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Original article © Schattauer 2011 93

131Itherapy in patients with benign


thyroid disease does not
conclusively lead to a higher risk of
subsequent malignancies
F. A. Verburg1; M. Luster1; M. Lassmann2; C. Reiners2
1Department of Nuclear Medicine, University of Ulm; 2Department of Nuclear Medicine,
University of Würzburg,Germany

Keywords studies even reported a slightly lower risk of Zusammenhang zwischen RIT und „sekundä-
131
I treatment, benign thyroid disease, malignant (thyroid) disease after 131I therapy rem“ Malignom als nachgewiesen anzuse-
malignancy, incidence for benign thyroid diseases. Conclusion: As hen: a. zwischen Strahlenexposition und Auf-
over 60 years of experience has thus far failed treten strahleninduzierter Malignome sollte
Summary to produce conclusive evidence to the eine Latenzzeit von mindestens 5 Jahren lie-
Due to its excellent tolerability and low inci- contrary, it can be concluded that there is no gen und b. sollte ebenso eine Dosisabhängig-
dence of side effects, 131I therapy has been the increased risk of malignancies after 131I ther- keit des Risikos dargestellt werden können,
treatment of choice for benign thyroid dis- apy for benign thyroid disease. wobei eine höhere absorbierte Strahlendosis
eases for over 60 years. A potentially in- mit einem höheren Risiko einher gehen sollte.
creased risk of malignancies due to this ther- Ergebnisse: Es wurden insgesamt 7 Studien
apy is however still subject of debate. Aim: To Schlüsselwörter mit Daten über die Krebs-Inzidenz und -Mor-
review the literature pertaining to 131I therapy 131
I-Behandlung, gutartige Schilddrüsen- talität in vier Patientenkollektiven von ins-
of benign thyroid diseases in order to estab- erkrankung, Malignität, Inzidenz gesamt 54 510 Patienten gefunden. Die Nach-
lish whether there is an increased incidence sorgedauer variierte von 2 bis 49 Jahren. Ob-
of, or increased mortality due to malignancies Zusammenfassung wohl einige Studien ein leicht erhöhtes Risiko
of the thyroid or other organs. Methods: In Wegen ihrer ausgezeichneten Verträglichkeit für Schilddrüsenmalignome oder Neoplasien
order to allow for sufficient long-term follow- und der niedrigen Rate von Nebenwirkungen des Magen-Darm-Traktes aufwiesen, konnten
up time after 131I therapy, only literature after ist die Radioiodtherapie (RIT) bereits seit über diese Effekte in andere Studien nicht reprodu-
1990 was reviewed. Two criteria were applied 60 Jahren die Therapie der Wahl bei benignen ziert werden – weitere Untersuchungen be-
to consider an increased incidence of malig- Schilddrüsenerkrankungen. Es ist jedoch un- richteten sogar über ein leicht erniedrigtes Ri-
nancies linked to 131I therapy: a) there should klar, ob die RIT zu einem erhöhten Risiko für siko für maligne Schilddrüsenerkrankungen
be a latency period of at least 5 years between das Auftreten maligner Folgeerkrankungen nach RIT wegen benigner Veränderungen.
131 führt. Ziel: Anhand der vorhandenen Literatur
I therapy and the observation of an in- Schlussfolgerung: Obwohl die 131I-Behand-
creased risk b) an elevated risk should in- zu prüfen, ob die RIT zu einer erhöhten Inzi- lung bereits seit mehr als 60 Jahren eine etab-
crease with increasing radiation exposure. Re- denz und/oder Mortalität bösartiger Folge- lierte Therapiemodalität für benigne Schild-
sults: A total of 7 studies reporting cancer inci- erkrankungen führt. Methode: Wir betrachte- drüsenerkrankungen darstellt und millionen-
dence and / or mortality in 4 different patient ten lediglich Studien, die nach 1990 publiziert fach durchgeführt wurde, finden sich in der Li-
collectives spanning a total of 54 510 patients wurden, um eine ausreichende Nachbeobach- teratur keine eindeutigen Hinweise für eine
over an observation period varying from 2–49 tungszeit nach der Radioiodtherapie zu ge- erhöhte Inzidenz von oder Mortalität auf-
years were found. Although some studies de- währleisten und somit z. B. auch das Risiko für grund von malignen Erkrankungen – weder
tected a slightly increased risk for malignan- ein strahleninduziertes Schilddrüsenkarzinom von der Schilddrüse – noch von anderen Orga-
cies of the thyroid or the digestive system, zuverlässig abschätzen zu können. Zwei Krite- nen ausgehend.
others did not find these effects – while other rien wurden verwendet um einen möglichen

