Radioiodine (131I) has been used for over half a century for diagnostic purposes and
for treating patients with hyperthyroidism and papillary or follicular thyroid carcinoma.
The radiation dose delivered by radioiodine to nonthyroidal tissues is relatively
low (International Commission on Radiological Protection (ICRP) 1988) and no increased
risk of second primary malignancies (SPMs) linked to 131I was found in adult patients
examined with 131I (Hall et al, 1996) or treated with 131I for hyperthyroidism (Ron
et al, 1998; Franklyn et al, 1999). Much higher activities of 131I are used to treat
thyroid cancer patients, resulting in significant radiation exposure. However, the
late health effects associated with 131I given as treatment for thyroid cancer are
difficult to assess since the number of thyroid cancer patients treated at each centre
is comparatively small. To date, the impact of 131I on the occurrence of SPM in thyroid
cancer patients has been studied in only three large cohorts (Hall et al, 1991; Dottorini
et al, 1995; de Vathaire et al, 1997). In an effort to obtain a more accurate quantification
of the overall risk of SPM, a pooled analysis of these three cohorts was performed
and follow-up data were extended beyond the original publications.
The aim of the present study was to evaluate the risk of second cancer and leukaemia
in a cohort of nearly 7000 Swedish, Italian, and French patients with papillary or
follicular thyroid cancer, and to distinguish any pattern of risk related to exposure
to internal radiation therapy given either alone or in association with external beam
radiation therapy.
PATIENTS AND METHODS
Patients
A common database was obtained by pooling patients with papillary or follicular thyroid
cancer of three major European cohorts. Patients with a malignancy prior to thyroid
cancer, with a second malignancy within the first 2 years of follow-up, or dying within
2 years of diagnosis were excluded. The treatment modalities in each cohort have been
described previously (Hall et al, 1991; Dottorini et al, 1995; de Vathaire et al,
1997).
The Swedish cohort consisted of patients initially treated between 1951 and 1977 at
the Departments of Oncology of the six university hospitals in Sweden (Hall et al,
1991). The Italian cohort included patients initially treated between 1958 and 1995
in the Nuclear Medicine Department of the General Hospital in Busto Arsizio (Dottorini
et al, 1995). The French cohort included patients initially treated between 1934 and
1995 in the Cancer Centres of Villejuif, Reims, and Caen (de Vathaire et al, 1997).
The end point of the study was fixed at 31 December 1997 and not later because, in
the absence of recurrent disease, medical surveillance became less frequent after
the first 5 years of follow-up.
The follow-up of patients of the Swedish cohort was updated through the Swedish Cancer
Registry, and the follow-up of patients of the other two cohorts was updated through
the medical records of each institution. Additionally, for each 131I administration,
the date and activity were recorded in order to perform a time-dependent analysis
(see Statistical analysis).
Compared to the previous reports, the Swedish cohort concerned the same patients but
with a mean follow-up extended for 5 years. In the Italian cohort, patients initially
treated between 1991 and 1995 were also included, as well as patients followed for
less than 3 years who were previously excluded; patients who received external radiotherapy
at the time of initial treatment were excluded, because technical parameters needed
for dose calculation could not be obtained. In the French cohort, patients initially
treated between 1992 and 1995 and patients initially treated by external radiotherapy
were also included.
Statistical analysis
A time-dependent analysis using external comparison was performed. Patients were considered
at risk for second cancer during the period of time beginning 2 years after thyroid
cancer diagnosis until any of the following four events: (1) 31 December 1997; (2)
occurrence of an SPM; (3) death; (4) last visit to the ‘Cancer Centre’. Additionally,
the occurrence of a third malignancy was considered in the site-by-site analysis only
if it occurred during the first 2 years after a second malignant neoplasm. Malignancies
that occurred later were excluded from the analysis since it was not possible to separate
the effects of the thyroid cancer and SPM treatments.
Histological diagnosis was obtained for all second primaries and this allowed to exclude
the possibility of metastases, especially in the lungs, bones, and brain.
