who received ra-
diation dose in one, two or three of the other fields. In
particular, the relative risk was statistically significantly
raised for patients who received radiation dose in two
fields, which—among 87% of the patients—were the
internal mammary chain and supraclavicular nodes. How-
ever, the relative risk dropped below one for subjects
irradiated in all four fields (internal mammary chain,
supraclavicular nodes, axillary nodes and chest wall).
After adjustment for chemotherapy and hormonal therapy,
there was strong evidence of differences in the relative
risk between the radiation treatment groups (p = 0.002).
The relative risks for some specific types of second
cancer have been studied previously [17]. We further
analysed the rela tive risk of leuk aemia, contr alatera l breas t
cancer and other cancers respectively, according to the
region of radiation treatment. Table 4 shows the relative
risks for leukaemia amongst patients given radiotherapy
according to the region of radiation treatment based on
a follow-up of 2 or more years. Although the numbers
of leukaemia cases were small, the relative risks were
statistically significantly raised for patients having either
one or three other fields irradiated, based on 1 and 2
cases in the corresponding irradiated groups. In contrast,
the relative risks appeared to be smaller amongst patien ts
who received a breast dose only or who received doses in
either two or all four fields other than the breast, com-
pared to other the irradiated groups. The differences in
relative risk between the radiation treatment groups were
statistically significant (p = 0.04, after adjusting for che-
motherapy and hormonal therapy).
Table 5 shows the relative risk of contralateral breast
cancer amongst patients given radiotherapy according to
the region of radiation treatment based on a follow-up of
5 or more years. The relative risks were below one for
patients who received a breast dose only, or who had
either three or all fo ur of the non-breast fields irradiated.
In particularly, the relative risk was statistically sig-
nificantly less than one for patients with radiation ex-
posure only of the breast. The relative risks for patients
who received radiation doses to either one or two of the
Table 2. Region of treatment and corresponding number of
subjects, based on the follow-up of 5 or more years. The
numbers of subjects who received breast dose in addition to
other fields are represented as + numbers.
Fields exposed Number of subjects Percentage (%)
None 1813 58.86
Breast only 804 26.10
One other field exposed
Internal mammary nodes2 + 1
Supraclavicular nodes 4 + 1
Chest wall 5
Axillary nodes 1
subtotal 14 0.45
Two other fields exposed
Internal mammary nodes
and chest wall 1
Internal mammary nodes
and supraclavicular nodes118 + 2
Supraclavicular nodes and
axillary nodes 12 + 1
Supraclavicular nodes and
chest wall 4
Subtotal 138 4.48
Three other fields exposed
Internal mammary nodes,
supraclavicular nodes and
axillary nodes 178 + 6
Internal mammary nodes,
supraclavicular nodes and
chest wall 5
Supraclavicular nodes, chest
wall and axillary nodes 1
Subtotal 190 6.17
Four other fields exposed
Internal mammary nodes,
supraclavicular nodes, chest
wall and axillary nodes 111 + 3
Subtotal 114 3.70
Fields unknown 7 0.23
Total 3080 100

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients
771
Table 3. Relative risk of all second cancers combined among patients given radiation therapy, by region of radiation treat-
ment and based on a follow-up of 5 or more years.
Region of radiation treatment RR unadjusted for chemotherapy and
hormonal therapy (95% CI) RR adjusted for ch emotherapy and hormonal therapy (95% CI) Cases/women
None 1 1 94/1813 (5.2%)
Any radiation treatment 1.22 (0.88, 1.69) 1.14 (0.82, 1.58) 73/1267 (5.8%)
Subgroups
Breast only 0.79 (0.49, 1.28) 0.70 (0.43, 1. 1 4) 24/804 (3.0%)
One other field** 2.95 (0.71, 12.14) 3.13 (0.76, 12.91) 2/14 (14.3%)
Two other fields** 1.99 (1.15, 3.43)* 2.05 (1.19, 3.56)* 16/138 (11.6%)
Three other fields** 1.59 (0.93, 2. 74) 1.50 (0.87, 2.56) 18/190 (9.5%)
Four other field s** 0.83 (0.36, 1. 94) 0.76 (0.33, 1.77) 6/114 (5.3%)
Test for heterogeneity in RR between
radiation treatment subgroups p = 0.054 p = 0.002
*p < 0.05, ** defined in Table 2.