Correspondence to: 131I-Therapie führt bei Patienten mit benignen

Frederik A. Verburg, MD, PhD Schilddrüsenerkrankungen nicht eindeutig zu


University of Würzburg, einem höheren Risiko auf Folgemalignitäten
Department of Nuclear Medicine Nuklearmedizin 2011; 50: 93–99
Oberdürrbacher Str. 6, 97080 Würzburg doi:10.3413/Nukmed-0341-10-08
Tel. +49/(0)931/201–35412 received: August 5, 2010
Fax +49/(0)931/201–635100 accepted in revised form: December 6, 2010
E-mail: verburg_e@klinik.uni-wuerzburg.de prepublished online: December 17, 2010

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94 F. A. Verburg et al.: 131I therapy and risk of malignancies

Since its introduction in the early 1940s, creased incidence or increased mortality Definitions
131I has been the therapy of choice for a because of radiation induced malignancies
number of benign thyroid diseases and rep- of the thyroid or other organs has been ob- In literature, a number of definitions are
resents the most commonly used thera- served. commonly used:
peutic nuclear medicine procedure (15). ● Standardized incidence ratio (SIR),

The main indications for 131I therapy con- which is defined as the number of cases
sist of Methods observed in the study population di-
● Graves’ disease and vided by the number of cases that would
● nodular goitre with or without thyroid We conducted a literature search using the be expected based on the age and sex of
autonomy. online search tool of the United States the study subjects.
National Library of Medicine ● Standardized mortality ratio (SMR),
131I is a more efficient therapeutic nuclide (씰www.pubmed.org). As thyroid carcino- which is defined as the number of deaths
than other potential sodium-iodine-sym- ma is a slow growing process and secondary occurring in the study population di-
porter. In-vivo it causes more cellular dam- malignancies may take decades to be dis- vided by the number of deaths expected
age than e. g. 188Re-perrhenate (24). covered, only literature after 1990 was re- to occur based on the age and sex of the
Many observational studies have con- viewed in order to allow for sufficient fol- study subjects.
cluded, that the accidental intake of radio- low-up time after 131I therapy. Studies pub-
active substances (such as e. g. after the lished before this time cannot be consider-
atomic bombing of Hiroshima and Naga- ed to have followed patients long enough to Results
saki or the Chernobyl reactor disaster (1)) produce a reliable estimate of the risk of
leads to an increased incidence of malig- thyroid carcinoma. In literature a number of reports at least
nant thyroid disease. This increase is es- For establishing whether there is a rela- partially considering the criteria men-
pecially noticeable in the case of childhood tionship between radiation exposure and tioned above were available about four dif-
papillary thyroid carcinoma (20). Such in- the risk of malignancy due to this exposure ferent patient cohorts. They stem from a
take also takes place, albeit intentionally, in the following difficulties and criteria patient collective studied at the University
the case of 131I therapy of benign thyroid should be taken into account: of Helsinki (17, 18), a collective from the
disorders, but in this case the absorbed 1. The age at the time of radiation expo- University of Birmingham (5–7), a Swedish
radiation dose in the thyroid is usually sure is of great importance, as the risk of multicentre cohort (2, 9–12) and the co-
much higher than in the case of an acciden- radiation induced malignancies is con- hort studied in the American Cooperative
tal incorporation. Unintended intake of siderably higher in children/adolescence Thyrotoxicosis Therapy Follow-Up Study
low radioiodine activities may lead to sub- than in adults (3). (22). In all of these cohorts both the inci-
lethal cellular damage, which in turn may 2. There should be a latency time of at least dence of malignant diseases and the cancer
contribute to malignant transformation, 5 years between radiation exposure and related mortality were studied extensively.
whereas in the case of 131I therapy apoptosis the occurrence of radiation induced Each study was reviewed with regard to
and necrosis may play a greater role, malignancies; therefore the risk pertain- its findings and its adherence to the criteria
thereby reducing the probability of malig- ing to the radiation exposure should be outlined in the materials and methods sec-
nant transformation of thyroid cells. increasing over time (19). tion as well as for the control groups used.
Over the past decades, several studies 3. A dose dependency of the risks found
have been published in literature on the should be established; a higher absorbed
risk of 131I therapy for induction of thyroid radiation dose should be associated with Radiation absorbed dose to the
carcinoma and other carcinomas (2, 5–7, a higher risk of malignant diseases. thyroid
9–12, 17, 18, 22). Some of this literature was 4. Taking these considerations into ac-
already briefly summarized by Lucignani in count it also follows that a comparison The method of reporting the radiation ex-
2007 (16), however no extensive reviews of only with a control group consisting of posure of thyroid tissue vary widely be-
the literature on this subjects exist that can completely healthy subjects is insuffi- tween the studies. The studies originating
be of help in decision making in clinical cient for proving an increased risk of or from the English cohort did not attempt to
practice. In addition, patients remain scep- mortality due to malignant diseases; to estimate the radiation absorbed dose to the
tical about the risk of cancer after radionu- conclusively prove such an effect the thyroid; they report the cumulative total
clide therapy (8). Therefore, it seems ap- study population should also be com- 131I activity given by dividing the cohort in