The expected numbers of SPM were calculated by multiplying the gender, age, and calendar-year-specific
person-years at risk with the corresponding incidence rates in each country. The data
of the Swedish Cancer Registry (Cancer Incidence in Sweden, 2000) were used as reference
rates for the Swedish cohort. Data of the registry of Varese, Lombardy, were used
as reference rates for the patients included in the Italian cohort (Muir et al, 1987;
Parkin et al, 1992, 1997) and for the 229 patients of the French cohort who came from
Italy. The reference rates for the French patients were estimations of cancer incidences
in France during the period 1975–1995 (Menegoz and Cherié-Challine, 2000). For sites
not included in this estimation, two other data sets were used, covering the periods
1978–1982 (Benhamou et al, 1990) and 1983–1987 (de Vathaire et al, 1996). As no incidence
rate was available before 1958 for Sweden, before 1976 for Italy, and before 1975
for France, the expected numbers of malignancies before these dates were calculated
with the incidence rates of the following nearest period of time for each country.
This approximation concerned only 6% of the follow-up.
The observed number of cancers was assumed to follow a Poisson distribution (Breslow
and Day, 1987) and standardised incidence ratios (SIRs) were calculated as the ratio
of observed to expected numbers. As age, gender, and calendar period were taken into
account in the calculation of the expected numbers, the modelling of the SIRs was
stratified only on country.
The exposure to external radiotherapy was considered as a binary variable. All 131I
treatment courses administered up to 2 years before the end of the follow-up were
taken into account. The 131I activity administered was analysed as a time-dependent
variable: a patient, at a given time, was considered to be exposed to a risk of SPM
related only to the cumulative activity administered previously. In this time-dependent
analysis, the risk of SPM at a given calendar period, gender, and attained age was
modelled as a function of the expected number of SPMs from the reference rates, and
of the cumulative 131I activity administered 2 years or more before.
In order to estimate the risk of SPM per administered activity, excess relative risk
(ERR) per GBq and excess absolute risk (EAR) per GBq and 100 000 person-years of follow-up
were modelled as a linear function of the cumulative activity of 131I administered
2 years or more before. Radioiodine activity was also treated as a categorised variable,
reflecting 1–4 standard treatments of 3.7 GBq. This could not be done for leukaemias
due to insufficient numbers.
The significance of the parameters was tested by comparing the module of EPICURE deviance
of nested models. The analysis was done by using AMFIT software (Preston et al, 1991).
Confidence intervals (95% CI) of the risk were estimated using maximum likelihood
methods (Moolgavkar and Venzon, 1987). When convergence was not obtained and lower
or upper bounds not estimable with this technique, a question mark was reported in
the results. All analyses of the pooled cohort were stratified on the study groups
and heterogeneity between study groups was sought.
RESULTS
The study concerned 6841 thyroid cancer patients diagnosed during the period 1934
and 1995 (Table 1
Table 1
Characteristics of the patients treated for a papillary or a follicular thyroid cancer
of the three cohorts and of the pooled cohort
Swedish cohort
Italian cohort
French cohort
Pooled cohort
Patients
Number
1894
1894
3053
6841
Treatment period (years)
1951–1977
1958–1995
1934–1995
1934–1995
Males (%)
460 (24)
433 (23)
688 (23)
1581 (23)
Mean age at thyroid cancer diagnosis (range)
49 (5–91)
44 (5–82)
42 (2–91)
44 (2–91)
Mean follow-up duration (years)
20 (2–46)
8 (2–35)
12 (2–55)
13 (2–55)
Treatment
Thyroid surgery (%)
1783 (94)
1891 (100)
3002 (98)
6676 (98)
External beam radiotherapy (%)
725 (38)
17 (1)
452 (15)
1194 (17)
Treatment with 131I (%)
795 (42)
1576 (83)
1854 (61)
4225 (62)
Mean cumulative 131I activity in GBqa (range)
3.8 (0.4–49.2)
5.9 (0.9–34.4)
6.9 (0.2–55.5)
6.0 (0.2–55.5)
a
In case of treatment with 131I, cumulative activity administered up to 2 years before
the end of follow-up or the diagnosis of second primary malignancies is measured.