Table 4. Relative risk of leukaemia among patients given radiation therapy, by region of radiation treatment and based on a
follow-up of 2 or more years.
Region of radiation treatment RR unadjusted for chemotherapy
and hormon a l therapy (95% CI) RR adjusted for ch emotherapy and hormonal therapy (95% CI) Cases/women
None 1 1 1/2377 (0.04%)
Any radiation treatment 8.13 (0.96, 69.10) 6.67 (0.76, 58.00) 7/2339 (0.3%)
Subgroups
Breast only 4.17 (0.41, 42. 6 2) 3.27 (0.32, 33.72) 3/1691 (0.18%)
One other field** 72.09 (4.05, 1284)* 88.61 (4.54, 1728)* 1/25 (4%)
Two other fields** NC NC 0/187 (0%)
Three other fields** 24.71 (3.44, 278.90)* 18.85 (1.69, 210.80)* 2/252 (0.8%)
Four other field s** 15.13 (0.92, 247. 60) 9.58 (0.57, 161. 30) 1/176 (0.6%)
Test for heterogeneity in RR between radi a tion
treatment subgroups p = 0.03 p = 0.04
*p < 0.05, **defined in Table 2. NC: not calculated due to zero cases.
Table 5. Relative risk of contralateral breast cancer among patients given radiation therapy, by region of radiation treatment
and based on a follow-up of 5 or more years.
Region of radiation treatment RR unadjusted for chemotherapy
and hormon a l therapy (95% CI)RR adjusted for ch emotherapy and hormonal therapy (95% CI) Cases/women
None 1 1 67/1813 (3.7%)
Any radiation treatment 0.87 (0.58, 1.32) 0.82 (0.54, 1.24) 41/1267 (3.2%)
Subgroups
Breast only 0.57 (0.31, 1. 08 ) 0.52 (0.27, 0. 98 )* 13/804 (1.6%)
One other field** 2.20 (0.30, 16. 22) 2.33 (0.32, 17. 13) 1/14 (7.1%)
Two other fields** 1.25 (0.59, 2. 66) 1.28 (0.60, 2.73) 8/138 (5.8%)
Three other fields** 0.94 (0.43, 2. 04) 0.89 (0.41, 1.94) 8/190 (4.2%)
Four other field s** 0. 68 (0.24, 1.94) 0.63 (0.23, 1.80) 4/114 (3.5%)
Test for heterogeneity in RR between radiation
treatment subgroups p = 0.43 p = 0.06
*p < 0.05, **defined in Table 2.

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients
772
fields were greater than 1, but were based on small num-
bers of cases and were not statistically significantly raised.
The differences in relative risk between the radiation
treatment groups were close to being statistically sig-
nificant (p = 0.06), after adjusting for chemotherapy and
hormonal therapy).
Table 6 shows the relative risk of all second cancers
other than leukaemia and contralateral breast cancer
among patients given radiotherapy according to the re-
gion of radiation treatment based on a follow-up of 5 or
more years. The relative risk was close to 1 for patients
who received a breast dose only or who were irradiated
in all four of the other fields. There were no cases
amongst the 14 patients who received a radiation dose in
only one of the fields. However, for patients who re-
ceived radiation doses in two or three of the fields, statis-
tically significantly raised relative risks were observed.
The test for heterogeneity in the relative risk between
radiation treatment groups was borderline statistically
significant (p = 0.05, after adjusting for chemotherapy
and hormonal therapy).
4. Discussion
In this study, we have used a clinical records-based
cohort to analyse the effects of region of treatment in
radiotherapy for breast cancer on the incidence of sub-
sequent second cancers. All patients in this cohort re-
ceived surgery for breast cancer. An advantage of res-
tricting the cohort to women treated for breast cancer is
to minimize any possible systematic difference between
the study groups. Such an approach has been used in
other epidemiological studies of a similar nature, as
reported by Roychoudhuri et al. [13].