propriate to expound more elaborately on pared to a control group consisting of patients receiving less than 220 MBq
the existing literature on the subject in the patients with the same benign thyroid (49.3% of the cohort), 221–480 MBq
form of an in-depth review. Thus the aim of disease, who were treated by non-radio- (34.0%) and those receiving more than 480
this study is to review the literature pertain- active procedures (e. g. surgery). MBq 131I (16.6%) (6). Holm et al. used
ing to 131I therapy of benign thyroid dis- ICRP tables to estimate the average organ
eases in order to establish whether an in- dose for each organ during 131I therapy;

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F. A. Verburg et al.: 131I therapy and risk of malignancies 95

however, they only report that the average Malignancies of the thyroid of 1.6–3.5 MBq of 131I, between 1952 and
absorbed dose to the thyroid was at over 1969. In this study patients who were diag-
100 Gy (13). In their cohort 30% of patients Incidence after diagnostic 131I nosed with thyroid cancer within two years
received 220 MBq or less, 38% received be- activity after the diagnostic 131I scintigraphy were
tween 220 and 480 MBq and the remaining excluded. The estimated mean absorbed
32% of patients received more than 480 Although 131I is currently only used for radiation dose in the thyroid was 0.94 Gy.
MBq 131I. therapeutic purposes, in earlier days it has After 886 618 person-years of follow-up
Ron et al., for lack of data on gland size also been used for diagnostic procedures. they only found an increased incidence of
and 131I kinetics, estimated the radiation As already mentioned in the introduction, thyroid carcinoma in those patients with a
dose to the thyroid and other organs by it is, on principle, possible that lower activ- previous history of external beam radiation
multiplying the administered activity with ities lead to a higher chance of malignancy therapy of the neck (SIR 9.8, 95% con-
standard dose factors. In this study the than therapeutic activities. Therefore, it fidence interval (CI): 6.3–14.6) and in pa-
mean cumulative administered 131I activity seems fitting to briefly discuss the available tients who were originally referred for thy-
was 385 MBq; no further data on the dis- literature here. roid scintigraphy with a suspicion of a thy-
tribution of activities was given. Both Hall et al. (11) and nearly a decade roid tumour (SIR 3.5, 95% CI: 2.7–4.4).
Metso et al. did not attempt to calculate later Dickman et al. (2) studied the inci- External beam radiation beam therapy
radiation absorbed doses to the thyroid or dence of thyroid cancer in a Swedish cohort is a well-known etiologic factor in the pa-
other organs; they only reported the medi- of eventually 36 792 patients who under- thogenesis of thyroid carcinoma (21,23).
an cumulative 131I activity given: 259 MBq, went diagnostic 131I scintigraphy with, de- The elevated incidence of thyroid carcino-
with a range of 55–2664 MBq. pending on the subgroup, a median activity ma in patients with a prior clinical suspi-

