Population- and hospital-based studies suggested that among breast cancer survivors,
the risk of developing a second cancer at other sites is 10–40% higher than in the
general population (Harvey and Brinton, 1985; Rubino et al, 2000). Genetic and hormonal
factors may play a role in this increased risk, as indeed may radiation, chemo- and
hormonal treatments of breast cancer.
The risk of cancer following ionising radiation has been extensively studied and is
relatively well known compared to the risks due to other carcinogens (UNSCEAR, 2000).
However, little data are available for breast cancer patients even though radiation
therapy is widely used to reduce the risk of local recurrence. The relative risk of
second malignant neoplasm (SMN) associated with external radiotherapy is between 0.7
and 1.8 (Harvey and Brinton, 1985; Herring et al, 1986; Murakami et al, 1987; Lavey
et al, 1990; Andersson et al, 1991; Cuzick et al, 1994; Fisher and Anderson, 1994;
Valagussa et al, 1994; EBCTCG, 2000; Tanaka et al, 2001). The conditions in radiotherapy
units delivering high doses to limited volumes are quite different from those in the
cohorts studied to estimate the risk of ionising radiation (UNSCEAR, 2000). Consequently,
predicting the risks of radiation for breast cancer requires an estimate of the relationship
between the radiation dose at a given site and the risk of SMN at this site. Owing
to the heterogeneity of the distribution of the radiation dose through the body, the
overall role of radiotherapy in SMN risk can only be directly investigated by studying
this relationship for all the sites of SMN together.
To this end, we performed a case–control study nested in a cohort of 7711 women treated
for breast cancer between 1954 and 1983. The general characteristics of this cohort,
as well as results for secondary lung cancer have been reported (Rubino et al, 2000,
2002). This is the first report concerning the dose of radiation received for breast
cancer treatment and the risk of overall second cancer.
PATIENTS AND METHODS
Patients
Cases were defined as women who developed an SMN at least 1 year after the diagnosis
of breast cancer, among a cohort of 7711 women treated for breast cancer at the IGR
between 1954 and 1983. We included all women with histologically confirmed SMN, except
those with contralateral breast cancer, nonmelanoma skin cancer and second cancers
of unknown origin. The 281 patients who met these criteria were included in the case–control
study (Table 1
Table 1
Number of cases of each type of SMN, mean age at breast cancer treatment and mean
latency between breast cancer treatment and SMN occurrence
Cancer site
ICD-9
Number of Cases
Mean age at breast cancer treatment (min–max)
Mean latency in years (min–max)
Oral cavity and esophagus and larynx
140–150, 161
11
55 (40–70)
9 (2–25)
Stomach
151
15
58 (44–79)
9 (2–23)
Colon
153
33
57 (37–81)
10 (1–26)
Rectum
154
17
51 (32–75)
11 (1–26)
Liver+gall bladder
155–156
2
57 (49–65)
8 (1–14)
Pancreas
157
5
71 (58–80)
7 (1–16)
Lung and bronchus
162–163
11
50 (3–79)
15 (4–23)
Endometrium uterus
182
42
53 (34–76)
11 (1–33)
Cervix uterus
180
27
49 (16–323)
8 (2–6)
Vulva and vagina
184
3
68 (66–69)
12 (9–16)
Ovaries
183
28
50 (35–69)
11 (1–28)
Bladder
188
6
62 (38–80)
9 (3–16)
Kidney
189
10
55 (37–73)
10 (2–29)
Melanoma
172
14
53 (30–79)
13 (2–32)
Nervous system
191–192
1
40
13
Thyroid
193
8
48 (37–68)
9 (3–27)
Bone and soft tissue
170–171
14
55 (41–77)
11 (3–31)
Myeloma
203
5
58 (49–64)
13 (9–17)
Lymphoma
200–202
15
63 (44–87)
11 (1–30)
Leukaemia
204–208
14
56 (41–71)
11 (1–22)
). Each case was matched with two or three controls from the cohort. Patients were
matched for age at first cancer (±6 years) and period of treatment (1954–1963, 1964–1973,
1974–1983). Controls had to be followed up over a period that was at least as long
as the interval between the breast cancer and SMN diagnosis in the corresponding case
(reference date).