Our cohort contains 26% of radiotherapy patients who
had the mammary chain and supraclavicular nodes or
chest wall irradiated. This provided an opportunity to
examine the relationship between the region of treatment
and second cancers. Based on a follow-up of five or more
years, the relative risk of all second cancers was highest
for patients who received radiation to one or two fields
apart from the breast; in particular, the risk was sta-
tistically significantly raised for patients irradiated in two
fields. Amongst them, 87% received radiation exposure
in internal mammary chain and supraclavicular nodes.
This result is consistent with the finding of Obedian et al.
[19], which suggested a raised risk of second cancer
when the internal mammary chain was ex posed. Further-
more, we also found that the relative risk started to de-
crease when axillary lymph nodes was also irradiated and
was less than one (although not significantly so) for those
subjects irradiated in all four fields. Thus, in order to
reduce the risk of second cancer following radiotherapy
for breast cancer, it might be important when irradiating
the internal mammary chain and supraclavicular nodes to
also irradiate the chest wall and axillary lymph nod es.
An increased risk of leukaemia can start to arise two to
five years after exposure to radiation [22] and raised
leukaemia risks have been reported in previous epide-
miological studies of breast cancer patients treated with
radiation [23]. This raised risk might be associated with
regional radiation therapy that includes an internal mam-
mary node field, which may expose the thoracic spine to
a relatively high radiation dose [9]. In our previous
Table 6. Relative risk of second ca ncers othe r than leukaemia and contralate ral breast cancer among patients given radiation
therapy, by region of radiation treatment and base d on a follow-up of 5 or more years.
Region of radiation treatment RR unadjusted for chemotherapy and hormonal therapy
(95% CI)
RR adjusted for ch emotherapy and
hormonal therapy
(95% CI) Cases/women
None 1 1 29/1813 (1.6%)
Any radiation treatment 1.84 (1.06, 3.16) 1.70 (0.98, 2.94) 29/1267 (2.3%)
Subgroups
Breast only 1.34 (0.63, 2.82) 1.17 (0.55, 2. 5 0) 11/804 (1.4%)
One other field** NC NC 0/14 (0.0%)
Two other fields** 3.65 (1.63, 8.21)* 3.88(1.72, 8.77)* 8/138 (5.8%)
Three other fields** 2.36 (1.02, 5.48)* 2.19 (0.94, 5.08) 8/190 (4.2%)
Four other field s** 1.08 (0.25, 4. 65) 0.98 (0.23, 4.20) 2/114 (1.8%)
Test for heterogeneity in RR between radi a tion
treatment subgroups p = 0.06 p = 0.0 53
*p < 0.05, **defined in Table 2. NC: not calculated due to zero cases.

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients 773
analysis [17], there was suggestion of a raised incidence
of leukaemia among radiotherapy patients in the period
two or more years after radiotherapy. There were seven
cases in the radiotherapy group compared with only one
case in non-radiotherapy group, with a relative risk of
6.67 (95% CI 0.76, 58.00) after adjustment for che-
motherapy and hormonal therapy. The raised risk was not
statistically significant, reflecting the small number of
cases in this cohort. In the current analysis, the relative
risk of leukaemia peaked when one of the fields other
than the breast was irradiated, albeit based on only one
case. The relative risk was lower if more fields were
irradiated, or if only the breast was irradiated. There were
no leukaemia cases among the subjects who was ir-
radiated in two of the fields; this might be due to ch ance,
since there was only a total of 7 cases in the irradiated
groups.