Tab. 1 Summary of the literature pertaining to thyroid carcinoma incidence and mortality after 131I therapy of benign thyroid disorders

study USA Sweden England Finland


Ron et al. (22) Hall et al. (9), Franklyn et al. (6) Metso et al. (17, 18)
Holm et al. (13),
Hall and Holm (12)
no. of patients 33748 10552 7417 2793
● Graves’ disease 30725 not separated not separated 1604
● (nodular) goitre 2694 further further 1189
age of patients (mean) 46 years 57 years 57 years 62 years
duration of follow-up 26–44 years 26–47 years 8–49 years 2–39 years
control group SMR for the American SIR, SMR for the Swedish SIR, SMR for the English age- and sex-matched controls
population population population from the general population
effect 2.08 1.32 (n.s.) 3.25 not elevated
● SIR 6.53 0.81 2.78 not elevated
● Graves’ disease 1.74
● (nodular) goitre not elevated
● SMR
● RR (incidence)
● RR (mortality)
● Graves’ disease
● (nodular) goitre

dose dependency? none Graves’ disease: n.a. not described n.a.


(nodular) goitre: none
latency period none; mortality only Graves’ disease: n.a. yes; diagnosis of all carcinomas n.a.
elevated within the first five (nodular) goitre: none >4 years after 131I therapy
years after 131I therapy
conclusion probably no effect of 131I no effect of 131I therapy Cannot be assessed as dose de- no effect of 131I therapy
therapy pendency and effect of thyroid
pathology were not analyzed
separately.
n.s.: not significant; n.a.: not analyzed; SIR: standardized incidence ratio; SMR: standardized mortality ration; RR: relative risk

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96 F. A. Verburg et al.: 131I therapy and risk of malignancies

cion of a thyroid tumour constitutes an ob- no increased thyroid cancer incidence or dence time, which generally is considerably
vious bias where the tumour is the cause of mortality has been encountered. Only in larger in goiter patients than in patients
rather than caused by the 131I exposure. the collective studied at the University of with Graves disease (14), thus leading to a
Considering these last two factors, no Birmingham (6) such an increased inci- higher absorbed radiation dose, plays a
evidence remains that a diagnostic 131I ac- dence and mortality was described, but the role.
tivity can cause an elevated incidence of authors of this study neither investigated In conclusion, it can be stated that no
thyroid cancer. the dose dependency of the incidence / conclusive evidence for an elevated, radi-
mortality, nor did they correlate this in- ation-induced thyroid carcinoma inci-
Thyroid carcinoma incidence and/or creased incidence with the prior thyroid dence or mortality after the treatment of
mortality after 131I therapy for history of patients. This makes it imposs- benign thyroid diseases currently exists in
benign thyroid disorders ible to form a conclusive opinion on literature.
whether the increased thyroid carcinoma
In relation to 131I therapy for benign thy- incidence / mortality rate in this collective Incidence of other malignancies
roid diseases thyroid carcinoma is the most is actually related to the 131I therapy of be-
important late consequence of interest for nign thyroid disorders. Even though 131I therapy results in far
the nuclear medicine physician: patients An interesting observation is made in higher radiation doses being absorbed by
often ask whether they will have an elevated the study by Holm et al.: The incidence of thyroid tissue than by any other type of tis-
risk of thyroid cancer after 131I treatment. non-thyroid carcinomas tends to be some- sue in the body, several organs, such as the
In 씰Table 1 we have summarized the litera- what higher in patients with multinodular stomach, kidney and bladder, do receive
ture on this subject. goiter than in patients with Graves’ disease. non-negligible radiation doses as well, and
In most studies pertaining to the four The precise cause for this remains unclear, may therefore be at risk for a higher inci-
patient collectives described in literature but it can be speculated that the 131I resi- dence of malignant transformation in these