Information concerning the initial characteristics of the breast cancer and the radiotherapy,
chemotherapy and hormonal therapy received between the breast cancer diagnosis and
the reference date was collected from technical and medical records for each case
and control. We thereafter considered the treatment received from the diagnosis of
breast cancer until 1 year before the reference date (i.e. the ‘useful period’).
Radiation dosimetry
The individual dose was calculated using Dos_EG, a software package that was developed
at the IGR for retrospective studies and described in detail elsewhere (Grimaud et
al, 1994; Diallo et al, 1996; Shamsaldin et al, 1997, 1998, 2000). The doses absorbed
at 151 anatomical sites during external beam radiotherapy were estimated for every
patient in the case–control study. The corresponding treatment conditions, generator
and energy were considered, including the use of a shielding block, wedge modifications,
field shapes and field sizes.
To determine whether a dose–response relationship exists, we determined local doses
of radiation, defined as the cumulative dose absorbed at the site of (or closest to
the site of) the SMN for a case, and at the same site for the matched controls during
the useful period. The location of each SMN was determined from medical records. According
to this location, one or more of the 151 points estimates were used to estimate the
local dose of irradiation received by each case and their matched controls.
Dose reconstruction was not possible for 11 (5%) cases and 18 (4%) controls treated
by external radiotherapy due to the absence of technical data. For one control, who
was treated by radiotherapy for castration, the local dose of radiation was considered
to be the mean dose received at this site after a castration by radiotherapy in the
control group. For the other patients, regression analysis was used to explore a correlation
among the cases and the controls between the dose received at the site of SMN (or
equivalent site for the controls) and both clinical characteristics and treatment
features. For 10 cases and 11 controls, a good fit was obtained (R
2>0.4) and the local dose was calculated from the estimated coefficients for each
anatomic site among all the cases and the controls, respectively. For one case and
six controls, the mean dose received at the anatomic site among, respectively, all
the cases and all the controls was attributed.
Chemotherapy
Any chemotherapy for initial breast cancer or its recurrence or distant metastasis
prior to the occurrence of the secondary cancer was recorded for the 281 cases, as
was any chemotherapy received before the reference date for the controls. The details
collected for each course or cycle of chemotherapy included the name and total dose
of each drug used. The doses of each drug received by each case or control either
as initial treatment or for recurrences of the breast cancer (local relapses or distant
metastasis) during the useful period were summed per cycle. Drugs were then classified
into four categories according to their known mechanism of action in cells, rather
than according to their chemical structure: electrophilic agents, spindle inhibitors,
inhibitors of nucleotide synthesis and topoisomerase II inhibitors. To determine the
total amount of drug in each treatment category, we converted the dose of each chemotherapy
agent from milligrams into moles. This was carried out because one molecule of a given
drug generally has one active site, whatever its weight. Even if a particular drug
has more than one active site per molecule, the error introduced by this hypothesis
is probably lower than that introduced when summing the weights.
Hormonal therapy
Data concerning castration (by surgery or radiotherapy), tamoxifen treatment and other
treatments such as progestational agents, oestrogen, androgen or corticoids were collected.
For each category, the total duration of treatment during the useful period was calculated.
Methods
Cases and controls were compared using conditional logistic regression methods (Breslow
and Day, 1980). Generalised risk models were used to evaluate the shape of the dose–response
relationship for radiation dose (Preston et al, 1991): linear and quadratic increases
in the risk of SMN with the radiation dose were tested and the presence of a negative
exponential term to take into account a possible cell killing effect at very high
dose was researched. In these models, the odds ratio (OR) is expressed as follows:
In order to compare our results with those obtained with a single exposure, we used
models that took into account the dose per faction and the number of fractions. In
these models, the OR associated with n fractions delivering a given dose per fraction
dosef is expressed as follows:
An equivalent formulation of the OR is described in two models (3) and (4) where the
OR is expressed as a function of the total dose and the number of fractions,
It is noteworthy that these models show that the fractionation effect, if it exists,
concerns the quadratic and the exponential terms, but not the linear model. The significance
of parameters was tested by comparing nested models. Confidence intervals of the parameters
were estimated by likelihood calculations. The analysis was performed using the Epicure
epidemiological software (Preston et al, 1991).