Raised risks of breast cancer has been reported in
various studies of women exposed to radiation; for ex-
ample, Japanese atomic bomb survivors [5,6,24], female
tuberculosis patients who received multiple fluoroscop ies
[25,26], and female patients who received radiotherapy
for various benign conditions [27]. Raised risks have also
been seen specifically in women who had direct breast
exposure prior to the age of 30 years [26-30]. However,
the causes of contralateral breast cancer amongst breast
cancer patients given radiotherapy are less obvious. In
the Early Breast Cancer Trialists’ Collaborative Group
report which evaluated the effects of radiotherapy, a sig-
nificantly increased risk of contralateral breast cancer
was found [31]. However, in another large case-control
study from Denmark, there was no significant raised risk
of contralateral breast cancer among women who re-
ceived radiotherapy [32]. A more recent large-scale study
included 13,472 women also failed to show an increased
risk of contralateral breast cancer for those received
radiotherapy [33]. The WECARE study [34] also re-
ported that no excess risk was observed in women who
received radiotherapy at more than 40 years of age, but a
relative risk of 3.0 (95% CI: 1.1 - 8.1) was reported in
women aged < 40 years with follow up greater than 5
years. Further analysis of data from the WECARE study
found a raised risk of contralateral breast cancer among
nulliparous (but not parous) women who received radio-
therapy [35]. In some studies, it was reported that the
increased risks of contralateral breast cancer were most
likely observed within the first year following diagnosis
of the primary breast cancer [36], or associated with
patients with more advanced stage disease [37-39]. This
suggests metastatic disease in the opposite breast could
be mistakenly classified as a new primary second breast
cancer. Since some patients selected for post-mastectomy
radiation have a poorer prognosis than other patients,
there may well be bias in estimates of the risk of contra-
lateral breast cancer that can be attributed to radiotherapy.
In order to minimise any effect of metastatic disease in
the opposite breast, our analyses excluded the first five
years following treatment. In our previous analysis [17],
no raised relative risk for contralateral breast cancer was
observed during the period five or more years after
exposure. This is in agreement with previous epidemio-
logical studies [9,32,33,40]. However, our current analysis
showed that the relative risk was significantly below one
for patients who received radiation exposure of the af-
fected breast only. In contrast, the relative risk for pa-
tients irradiated in one or more other fields was not
statistically significantly different from one. However, it
has to bear in mind that our findings are based on small
numbers of cases and should be verified by a larger study
of similar kind.
Other solid cancers have also been reported to link
with radiotherapy following breast cancer [10,41,42]. In
our previous analysis, the relative risk of all second
cancers excluding leukaemia and contralateral breast
cancer appeared to be increased five or more years after
radiotherapy, particularly amongst those women treated
at ages 50 - 64 years age-at-treatment group. This may
indicate an association with menopausal status [17]. The
current analysis showed that the relative risk of all
second cancers excluding leukaemia and contralateral
breast cancer was statistical significantly raised among
patients who received radiation dose in two fields, even
after adjustment for chemotherapy and hormonal therapy.
The relative risk was lower if three fields were exposed
and dropped to around one when all four fields were
exposed. These results are similar to those for all second
cancers combined.
The findings in this paper could have clinical impli-
cations if they can be verified by other large cohort
studies or randomised clinical trials. In this cohort study,
we have no information on how the decisions were made
about nodal irradiation treatment, which limits our
interpretation of the results. With a fairly small total
number of second cancers in this cohort, the excess risk
associated with radiotherapy was small over the period of
follow-up. Nevertheless, since many of the women were
still alive at the end of follow-up, the possibility of raised
risks continuing several decades over radiotherapy can-
not be ruled out and—based on other studies (e.g.
Preston et al. [6])—would be expected.
5. Conclusion
This study indicated a raised risk of second malignancies
associated with region of treatment in radiotherapy for
breast cancer, particularly among women irradiated in
the internal mammary chain and supraclavicular nodes.
The relative risk was lower if the axillary nodes and

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients
774
chest wall were also irradiated. This may have impli-
cations in clinical practice when deciding upon the
targeted areas for radiotherapy; partial radiation treat-
ment of the locoregional lymph nodes could raise the risk
of second malignancies and should ideally be avoided.
The interpretation of patterns in risk for specific cancers,
such as leukaemia and contralateral breast cancer, was
complicated by the small numbers of cases. However, for
both of these type of cancer, the similar risk patterns
exist and the relative risk varied significantly between
radiotherapy groups, after adjusting for chemotherapy
and hormonally therapy.
REFERENCES
[1] V. L. Ernster, J. Barclay, K. Kerlikowske, D. Grady and I.