). About 20% of them were lost to follow-up. An approximate 3 : 1, female to male
ratio was seen and the mean age at diagnosis was 44 years. In all, 17% were treated
with external radiotherapy and 62% received 131I. Only 9% received both external radiotherapy
and 131I. The mean follow-up period after thyroid cancer diagnosis was 13 years (range:
2–55 years) (Table 1). The mean interval of time between thyroid cancer diagnosis
and SPM was 15 years (range: 2–55 years), and the mean age at SPM diagnosis was 64
years (range: 21–99 years; data not shown).
In total, 576 patients were diagnosed with an SPM, among whom 13 developed a third
malignant neoplasm less than 2 years after the SPM. For all the 6841 thyroid cancer
patients, an overall significantly increased risk of cancer of 27% (95% CI: 15–40)
compared to the general population of each of the three countries was seen and the
risk did not differ between men and women (data not shown). Significantly increased
risk of cancer in the digestive tract (SIR=1.2, n=126), bone and soft tissue (SIR=5.9,
n=19), skin melanoma (SIR=2.3, n=25), kidney (SIR=2.6, n=31), central nervous system
(SIR=2.1, n=21), endocrine glands other than thyroid (SIR=3.6, n=18), and leukaemias
(SIR=1.8, n=18) was seen for the 6841 patients. No significant gender difference was
seen (data not shown). Furthermore, a significantly increased risk was seen for female
breast cancer (SIR=1.3, n=128) and for genital male cancers (SIR=1.5, n=30).
No significant association was found between exposure to external radiotherapy and
risk of SPM, except for bone and soft-tissue cancers (RR=2.9, 95% CI: 1.2–7.3). Furthermore,
no interaction was evidenced between external radiotherapy and 131I administration
for the risk of SPM.
The risk of SPM occurrence in relation to 131I administration is described in Table
2
Table 2
Observed number of SPMs, standardized incidence ratio (95% confidence interval) and
risk of SPM in relation to 131I administration, among the 6841 patients treated for
a papillary or follicular thyroid cancer
All the patients (PYR=77 955)
131I therapy (PYR=37 702)
No 131I therapy (PYR=40 253)
Cancer site (ICD9 code)
Number of SPMs
SIRa
(95% CI)
Number of SPMs
SIRa
(95% CI)
Number of SPMs
SIRa
(95% CI)
Relative riskb: 131I vs no 131I (95% CI)
Oral cavity (140–145)
13
2.0
(1.0–3.4)
10
2.6
(1.2–4.8)
3
0.8
(0.2–2.2)
2.8 (0.8–13.0)
Salivary glands (142)c
7
–
6
–
1
–
7.5 (1.2–143)
Pharynx (146–149)
3
0.5
(0.09–1.6)
1
0.3
(0.02–1.5)
2
0.9
(0.2–2.9)
0.4 (0.02–4.7)