RESULTS
Characteristics of the cases and controls
A significant global heterogeneity was evidenced between the cases according to the
type of SMN (Table 1) for age at breast cancer diagnosis (P=0.01) and for age at SMN
(P=0.01), but not for the delay between breast cancer and SMN (P=0.2). SMN of the
thyroid and cervix uterus occurred at an earlier age than the other types of SMN,
among patients who had their breast cancer earlier (Table 1).
Cases and controls were on average 54 years old at the time of breast cancer treatment
(ranging from 28 to 87 years), which occurred on average in 1976 (1954–1983). The
SMN occurred on average 10 years after breast cancer treatment (up to 33 years). Clinical
characteristics of cases and controls were very similar: 76% of cases and 78% of controls
had a stage ⩽2 (i.e. M0/N0/T0 to T3, or M0/N1/T0 to T2) cancer, by the UICC classification;
12 cases and 21 controls were M1 (five cases and 10 controls had a primary bilateral
breast cancer, and seven cases and 11 controls had metastasis). At the time of breast
cancer diagnosis, half of the cases and controls had no ovarian activity.
About three-quarters of the cases and controls underwent mastectomy and less than
one-fifth underwent conservative surgery (lumpectomy or partial mastectomy); 209 (74%)
of the cases and 443 (72%) of the controls received radiotherapy (Table 2
Table 2
Details of the breast cancer treatments received by the patients
Cases
Controls
Treatment characteristics
(N=281)
(N=614)
Loco-regional treatments
Radiotherapya: number of patients(%)
209 (74)
443 (72)
Fractions: mean (range)
27 (2–78)
28 (4–189)
Dose (Gy) to the breastb: median (min–max)
52.1 (19.7–112)
54.0 (12.4–117)
Dose (Gy) to the site of SMNc: median (min–max)
3.1 (0.01–68.4)
1.3 (0.002–79.8)
Systemic treatments
Chemotherapyd: number of patients (%)
29 (10)
62 (10)
Electrophilic agents
26 (9)
58 (9)
Spindle inhibitors
25 (9)
45 (7)
Inhibitors of nucleotide synthesis
29 (10)
60 (10)
Topoisomerase II inhibitors
19 (7)
40 (7)
Hormonal treatmente: number of patients (%)
71 (25)
132 (22)
Tamoxifen
46 (16)
93 (15)
Progesterone
13 (5)
35 (6)
Oestrogens
6 (2)
11 (2)
Androgen
25 (9)
27 (4)
Corticoid
5 (2)
10 (2)
Other hormonal treatments
5 (2)
11 (2)
Castration: number of patients (%)
Radiotherapy
68 (24)
150 (24)
Surgery
8 (3)
24 (4)
a
Including treatments for distant metastases and castration; 48 cases and 105 controls
were treated with several machines and the type of machine was unknown for 11 cases
and 18 controls.
b
Cumulative dose of radiation received to the site of the breast treated for a breast
cancer.
c
Cumulative dose of radiation received to the same site of the breast for the matched
controls.
d
Each patient received one or more types of treatment.
). Radiotherapy was performed with Cobalt-60 gamma rays in 96% of the cases and 97%
of the controls, associated with electron beams in 24% of the cases and 22% of the
controls. Only 3% of the cases and 5% of the controls were treated with low-energy
X-rays produced by orthovoltage machines (200–250 KV) and 3% of the cases and 2% of
the controls with megavoltage X-rays (4–20 MeV). Although the cumulative dose to the
breast and the number of fractions were very similar in cases and in controls, the
local dose was about three times higher among cases (3.1 Gy in median) than controls
(1.3 Gy).