C. Henderson, “Incidence of and Treatment for Ductal
Carcinoma in Situ of the Breast,” The Journal of the
American Medical Association, Vol. 275, No. 12, 1996,
pp. 913-918. doi:10.1001/jama.1996.03530360023033
[2] K. S. Hughes, L. A. Schnaper, D. Berry, C. Cirrincione, B.
McCormick, B. Shank, J. Wheeler, B. A. Lorraine, L. A.
Champion, T. J. Smith, B. L. Smith, C. Shapiro, H. B.
Muss, E. Winer, C. Hudis, W. Wood, D. Sugarbaker, I. C.
Henderson and L. Norton, “Lumpectomy Plus Tamoxifen
with or without Irradiation in Women 70 Years of Age or
Older with Early Breast Cancer,” The New England
Journal of Medicine, Vol. 351, 2004, pp. 971-977.
doi:10.1056/NEJMoa040587
[3] V. Vinh-Hung, C. Verschraegen for the Breast Conserv-
ing Surgery Project, “Breast-Conserving Surgery with or
without Radiotherapy: Pooled-Analysis for Risks of Ip-
silateral Breast Tumour Recurrence and Mortality,” Jour-
nal of the National Cancer Institute, Vol. 96, No. 2, 2004,
pp. 115-121. doi:10.1093/jnci/djh013
[4] V. Gebski, M. Lagleva, A. Keech, J. Simes and A. O.
Langlands, “Survival Effects of Postmastectomy Adju-
vant Radiation Therapy Using Biologically Equivalent
Doses: A Clinical Perspective,” Journal of the National
Cancer Institute, Vol. 98, No. 14, 2006, pp. 26-38.
[5] C. E. Land, M. Tokunaga, K. Koyama, M. Soda, D. L.
Preston, I. Nishimori and S. Tokuoka, “Incidence of Fe-
male Breast Cancer among Atomic Bomb Survivors, Hi-
roshima and Nagasaki, 1950-1990,” Radiation Research,
Vol. 160, No. 6, 2003, pp. 707-717. doi:10.1667/RR3082
[6] D. L. Preston, Y. Shimizu, D. A. Pierce, A. Suyama and
K. Mabuchi, “Studies of Mortality of Atomic Bomb Sur-
vivors. Report 13: Solid Cancer and Noncancer Disease
Mortality: 1950-1997,” Radiation Research, Vol. 160, No.
4, 2003, pp. 381-407. doi:10.1667/RR3049
[7] United Nations Scientific Committee on the Effects of
Atomic Radiation (UNSCEAR 2008), “2006 Report to
the General Assembly with Scientific Annex,” United
Nations, New York.
[8] E. B. Harvey and L. A. Brinton, “Second Cancer Follow-
ing Cancer of the Breast in Connecticut, 1935-82,” Na-
tional Cancer Institute Monograph, Vol. 68, 1985, pp.
99-112.
[9] A. I. Neugut, M. D. Weinberg, H. Ahsan and J. Rescigno,
“Carcinogenic Effects of Radiotherapy for Breast Can-
cer,” Oncology, Vol. 13, 9, 1999, pp. 1245-1256.
[10] L. M. Brown, B. E. Chen, R. M. Pfeiffer, C. Schairer, P.
Hall, H. Storm, E. Pukkala, F. Langmark, M. Kaijser, M.
Andersson, H. Joensuu, S. D. Fossa and L. B. Travis,
“Risk of Second Non-Hematological Malignancies among
376,825 Breast Cancer Survivors,” Breast Cancer Re-
search and Treatment, Vol. 106, No. 3, 2007, pp. 439-
451. doi:10.1007/s10549-007-9509-8
[11] L. Mellemkjaer, S. Friis, J. H. Olsen, G. Scelo, K. Hem-
minki, E. Tracey, A. Andersen, D. H. Brewster, E. Puk-
kala, M. L. McBride, E. V. Kliewer, J. M. Tonita, C.
Kee-Seng, V. Pompe-Kirn, C. Martos, J. G. Jonasson, P.
Boffetta and P. Brennan, “Risk of Second Cancer among
Women with Breast Cancer,” International Journal of
Cancer, Vol. 118, No. 9, 2006, pp. 2285-2292.
doi:10.1002/ijc.21651
[12] J. S. Raymond and C. J. Hogue, “Multiple Primary Tu-
mours in Women following Breast Cancer, 1973-2000,”
British Journal of Cancer, Vol. 94, No. 11, 2006, pp.