Digestive tract (150–159)
126
1.3
(1.0–1.5)
61
1.2
(0.9–1.5)
65
1.4
(1.0–1.8)
1.1 (0.8–1.5)
Stomach (151)
20
1.1
(0.6–1.7)
10
1.0
(0.5–1.7)
10
1.0
(0.5–1.7)
1.3 (0.5–3.2)
Colon and rectum (153–154)
69
1.3
(0.9–1.6)
37
1.4
(0.9–1.9)
32
1.1
(0.7–1.7)
1.3 (0.8–2.0)
Respiratory organs (161–163)
37
0.9
(0.6–1.3)
20
1.0
(0.6–1.6)
17
0.8
(0.4–1.4)
1.1 (0.5–2.3)
Lung cancer (162)
32
1.0
(0.6–1.4)
18
1.0
(0.6–1.6)
14
0.9
(0.4–1.7)
1.1 (0.5–2.3)
Bone and soft tissue (170–171)
19
5.9
(3.6–9.0)
14
5.8
(2.5–11.2)
5
1.8
(0.3–5.5)
4.0 (1.5–12.4)
Skin melanoma (172)
25
2.5
(1.6–3.7)
11
2.1
(1.1–3.8)
14
2.9
(1.6–4.9)
0.8 (0.3–1.8)
Breast (174)
128
1.3
(1.0–1.5)
54
1.2
(0.9–1.6)
74
1.3
(1.0–1.7)
0.8 (0.5–1.1)
Female genital organs (179–183)
57
0.7
(0.5–1.0)
36
0.9
(0.6–1.3)
21
0.6
(0.3–0.9)
2.2 (1.3–3.9)
Uterus (179–182)
39
1.0
(0.7–1.4)
25
1.1
(0.7–1.7)
14
0.8
(0.4–1.4)
2.3 (1.2–4.7)
Ovary (183)
20
0.5
(0.3–0.8)
12
0.7
(0.3–1.2)
8
0.4
(0.1–0.8)
2.0 (0.8–5.2)
Male genital organs (185–186)
30
1.6
(1.0–2.4)
16
1.3
(0.6–2.3)
14
2.0
(1.1–3.4)
1.1 (0.5–2.3)
Urinary tract (188–189)
50
1.8
(1.3–2.4)
31
2.1
(1.4–3.1)
19
1.4
(0.7–2.3)
1.5 (0.9–2.8)
Bladder (188)
19
1.2
(0.7–1.9)
12
1.4
(0.7–2.3)
7
0.4
(0.1–1.2)
1.6 (0.6–4.5)
Kidney (189)
31
2.6
(1.7–3.8)
19
2.6
(1.5–4.4)
12
2.6
(1.3–4.5)
1.5 (0.7–3.3)
Central nervous system (191–192)
21
2.5
(1.5–3.8)
13
3.0
(1.6–5.2)
8
1.9
(0.8–3.7)
2.2 (0.9–5.7)
Endocrine glands (194)
18
3.1
(1.6–5.3)
10
5.2
(2.4–9.7)
8
1.5
(0.4–1.4)
1.6 (0.6–4.3)
Lymphoma (200–202)
17
1.1
(0.6–1.8)
10
1.1
(0.5–2.2)
8
1.2
(0.5–2.5)
1.0 (0.4–2.8)
Multiple myeloma (203)
6
1.4
(0.5–2.9)
4
1.6
(0.5–3.6)
2
0.6
(0.03–2.6)
1.4 (0.3–0.7)
Leukaemia (204–208)d
18
1.6
(0.8–2.7)
12
1.9
(0.8–3.6)
6
1.2
(0.4–2.8)
2.5 (1.0–7.4)
Othere
21
0.9
(0.5–1.5)
8
0.6
(0.2–1.3)
13
1.2
(0.6–2.1)
0.6 (0.2–1.5)
At least one cancerf
576
1.3
(1.2–1.4)
301
1.3
(1.1–1.5)
275
1.3
(1.1–1.4)
1.2 (1.0–1.4)
PYR=Number of person-years of follow-up.
a
Standardised incidence ratio adjusted on external radiotherapy.
b
Relative risk stratified on study group and adjusted on external radiotherapy.
c
No SIR could be calculated for this cancer since French reference rates are lacking
for this localization.
d
One woman developed a leukaemia less than 1 year after the occurrence of a breast
cancer.
e
Including the following sites (ICD9 code): 160, 164, 165, 175, 184, 187, 190, 195–199.
f
Number of patients with at least one cancer excluding thyroid cancers and nonmelanoma
skin cancers: 13 patients with two second malignancies within 2 years.