In total, 10% of the cases and controls were treated by chemotherapy. The treatment
protocols associated mostly two or more of the following drugs: cyclophosphamine,
5 fluorouracil, methotrexate, adriamycin and vincristine. Each group of chemotherapy
drug was given to an approximately equal proportion of cases and controls, with no
major differences in the mean number of moles administered between the two groups.
Hormonal treatment with one or more drugs was prescribed to 25% of the cases and 22%
of the controls. About 15% of the cases and controls received tamoxifen, with a treatment
duration about two times higher among cases (43 months in median) than controls (27
months). This hormone was either administered for the initial treatment of advanced
cancer among postmenopausal or for the treatment of relapses. The other hormones administered
were mostly progesterone and androgens. Progesterone was mainly prescribed to women
around 50 years old, who were not receiving any other hormone treatments, whereas
androgens were mostly given to older women in association with tamoxifen for the treatment
of distant metastases.
Ovarian function was suppressed in 76 cases and 174 controls, by pelvic radiotherapy
in 68 cases (24%) and 150 (24%) controls. The remaining eight cases and 24 controls
underwent surgery.
Risk associated with radiotherapy
The overall OR of SMN associated with initial radiotherapy was 1.1 (95% CI: 0.8–1.6).
A significant dose–response relationship was found between the radiation dose to the
anatomic site of SMN and the risk of SMN (P<0.01), as shown in Table 3
Table 3
Odds ratios (OR) of second cancer as a function of the local dose of radiation
Local radiation dose in Gy
Number of cases/controls
Mean dose in controls
Unadjusted OR (95% CIb)
Adjusted ORa (95% CIb)
Test of trendc P-value
0
72/171
0
1 (ref)
1 (ref)c
]0–1[
94/212
0.19
1.1 (0.8–1.7)
1.1 (0.7–1.6)
[1–5[
20/56
2.7
0.9 (0.4–1.6)
0.8 (0.4–1.6)
[5–10[
30/54
7.3
1.3 (0.7–2.5)
1.2 (0.6–2.2)
<0.01
[10–15[
30/69
12.9
1.1 (0.6–1.9)
1.1 (0.6–1.9)
[15–20[
16/34
15.9
1.3 (0.6–2.8)
1.3 (0.6–2.8)
[20–25[
4/3
22.9
4.5 (0.9–27.2)
4.0 (0.8–23.2)
⩾25
15/15
41.1
6.4 (1.8–31.4)
6.7 (1.9–33.2)
Any dose
209/443
6.1
1.14 (0.82–1.59)
1.11 (0.80–1.56)
a
OR adjusted for duration of tamoxifen treatment in months and chemotherapy (Y/N).
b
95% CI=95% confidence interval.
c
Test of trend using a quadratic dose–effect relation, after adjustment for duration
of tamoxifen treatment in months and chemotherapy (Y/N).
. Different dose–responses relationships were considered (Table 4
Table 4
OR models and regression coefficients of second cancer for the local dose of radiation
in Gy, adjusted for chemotherapy administration (yes/no) and for duration of tamoxifen
treatment
Regression coefficients
Models
β
1
β
2
γ
1
Deviance
Baseline: OR=exp(α
1 chemo+α
2 tmx)
—
—
—
642.2
Linear: OR=exp(α
1 chemo+α
2 tmx) × [1+β
1(dose)]
0.04
—
—
634.4
Quadratic: OR=exp(α
1 chemo+α
2 tmx) × [1+β
2(dose × dose)]
—
0.002
—
631.0
Linear-quadratic: OR=exp(α
1 chemo+α
2 tmx) × [1+β
1(dose)+β
2(dose × dose)]
−0.03
0.003
—
630.6
Linear-quadratic-exponential: OR=exp (α
1 chemo+α
2tmx) × [1+((β
1(dose)+β
2 (dose × dose)) × exp (γ
1 × dose)]
−0.02
0.003
0.01
630.6
Chemo=chemotherapy; tmx=tamoxifen.