1745-1750.
[13] R. Roychoudhuri, H. Evans, D. Robinson and H. Møller,
“Radiation-Induced Malignancies following Radiotherapy
for Breast Cancer,” British Journal of Cancer, Vol. 91,
No. 5, 2004, pp. 868-872.
[14] S. Galper, R. Gelman, A. Recht, B. Silver, A. Kohli, J. S.
Wong, T. Van Buren, E. H. Baldini and J. R. Harris,
“Second Nonbreast Malignancies after Conservative Sur-
gery and Radiation Therapy for Early-Stage Breast Can-
cer,” International Journal of Radiation Oncology, Biol-
ogy and Physics, Vol. 52, No. 2, 2002, pp. 406-414.
doi:10.1016/S0360-3016(01)02661-X
[15] B. Fowble, A. Hanlon, G. Freeman, N. Nicolaou and P.
Anderson, “Second Cancer after Conservative Surgery
and Radiation for Stages I-II Breast Cancer: Identifying a
Subset of Women at Increased Risk,” International
Journal of Radiation Oncology, Biology and Physics, Vol.
51, No. 3, 2001, pp. 679-690.
[16] A. Becciolini, A. Biggeri, P. Pacini and M. Baccini,
“Breast Cancer Cohort: Florence 1965-1994,” The Pro-
ceedings of the XV International Scientific Meeting of the
International Epidemiological Association, Florence, 31
August-4 September 1999.
[17] W. Zhang, A. Becciolini, A. Biggeri, P. Pacini and C. R.
Muirhead, “Second Malignancies in Breast Cancer Pa-
tients Following Radiotherapy: A Study in Florence, It-
aly,” Breast Cancer Research, Vol. 13, No. 2, 2011, p.
R38. doi:10.1186/bcr2860
[18] T. J. Whelan, I. Olivotto, I. Ackerman , J. W. Chapman, B.
Chua, A. Nabid, K. A. Vallis, J. R. White, P. Rousseau, A.
Fortin, L. J. Pierce, L. Manchul, P. Craighead, M. C.
Nolan, J. Bowen, D. R. McCready, K. I. Pritchard, M. N.
Levine and W. Parule kar, “NCIC-CTG MA.20: An Inter-
group Trial of Regional Nodal Irradiation in Early Breast
Cancer,” Journal of Clinical Oncology, Vol. 29, No. 18,
2011, Abstract LBA1003.
[19] E. Obedian, D. B. Fischer and B. G. Haffty, “Second
Malignancies after Treatment of Early-Stage Breast Can-

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients 775
cer: Lumpectomy and Radiation Therapy versus Mastec-
tomy,” Journal of Clinical Oncology, Vol. 18, No. 12,
2000, pp. 2406-2412.
[20] N. E. Breslow and N. E. Day, “The Design and Analysis
of Cohort Studies,” In: Statistical Methods in Cancer Re-
search, Vol. 2, International Agency for Research on
Cancer, Lyon, 1987, pp. 120-178.
[21] D. L. Preston, J. H. Lubin, D. A. Pierce and M. E. Mc-
Conney, “Epicure User Guide,” Hirosoft International
Corporation, Seattle, Washington, 1993.
[22] J. D. Boice, C. E. Land and D. L. Preston, “Ionizing Ra-
diation,” In: D. Schottenfeld and J. F. Fraumeni, Eds.,
Cancer Epidemiology and Prevention, Oxford University
Press, New York, 1996, pp. 319-341.
[23] R. E. Curtis, J. D. Boice, Jr., M. Stovall, L. Bernstein, R.
S. Greenberg, J. T. Flannery, A. G. Schwartz, P. Weyer,
W. C. Moloney and R. N. Hoover, “Risk of Leukemia af-
ter Chemotherapy and Radiation Treatment for Breast
Cancer,” The New England Journal of Medicine, Vol. 326,
1992, pp. 1745-1751.
doi:10.1056/NEJM199206253262605
[24] D. L. Preston, A. Mattsson, E. Holmberg, R. Shore, N. G.