. When contrasting those exposed and not exposed to 131I, after stratifying for study
cohort and adjusting for external radiotherapy, increased relative risks were seen
for the bone and soft tissue (RR=4.0), female genital organs (RR=2.2), central nervous
system (RR=2.2), and leukaemia (RR=2.5) (Table 2). Of the 13 cancers of oral cavity,
seven were cancers of the salivary glands: six of them occurred in patients treated
with 131I (n=4225), and only one in patients treated by other means (n=2616). SIR
was not calculated for salivary gland cancer since French reference rates are lacking
for this localisation but analysis using internal comparison yielded a relative risk
of 7.5 (95% CI: 1.2–143).
Among the 344 patients aged less than 20 years at thyroid cancer diagnosis, 13 SMNs
occurred, including two digestive tract, one lung, two bone, five breast, two endocrine
cancers, and one malignant lymphoma. Compared to the general population, the overall
risk of SPM was significantly increased (SIR=2.5), as well as the risk of secondary
breast cancer (SIR=3.4). In all, 61% of the young patients were treated by 131I and
no carcinogenic effect of 131I was found (RR=1.1).
An increased risk of both solid tumours and leukaemias was seen with increasing cumulative
activity of 131I administered after adjustment for external radiotherapy (Table 3
Table 3
Risk of SPMs as a function of the cumulative 131I activity administered 2 years or
more before the diagnosis of SPM
No external radiotherapy
External radiotherapy
All patients
Type of SPM
Amount of 131I (GBq)
Number of SPM/PYR
RRa (95% CI)
Number of SPM/PYR
RRa (95% CI)
Number of SPM/PYR
RRb (95% CI)
Solid cancers
c
⩽0.2
186/29625
1 (ref)
84/10629
1 (ref)
270/40254
1 (ref)
[0.2–3.6]
98/10795
1.2 (0.9–1.5)
23/2553
1.1 (0.7–1.7)
121/13348
1.2 (0.9–1.4)
[3.7–7.3]
78/14330
0.9 (0.7–1.2)
24/2178
1.4 (0.9–2.3)
102/16508
1.0 (0.8–1.3)
[7.4–14.7]
32/4693
1.4 (1.0–2.1)
12/1184
1.6 (0.9–3.0)
47/5877
1.5 (1.0–2.0)
⩾14.8
12/1475
1.5 (0.8–2.6)
7/495
2.1 (0.9–4.7)
19/1970
1.6 (1.0–2.6)
Leukaemias
⩽0.2
4/29625
1 (ref)
2/10629
1 (ref)
6/40254
1 (ref)
[0.2–3.6]
3/10795
1.4 (0.3–6.6)
1/2553
2.2 (0.1–23.5)
4/13348
1.8 (0.4–6.3)
[3.7–18.4]
4/19644
2.6 (0.5–11.8)
3/3485
4.3 (0.7–34.9)
7/23129
3.1 (1.0–10.3)
⩾18.5
0/853
–
1/372
14.0 (0.6–167.4)
1/1225
7.5 (0.4–48.7)
PYR=Number of person-years of follow-up.
a
Relative risks stratified on study group.
b
Relative risks adjusted on external radiotherapy and stratified on study group.
c
All cancers excluding leukaemias, thyroid cancers, and nonmelanoma skin cancers.
). A linear relationship without any significant quadratic effect best fitted the
description of the solid tumours (χ
2=0.46, P=0.5). An ERR of 3.5 % (95% CI: 0.9–6.9%) per GBq of 131I was seen. The ERR
was similar for patients who did or did not receive external radiotherapy, being 3.4%
(95% CI: 0.2–7.8%) and 3.5% (95% CI: 0.01–8.6%), respectively (Table 4
Table 4
Excess of relative risk per cumulative activity of 131I in GBq (ERR) according to
external radiotherapy for major types of SPMs
No external radiotherapy
External radiotherapy
All the patients
Type of SPM
ERR per GBq of 131Ia (95% CI)
Test of trendb
ERR per GBq of 131Ia (95% CI)
Test of trendb
ERR per GBq of 131Ic (95% CI)
Test of trendb
Test of heterogeneityd
Solid cancerse
0.03 (0.002–0.08)
0.03
0.04 (0.00006–0.09)
0.05
0.04 (0.009–0.07)
<0.01
0.6
Soft-tissue and bone cancer
0.29 (?–1.74)f
0.2
1.04 (?–3.93)f
<0.001
0.61 (?–2.41)f
<0.001
0.9
Colorectal cancer
0.15 (0.02–0.38)
0.01
0.02 (?–0.20)f
0.7
0.10 (0.08–0.27)
0.03
0.4
Breast cancer
0.002 (?–0.07)f
1.0
−0.02 (?–0.04)f
0.3
−0.01 (?–0.04)f
0.6
0.3
Leukaemias
0.22 (?–1.30)f
0.2
0.59 (?–2.34)f
<0.01
0.39 (?–1.54)f
0.01
0.4
a
Stratified on study group.