). The best fit was obtained for a purely quadratic dose–response relationship, without
a negative exponential term for cell killing at high doses. Indeed, the deviance of
the quadratic model (deviance=631.0) was lower than that of the linear model and was
not significantly reduced by the addition of a linear term (deviance=630.6) or both
linear and exponential terms (deviance=630.6). The estimated excess odds ratio for
a dose of 1 Gy was 0.002 (95% CI: 0.0005–0.005) with the quadratic model. Figure 1
Figure 1
OR of second malignant neoplasm (SMN) as a function of the radiation dose received
to the site of the SMN for cases and the equivalent site for controls (with 95% CI).
The curves correspond to the estimated excess of the OR of SMN as a quadratic function
of the radiation dose (dotted curves: upper and lower 95% CI).
illustrates the dose–effect relationship with the expected values according to a quadratic
dose–effect model. These results were verified taking the effects of latency, age
at diagnosis of breast cancer, type of SMNs and effect of fractionation into account
successively.
The results were similar after excluding the 85 cases of SMN that occurred during
the first 5 years after breast cancer treatment and their matched controls: the best
fit was obtained with a purely quadratic model and the OR at 1 Gy estimated with a
quadratic model was similar to the previous estimate: 0.003 (95% CI: −0.0006 to 0.007).
Only 26 cases were less than 40 years old at the time of breast cancer treatment.
Among these women and their 64 controls, the overall OR associated with initial radiotherapy
was 2.5 (95% CI: 0.7–11.4), not significantly different from that in older patients
(P=0.2). In the same way, the dose–response for radiation dose was not significantly
different in these two groups (P=0.3).
Our case–control study included 11 patients with lung cancer and 14 with soft tissue
and bone cancer. A dose–response relationship has previously been described for each
of these two types of SMN. After excluding these cancers, the OR for radiotherapy
was 1.0 (95% CI: 0.7–1.5), without a significant dose effect–relationship (P=0.3),
and the OR at 1 Gy estimated with a quadratic model was 0.0006 (95% CI: −0.001 to
0.003). No significant, or near significant, dose–response was evidenced for any of
the other sites of SMN.
A purely quadratic model fitted the OR as a function of the dose per fraction (model
(2)). This result was not modified when a linear (P=0.7) and/or an exponential term
(P=0.6) were added. The excess of odds ratio at 1 Gy per fraction was 0.034 (95% CI:
0.007–0.09) with a quadratic model.
Effect of chemotherapy
No carcinogenic effect of chemotherapy was evidenced: the OR associated with chemotherapy
was 0.8 (95% CI: 0.5–1.2) and none of the four drug categories were significantly
associated with the occurrence of SMN, even after adjustment for radiotherapy and
hormonal therapy.
Effect of hormonal therapy
The overall OR of SMN associated with tamoxifen treatment was 1.2 (95% CI: 0.7–1.9).
A significant dose–response relationship was found between the cumulative length of
treatment and the risk of SMN occurrence (P=0.03) as shown in Table 5
Table 5
OR of SMN as a function of the total duration of tamoxifen treatment, adjusted for
radiation dose and chemotherapy administration (yes/no)
All SMNs
All SMNs excluding endometrial cancer (N=239)
Endometrial cancer (N=42)
Duration of tamoxifen treatment in months
Cases/controls
OR (95% CI)
Cases/controls
OR (95% CI)
Cases/controls
OR (95% CI)
None or less than 1
236/522
1 (ref)*
204/426
1 (ref)**
32/96
1 (ref)***
[1–24[
20/52
0.9 (0.5–1.7)
19/39
1.0 (0.5–1.9)
1/13
0.3 (0.01–1.4)
[24–48[
9/22
0.9 (0.4–2.1)
7/19
0.7 (0.3–1.7)
2/3
1.4 (0.2–9.0)
[48–72[
8/15
1.2 (0.4–3.1)
9/15
1.2 (0.5–2.9)
7/3
13.1 (2.2–249)
⩾72
8/3
5.9 (1.6–28.2)}
*
Test of trend=P<10−2;
**
test of trend=P=0.03;
***
test of trend=P=0.4.