Hildreth and J. D. Boice, Jr., “Radiation Effects on Breast
Cancer Risk: A Pooled Analysis of Eight Cohorts,” Ra-
diation Rese arch, Vol. 158, No. 2, 2002, pp. 220-235.
doi:10.1667/0033-7587(2002)158[0220:REOBCR]2.0.C
O;2
[25] M. P. Little and J. D. Boice Jr., “Comparison of Breast
Cancer Incidence in the Massachusetts Tuberculosis
Fluoroscopy Cohort and in the Japanese Atomic Bomb
Survivors,” Radiation Research, Vol. 151, No. 2, 1999,
pp. 218-224. doi:10.2307/3579773
[26] J. D. Boice Jr., D. Preston, F. G. Davis and R. R. Monson,
“Frequent Chest x-Ray Fluoroscopy and Breast Cancer
Incidence among Tuberculosis Patients in Massachu-
setts,” Radiation Research, Vol. 125, No. 2, 1991, pp.
214-222. doi:10.2307/3577890
[27] R. E. Shore, L. H. Hemplemann, E. Kowaluk, P. S. Man-
sur, B. S. Pasternack, R. E. Albert and G. E. Haughie,
“Breast Neoplasms in Women Treated with x-Rays for
Acute Post-Partum Mastitis,” Journal of the National
Cancer Institute, Vol. 59, No. 3, 1977, pp. 813-822.
[28] D. H. McGregor, C. E. Land, K. Choi, S. Tokuka, P. I.
Liu and T. Wakabayashi, “Breast Cancer Incidence among
Atomic Bomb Survivors, Hiroshima and Nagasaki 1950-
1969,” Journal of the National Cancer Institute, Vol. 59,
No. 3, 1977, pp. 799-811.
[29] A. Tinger, T. H. Wasserman, E. E. Klein, E. A. Miller, T.
Roberts, J. V. Piephoff and N. A. Kucik, “The Incidence
of Breast Cancer following Mantle Field Radiation Ther-
apy as a Function of Dose And Technique,” International
Journal of Radiation Oncology, Biology and Physics, Vol.
37, No. 4, 1997, pp. 865-870.
doi:10.1016/S0360-3016(97)00026-6
[30] S. L. Hancock, M. A. Tucker and R. T. Hoppe, “Breast
Cancer after Treatment of Hodgkin’s Disease,” Journal of
the National Cancer Institute, Vol. 85, No. 1, 1993, pp.
25-31. doi:10.1093/jnci/85.1.25
[31] M. Clarke, R. Collins, S. Darby, C. Davies, P. Elphin-
stone, V. Evans, J. Godwin, R. Gray, C. Hicks, S. Jame s,
E. MacKinnon, P. McGale, T. McHugh, R. Peto, C. Tay-
lor and Y. Wang, “Effects of Radiotherapy and of Dif-
ferences in the Extent of Surgery for Early Breast Cancer
on Local Recurrence and 15 Year Survival: An Overview
of the Randomised Trials,” Lancet, Vol. 366, No. 9503,
2005, pp. 2087-2106.
[32] H. H. Storm, M. Andersson, J. D. Boice, M. Blettner, M.
Stovall, H. T. Mouridsen, P. Dombernowsky, C. Rose, A.
Jacobsen and M. Pedersen, “Adjuvant Radiotherapy and
Risk of Contralateral Breast Cancer,” Journal of the Na-
tional Cancer Institute, Vol. 84, No. 16, 1992, pp. 1245-
1250. doi:10.1093/jnci/84.16.1245
[33] Y. M. Kirova, L. Gambotti, Y. De Rycke, J. R. Vilcoq, B.
Asselain and A. Fourquet, “Risk of Second Malignancies
after Adjuvant Radiotherapy for Breast Cancer: A Large-
Scale, Single-Institution Review,” International Journal
of Radiation Oncology, Biology and Physics, Vol. 68, No.
2, 2007, pp. 359-363. doi:10.1016/j.ijrobp.2006.12.011
[34] M. Stovall, S. A. Smith, B. M. Langholz, J. D. Boice, R.