Tab. 2 Summary of the literature pertaining to the incidence of non-thyroid carcinomas after 131I therapy of benign thyroid disorders

study Sweden England Finland


Holm et al. (13) Franklyn et al. (6) Metso et al. (17)
no. of patients 10552 7417 2793
age of patients (mean) 57 years 57 years 62 years
duration of follow-up mean 15 years, 8–49 years median 9.8 years,
max. 28 years range 2–39 years
control group SIR for the Swedish population SIR for the English population age- and sex-matched controls from the
general Finnish population
effect 1.06 (95% CI: 1.01–1.11) 0.83 (0.77–0.90) 1.25 (95% CI: 1.08–1.46)
● SIR 0.99 (95% CI: 0.93–1.12) stomach (RR 1.75)
● Graves’ disease 1.21 (95% CI: 1.08–1.35) kidney (RR 2.32)
● (nodular) goitre stomach (SIR 1.95) breast (RR 1.53)
● RR (Incidence) female genitals (SIR 1.42)
kidney (SIR: 1.81)
brain (SIR 2.21)
dose dependency? not statistically significant in any cancer significant positive association between significant dependency on activity:
131I activity and incidence of bladder RR = 1.06 / 100 MBq.
cancer (overall bladder cancer incidence
reduced) and uterine cancer (overall
uterine cancer incidence not different
from expected)
latency period only significant in stomach cancer, n.a. latency time of 10 years
not in other cancers
conclusion possibly an elevated incidence of no evidence for increased cancer inci- increased incidence of especially
stomach cancer; no other effects of 131I dence stomach, kidney and breast cancer due
to 131I therapy: 1 excess cancer case for
every 418 therapy courses
n.a.: not analyzed; SIR: standardized incidence ratio; RR: relative risk; 95% CI: 95 percent confidence interval

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F. A. Verburg et al.: 131I therapy and risk of malignancies 97

organs. In three of the four patient series across the board, i. e. both in patients with mortality – even though the mortality due
described in literature the incidence of nodular goiter and patients with Graves’ to small bowel malignancies was in-
other malignancies was extensively studied; disease. creased-, Hall et al. and Metso et al. found a
the results of these studies are summarized In summary, although the studies pub- slightly elevated mortality, especially due to
in 씰Table 2 and 씰Table 3. lished offer some evidence of an elevated cancers of the gastrointestinal tract. How-
Metso et al. (17) found an increased risk cancer incidence, especially in the gastro- ever, Hall et al. were unable to show an ad-
for stomach, kidney and breast cancer (all intestinal tract, this increase in incidence equate latency time or dose dependency be-
organs that receive a considerable 131I expo- mostly cannot be conclusively and repro- tween the 131I therapy and the increased
sure) subsequent to 131I therapy. These re- ducibly linked to the 131I therapy of benign mortality, so the effects reported in their
sults are not conclusively confirmed by thyroid disorders. study are most likely due to other con-
Holm et al., who found a possible associ- founders. Franklyn et al. and Metso et al.
ation between 131I therapy and stomach, Mortality due to other malignancies unfortunately report no analysis of either a
brain, kidney and female genital cancer – time- or dose-dependency between 131I
even though there was no significant dose In each of the four patient series described therapy and an increased cancer mortality
dependency of the cancer incidence or a in literature the cancer-related mortality rate, which leaves us unable to assess the
significant latency period. In contrast after 131I therapy for benign thyroid dis- causal relationship between the two.
Franklyn et al. (6) even suspected a lowered eases was analyzed. The results of these In summary, there is some evidence of
overall incidence of cancer after 131I ther- studies are summarized in 씰Table 4. an increase in mortality rates due to cancers
apy. Of note is that Holm et al. (13) only de- Taken together, three out of the four of the gastrointestinal tract in patients who
tected an elevated risk of some cancers in studies on this subject find no increased received 131I therapy for benign thyroid dis-
patients with nodular goiter and not in pa- over-all cancer mortality that can be at- ease, but there is currently no conclusive,
tients with Graves’ disease, whereas Metso tributed to 131I therapy. Whereas Franklyn reproducible evidence that this is actually
et al. (17) found an elevated cancer risk et al. even found a lowered overall cancer caused by the 131I therapy.