. However, this association was restricted to endometrial cancers, that is, 42 of
the 281 cases. In this group, the risk of SMN was 21.3-fold higher (95% CI: 2.4–563)
after 4 years of treatment compared to in the absence of such treatment. Among the
cases with second malignancies at other sites, the duration of tamoxifen treatment
had no effect (Table 5).
Interactions between radiotherapy and systemic treatments
No significant interaction was observed between radiation dose and chemotherapy or
tamoxifen administration. The odds ratio for a local dose of radiation higher than
1 Gy associated with chemotherapy was 1.0 (95% CI: 0.5–1.9), compared to a null or
lower radiation dose in the absence of chemotherapy (Table 6
Table 6
OR of SMN according to systemic treatment and radiotherapy dose received at the SMN
site of the case and at the same site for matched controls
Dose of radiotherapy at the SMN site
0–1 Gy
>1 Gy
Total
Systemic treatment
OR
(No.)
OR
(No.)
OR
(No.)
Chemotherapy
No
1a
(152/357)
1.2
(100/195)
1b
(252/552)
Yes
1.3
(14/26)
1.0
(15/36)
1.0
(29/62)
Tamoxifen
No
1a
(140/327)
1.2
(95/194)
1b
(235/521)
Yes
1.1
(26/56)
1.3
(20/37)
1.1
(46/93)
No.=Number of cases of SMN/ number of controls. 1a=Reference category for the risks
according to radiotherapy dose and systemic treatment. 1b=Reference category for the
risk of systemic treatment, adjusted for radiotherapy dose.
). Similarly, the odds ratio associated with doses over 1 Gy and tamoxifen was 1.3
(95% CI: 0.7–2.3). The estimates of the radiation dose–response relationship were
not modified by the adjustment for chemotherapy and/or duration of tamoxifen treatment.
DISCUSSION
Our case–control study of 281 cases of SMN and 614 controls, nested in a cohort of
7711 women treated for breast cancer at the IGR between 1954 and 1984 showed that
radiation increased the risk of SMN. A quadratic relationship was found between the
dose of radiation received at a given anatomical site and the risk of SMN occurrence
at this site. The radiation-induced risk was largely limited to lung cancer and bone
and soft-tissue sarcoma, and the dose–response relationship was no longer significant
when these two types of cancer were excluded. No carcinogenic effect of chemotherapy
was observed and there was a dose–effect relationship between the length of tamoxifen
treatment and SMN occurrence. This relationship was limited to endometrial cancers
and did not modify the relationship with radiation dose. This study is the first report
on the relationship between the dose of radiation received for breast cancer treatment
and the risk of overall second cancer.
The dose–response relationship observed has to be interpreted carefully. We estimated
the average relationship between the radiation dose at a set of anatomical sites (or
organs, if small and equivalent to a point) and the risk of SMN at the same sites.
In the case of whole body homogeneous irradiation, this dose–response relation would
directly predict the overall excess cancer risk for such a dose. In the case of radiotherapy,
this dose–response relationship is still an accurate estimate of the average dose–response
for all cancer sites together, but it cannot be used to predict the overall risk of
radiation-induced cancer in patients.
We estimated that the excess risk of SMN when 1 Gy was delivered to the target organ
was 0.2% (95% CI: 0.05–0.5%) when the total dose was delivered in an average of 28
fractions. This is far from that estimated from risk coefficients established with
Hiroshima and Nagasaki (HN) survivors, even when the age of the women in our cohort
at the time of breast cancer treatment was taken into account. For HN survivors, there
is a linear relationship between dose of radiation and risk of solid tumours and the
excess relative risk per Gy among women aged 30 years at the time of irradiation is
79% for all solid cancers (UNSCEAR, 2000). The excess relative risk decreases by 50%
for each additional decade of age at the time of irradiation and is thus about 10%
at 55 years of age. The risk we estimated for the total dose of radiation is an estimation
of the risk associated to the entire radiation treatment in several fractions and
is not directly comparable to the risk induced by a single exposure to radiation.