E. Shore, M. Andersson, T. A. Buchholz, M. Capanu, L.
Bernstein, C. F. Lynch, K. E. Malone, H. Anton-Culver,
R. W. Haile, B. S. Rosenstein, A. S. Reiner, D. C. Tho-
mas, J. L. Bernstein and WECARE Study Collaborative
Group, “Dose to the Contralateral Breast from Radio-
therapy and Risk of Second Primary Breast Cancer in the
WECARE Study,” International Journal of Radiation
Oncology, Biology and Physics, Vol. 72, No. 4, 2008, pp.
1021-1030. doi:10.1016/j.ijrobp.2008.02.040
[35] J. D. Brooks, J. D. Boice, M. Stovall, A. S. Reiner, L.
Bernstein, E. M. John, C. F. Lynch, L. Mellemkjaer, J. A.
Knight, D. C. Thomas, R. W. Haile, S. A. Smith, M. Ca-
panu, J. L. Bernstein and R. E. Shore, “Reproductive
Status at First Diagnosis Influences Risk of Radia-
tion-Induced Second Primary Contralateral Breast Cancer
in the WECARE Study,” International Journal of Radia-
tion Oncology, Biology and Physics, 2012, Epub 2012/
04/10.
[36] P. L. Horn, W. D. Thompson and S. M. Schwartz, “Fac-
tors Associated with the Risk of Second Primary Breast
Cancer: An Analysis of Data from the Connecticut Tumor
Registry,” Journal of Chronic Diseases, Vol. 40, No. 11,
1987, pp. 1003-1011. doi:10.1016/0021-9681(87)90114-7
[37] J. M. Kurtz, R. Amalric, H. Brandone, Y. Ayme and J. M.
Spitalier, “Contralateral Breast Cancer and Other Second
Malignancies in Patients Treated by Breast-Conserving
Therapy with Radiation,” International Journal of Radia-
tion Oncology, Bi ol ogy and Physics, Vol. 15, No. 2, 1988,
pp. 277-284. doi:10.1016/S0360-3016(98)90005-0
[38] Broet P, de la Rochefordiere A, Scholl SM, Fourquet A,
Mosseri V, Durand JC, Pouillart P and Asselain B, “Con-
tralateral Breast Cancer: Annual Incidence and Risk Pa-
rameters,” Journal of Clinical Oncology, Vol. 13, No. 7,
1995, pp. 1578-1583.
[39] B. F. Hankey, R. E. Curtis, M. D. Naughton, J. D. Boice,
Jr. and JT Flannery, “A Retrospective Cohort Analysis of
Second Breast Cancer Risk for Primary Breast Cancer
Patients with an Assessment of the Effect of Radiation
Therapy,” Journal of the National Cancer Institute, Vol.
70, No. 5, 1983, pp. 797-804.

Region of Treatment in Radiotherapy and Second Malignancies in Breast Cancer Patients
776
[40] J. D. Boice, E. B. Harvey, M. Blettner, M. Stovall and J.
T. Flannery, “Cancer in the Contralateral Breast after Ra-
diotherapy for Breast Cancer,” The New England Journal
of Medicine, Vol. 326, No. 12, 1992, pp. 781-785.
doi:10.1056/NEJM199203193261201
[41] E. L. Kaufman, J. S. Jacobson, D. L. Hershman, M. Desai
and A. I. Neugut, “Effect of Breast Cancer Radiotherapy
and Cigarette Smoking on Risk of Second Primary Lung
Cancer,” Journal of Clinical Oncology, Vol. 26, No. 3,
2008, pp. 392-398. doi:10.1200/JCO.2007.13.3033
[42] C. Rubino, A. Shamsaldin, M. G. Le, M. Labbé, J. M.
Guinebretiere, J. Chavaudra and F. De Vathaire, “Radia-
tion Dose and Risk of Soft Tissue and Bone Sarcoma af-
ter Breast Cancer Treatment,” Breast Cancer Research
and Treatment, Vol. 89, No. 3, 2005, pp. 277-288.
doi:10.1007/s10549-004-2472-8