b
Test of trend for a linear dose–effect relationship: P-value.
c
Adjusted on external radiotherapy and stratified on study group.
d
Test of heterogeneity of the ERR between patients exposed and nonexposed to external
radiotherapy.
e
All cancers except leukaemias, thyroid cancers, and nonmelanoma skin cancers.
f
Lower bound not calculable.
). An EAR of 14.4 solid cancers per GBq of 131I administered and per 105 person-years
of follow-up was estimated. No heterogeneity of the results was found between cohorts
(P=0.7). An even stronger relationship was found between the cumulative activity of
131I administered and the risk of leukaemia (Tables 3 and 4). The relationship was
linear, without any significant quadratic effect (χ
2=0.2, P=0.7). The ERR for leukaemia was 39% (95% CI: ?–154%) per GBq and the EAR
was estimated to be 0.8 cases per GBq of 131I administered and per 105 person-years
of follow-up. External radiotherapy, treated as a binary variable (exposed vs nonexposed),
did not influence significantly the relationship between the amount of 131I administered
and the risk of leukaemia.
A significant dose–effect relationship was found for bone and soft-tissue cancers
and for colorectal cancers after adjustment for external radiotherapy (Tables 4 and
5
Table 5
Relative risk of soft-tissue and bone cancer, colorectal cancer, and breast cancer
as a function of the cumulative 131I activity administered 2 years or more before
the diagnosis of SPMs
Number of SPMs and RRa (95% CI)
Amount of 131I (GBq)
Soft-tissue and bone cancer
Colorectal cancer
Breast cancer
⩽0.2
5
1 (ref)
32
1 (ref)
74
1 (ref)
[0.2–3.6]
5
2.9 (0.8–10.7)
12
0.9 (0.5–1.8)
23
0.9 (0.5–1.4)
[3.7–7.3]
4
3.4 (0.8–13.3)
13
1.1 (0.6–2.2)
19
0.6 (0.3–1.0)
[7.4–14.7]
3
7.7 (1.5–33.3)
8
2.5 (1.0–5.5)
9
1.0 (0.4–1.9)
⩾14.8
2
13.0 (1.7–67.1)
4
3.2 (0.9–8.7)
3
0.9 (0.2–2.5)
a
Relative risk adjusted on external radiotherapy and stratified on study group.
), the ERR per GBq of 131I administered being 61% (95% CI: ?–241%, P<0.01) and 10%
(95% CI: 1–27%, P=0.03), respectively, with no evidence for an interaction between
131I administration and external radiotherapy. A significant relationship was found
between the risk of female genital cancer and the amount of 131I administered, although
there was no significant increase in the overall SIR. For cancer of the central nervous
system, a nearly significant increase of the ERR with the amount of 131I administered
was found (P=0.13).
The ERR for solid tumours did not vary widely with time after exposure to 131I: among
the 3211 patients followed at least 10 years after thyroid cancer treatment, the ERR
of SPM more than 10 years after the last 131I treatment was 6% (95% CI: 1–12%) per
GBq of 131I administered.