Conversely, the excess risk we estimated at 1 Gy per fraction, that is, 3.4% (95%
CI: 0.7–9%), which can be compared to that of a single exposure, is lower but probably
not statistically different from the estimation for HN survivors (10%). In addition,
due to the quadratic shape of the relationship, this discrepancy reduces with increasing
dose. Thus, for example, for a dose per fraction of 2 Gy, the excess OR we estimated,
that is, 14% (95% CI: 2.8–36%), is not significantly different from that estimated
from HN-survivors with a linear model (20%).
In general, excess risks per dose unit in studies of cancer risk following radiotherapy
are lower than those estimated in HN survivors (Little, 2001). Little investigated
this finding in detail and concluded that this discrepancy can largely be explained
by cell sterilisation effects, although other factors such as difference in underlying
cancer risk and dose fractionation effects may also contribute (Little, 2001). Conversely,
our results do not support a role of cell sterilisation. This was nonsignificant,
whatever the model fitted. Instead, they support the hypothesis that this discrepancy
is due to dose fractionation.
The risk associated with radiotherapy in our case–control study is lower than that
previously estimated in a sub-cohort analysis including 4416 women (Rubino et al,
2000): 1.1 vs 1.6. This discrepancy is not due to overmatching, but is explained by
the patient selection in the sub-cohort. The low OR we estimated for radiotherapy
(yes/no), 1.1, is consistent with the low estimated coefficient for dose–response,
and with the general findings of 11 other studies on SMN incidence or mortality (0.7–1.8).
Only three studies (Herring et al, 1986; Lavey et al, 1990; Fisher and Anderson, 1994),
the smallest ones, which included less than 50 SMN cases, estimated a relative risk
of above 1.5. The other studies (Harvey and Brinton, 1985; Murakami et al, 1987; Andersson
et al, 1991; Cuzick et al, 1994; Valagussa et al, 1994; EBCTCG, 2000; Tanaka et al,
2001; Veronesi et al, 2002) included about 3500 SMN incident cases or deaths and estimated
a maximum relative risk of 1.2. The RR associated with radiotherapy generally estimated
in previous studies is probably very similar to our finding.
We did not find that the risk of SMN was increased by chemotherapy administration.
Chemotherapy was first used as part of the treatment of breast cancer during the late
1970s. Consequently, only a small proportion of the women in our study (10%) received
this treatment. At present, eight studies have investigated the role of chemotherapy
in the risk of all types of SMN. In two studies (Lavey et al, 1990; Rubagotti et al,
1996), which included a total of 59 SMN cases that occurred during an average follow-up
of 5 years, the relative risk associated with chemotherapy was between 2 and 3. In
the other six studies (Herring et al, 1986; Murakami et al, 1987; Valagussa et al,
1987, 1994; Matsuyama et al, 2000; Tanaka et al, 2001), this risk ranged from 0.5
to 1.05. Overall, there is currently no evidence that the overall SMN risk is increased
by the antineoplasic drugs administered for breast cancer treatment. However, new
drugs are regularly introduced and no published study has a long enough follow-up
period to study the risk associated with recent drugs.
Tamoxifen is increasingly used as adjuvant therapy and reduces recurrences and mortality
among breast cancer patients as well as the occurrence of contralateral breast cancers
(EBCTCG, 1998). We found a low increased risk associated with this hormonal therapy,
limited to endometrial cancer, as previously shown (Curtis et al, 1996; EBCTCG, 1998;
Mignotte et al, 1998). Tamoxifen treatment increases the risk of overall SMN by 0.7–1.2
depending on the study (Fornander et al, 1989; Andersson et al, 1991, 1992; Rutqvist
et al, 1995; Curtis et al, 1996; Rubagotti et al, 1996; EBCTCG, 1998; Newcomb et al,
1999; Tanaka et al, 2001).
In conclusion, our results suggest that radiotherapy plays a small role in the overall
risk of second malignancies after breast cancer.