DISCUSSION
We found a significant 30% increased risk of developing a SPM in one of the largest
cohorts of thyroid cancer patients reported to date. A linear dose–response relationship
with 131I administration was seen for all cancers combined and for leukaemia, and
we estimated that a treatment of 3.7 GBq of 131I will induce an excess of 53 solid
malignant tumours and 3 leukaemias, in 10 000 patients during 10 years of follow-up.
In addition, we identified a strong relationship between the cumulative activity of
131I and risk of bone and soft-tissue cancer, colorectal cancer, and salivary gland
cancer. The increased incidence of SPM seen in the present study and previously reported
(Tucker et al, 1985; Hall et al, 1990, 1991; Dottorini et al, 1995; Edhemovic et al,
1998) could also be related to an increased medical surveillance, common aetiological
factors including hereditary factors, or misclassified metastases. Although increased
medical surveillance could contribute to an earlier detection of cancers with a long
latency, it could hardly explain the excess of leukaemia and of solid cancers with
a poor prognosis and a rapid evolution.
Ionising radiation is the only established cause of thyroid cancer in humans (UNSCEAR,
2000). Other risk factors, such as diet, reproductive factors, deficiency or excess
of iodine, changes in height and weight, have been involved in some studies (La Vecchia
et al, 1999; Negri et al, 1999; Dal Maso et al, 2000; Horn-Ross et al, 2001). It is
not likely that any of these factors would profoundly influence the risk related to
radioiodine since we found a difference between exposed and nonexposed tumours, and,
for some tumours, a dose–response relationship. Some rare familial syndromes associated
with an excess risk of thyroid cancer include familial adenomatous polyposis, Carney
complex, and Cowden syndrome (Stratakis et al, 1997; Lindor and Greene, 1998). Owing
to their rarity, these syndromes probably did not influence our risk estimates.
In all, 20% of patients were lost to follow-up before 1997 as a result of the routine
long-term follow-up programmes. This has probably not introduced any bias in the study,
because the frequency of patients who lost to follow-up was quite similar among patients
who did or did not receive 131I treatment. Moreover, if the end point of the study
is fixed at 31 December 1992, a similar dose–effect relationship is found, with an
ERR of 3.3% per GBq of 131I (95% CI: 0.2–7.5%), whereas about 10% of patients are
lost to follow-up.
All efforts were made to increase the specificity of SPM through exclusion of distant
metastases particularly in the lungs, bones, and brain. When excluding the sites where
possible misclassification of SPM could occur, the overall risk of SPM remained significantly
increased in the 131I exposed group (P=0.02).
Despite the known carcinogenic effect of ionising radiation, no association was evidenced
between external radiotherapy and SPM occurrence in our study except for soft and
bone cancers, and no interaction was found between external radiotherapy and 131I
administration. This could result from the small number of patients treated by external
radiotherapy: less than 1/5 of the patients were treated by external radiotherapy
and less than 1/10 received external radiotherapy and 131I.
All the analyses were nevertheless adjusted on external radiotherapy in an attempt
to access the own effect of 131I on SPM occurrence.
The increased risk of leukaemia was previously observed in the Swedish cohort, but
not in the Italian and French cohorts, demonstrating the advantage of a pooled analysis.
The dose–response relationship was clearly linear, and most cases of leukaemia occurred
in patients treated with high cumulative activities of 131I. We also evidenced a significant
relationship between the cumulative activity of 131I administered and the risk of
solid cancer, with an excess of 4% per GBq. This major result was already suggested
in each of the three cohorts included in our pooled analysis.
Significantly increased risks with higher cumulative amount of 131I was only seen
for colorectal cancer, bone and soft-tissue cancer, and salivary gland cancer. The
excess of colorectal cancer was previously evidenced only in the French cohort (de
Vathaire et al, 1997), and the excess of salivary gland cancer was found in the Swedish
(Hall et al, 1991) and Italian (Dottorini et al, 1995) cohorts. In contrast, the excess
of bone and soft-tissue cancers following 131I administration has not been previously
reported. In fact, an excess of these cancers could only be shown in large cohorts,
because they are infrequent in the general population. These cancers have been frequently
associated to local high doses of radiation delivered by external radiotherapy (UNSCEAR,
2000); indeed, we found that they were associated with exposure to external radiotherapy.
However, the increasing risk of soft tissue and bone cancer with a higher cumulative
amount of 131I remained significant after adjustment on exposure to external radiation
therapy. Finally, the dose–response relationship seen in our series may be due to
the use of larger activities of 131I in patients with bone metastases, and in these
patients a dedifferentiation of metastatic lesions may occur and can rarely be totally
separated from a SPM. However, the rarity of this event argues against its large influence
on our risk estimate.
Ionising radiation can induce tumours of the central nervous system, although the
relationship is weaker than for many other tumours, and most radiation-associated
tumours are benign (UNSCEAR, 2000). The increased risk of central nervous system cancers
in our study leads to question about the radiation doses delivered to the brain after
repeated 131I administrations for thyroid cancer.
An increased incidence of breast cancer was found among women treated for thyroid
cancer as compared to the general population; however, this was not related to 131I
exposure, even among the women who were less than 40 years old at the time of thyroid
cancer diagnosis. This confirms that the radiation dose to the mammary tissue is low
following 131I treatment, despite the expression of the sodium iodide symporter in
some physiological or pathological conditions (Tazebay et al, 2000); in fact, the
mammary tissue is rarely visualised on 131I total body scanning (Hammami and Bakheet,
1996). This finding is in accordance with a case–control study nested in the Swedish
cohort (Hall et al, 1992) and may be related to a closer medical surveillance or to
common aetiological factors. In fact, some population-based cohort studies indicate
an increase of thyroid cancer after breast cancer treatment and an increase of breast
cancer after thyroid cancer (Ron et al, 1984; Teppo et al, 1985; Li et al, 2000).
However, other studies only identified an increased risk of breast cancer after thyroid
cancer treatment (Vassilopoulou-Sellin et al, 1999; Chen et al, 2001).
Similarly, an increased incidence of kidney cancer was found but was not related to
131I exposure. This is in accordance with a previous case–control study nested in
the Swedish cohort, and is not surprising as kidney cancer is not described as a frequently
radiation-induced cancer (UNSCEAR, 2000). All population-based cohort studies of patients
treated for thyroid cancer reported an increased incidence of kidney cancer (Osterlind
et al, 1985; Tucker et al, 1985; Shikhani et al, 1986; Akslen and Glattre, 1992; Ishikawa
et al, 1996; Edhemovic et al, 1998), which may be related to common etiological factors.
For each activity of 131I administered, the organ doses delivered by 131I to thyroid
cancer patients are higher than in euthyroid subjects due to a decreased renal clearance
and prolonged body retention of 131I caused by the hypothyroid condition (M'Kacher
et al, 1996). Due to the local accumulation of 131I, the stomach, salivary glands,
and bladder receive the highest radiation doses. In hypothyroid patients, 131I is
also accumulated in the colon lumen due to a decreased colonic motility. The risk
of colorectal and salivary gland cancers should be minimised by a simple routine of
having patients drink large quantities of fluids and lemon juice, and by the use of
laxatives. Despite the known accumulation of 131I in the stomach and bladder, we did
not find any increased risk for these sites.
Our results concern high activities of 131I and do not apply to the general population
or to patients treated with 131I for hyperthyroidism, since the accumulation of 131I
is low or absent in the colon lumen of euthyroid or hyperthyroid patients.
In conclusion, we report an excess of 53 cases of solid malignancy and of three cases
of leukaemia per 10 years among 10 000 patients treated with a standard activity of
3.7 GBq of 131I. Indeed, these results do not contraindicate the therapeutic use of
131I in patients for whom a clinical benefit is expected. However, as the dose–response
relationships for 131I administration were linear, it seems necessary to restrict
the repeated use of 131I to thyroid cancer patients in whom it may be beneficial (Schlumberger,
1998).