Tab. 3 study Holm et al. (13) Franklyn et al. (6) Metso et al. (17)
Summary of the affected organ Sweden England Finland
absolute numbers of
new tumours dis- observed expected observed expected patients controls
covered in patients oral cavity, pharynx 21 20.6 5 9.0 367 308
and controls or the
number of new salivary glands 3 3.6 none reported 2 0
tumours that was oesophagus none reported none reported 5 1
observed versus the
stomach 92 87.6 38 39 30 18
expected number,
given per organ liver 23 17.3 none reported 39 36
system.
pancreas 63 56.3 11 23
intestine, colon, rectum 209 190.0 intestine: 6 intestine: 1.2 44 45
lung 105 79.5 65 106 24 29
female breast 269 263.7 132 124 74 50
female genital organs 182 182.0 81 100 42 36
male genital organs 77 77.0 21 17
kidney 66 47.5 20 9
bladder 51 45.5 18 28 7 9
brain 48 36.9 4 7.4 7 4
thyroid gland 18 14.0 9 2.8 5 3
parathyroid glands 30 16.9 none reported none reported
lymphomas 28 38.9 12 16 22 18
multiple myeloma 21 20.0 none reported
leukaemias 34 36.2 10 13
unspecified site none reported none reported 19 9

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98 F. A. Verburg et al.: 131I therapy and risk of malignancies

Discussion It is quite striking that in the large adult malignant transformation, whereas in the
collectives studied, no elevated incidence of case of 131I therapy apoptosis and necrosis
Even though more than 60 years have pass- thyroid cancer is found despite the radiation may play a greater role, thereby reducing
ed since the first 131I therapy was adminis- exposure. the probability of malignant trans-
tered in patients with benign thyroid dis- formation of thyroid cells.
ease, it is still difficult to definitively answer This is in marked contrast with the situ- A large difficulty presented by the retro-
the question of whether an elevated cancer ation in children as could clearly be ob- spective nature of all the studies lies there-
incidence or mortality rate occurs after 131I served after the 1986 Chernobyl reactor ca- in, that it is extremely difficult if not im-
therapy for benign thyroid disorders, as the tastrophe (20). Age will certainly play a role possible to accurately reconstruct thyroid
data in literature is still deficient at some – especially in the post-Chernobyl situ- and whole body absorbed radiation doses.
points. Nearly all studies compare the pa- ation it has been clearly documented that As a surrogate some authors have taken the
tient data to controls from the general the incidence of thyroid cancer has es- administered activity, but large variations
population, or to standardized incidence or pecially risen in the very young (i. e. in in effective thyroid and whole-body 131I
mortality rates that were established based utero, babies and young children) (3). In clearance between patients make this ap-
on statistical data derived from the general contrast the collectives reviewed here had proach an approximation at best, and an
population. In the case of thyroid carcino- none or very few patients under 20 years of accurate assessment of radiation dose-re-
mas this is however incorrect, as patients age at the time of therapy. Another expla- sponse relationships is not reliably possi-
with a nodular goiter have an inherently nation for the difference between the two ble.
higher risk for developing thyroid carcino- cohorts might be found in the hypothesis A further deficiency is that many studies
ma (4, 25). Therefore, all these studies will which was already given in the introduc- have even entirely omitted a thorough
have considerably overestimated the risk tion: unintended intake of low radioiodine analysis of the latency time and dose de-
for thyroid cancer caused by 131I therapy activities may lead to sub-lethal cellular pendency of a possibly elevated incidence
due to an inadequate selection of controls. damage, which in turn may contribute to rate or mortality rate. Therefore, it cannot

Tab. 4 Summary of the literature pertaining to non-thyroid cancer mortality after 131I therapy of benign thyroid disorders

study USA Sweden England Finland


Ron et al. (22) Hall et al. (9) Franklyn et al. (6) Metso et al. (18)
no. of patients 33748 10552 7417 2793
age of patients 46 years 57 years 57 years 62 years
(mean)
duration of 26–44 years mean 15 years, max. 35 years 8–49 years median 9.8 years,
follow-up range 2–39 years
control group SMR for the American SMR for the Swedish SMR for the English age- and sex-matched controls
population population population from the general Finnish
population
effect 1.02 (0.98–1.07) 1.09 (95% CI: 1.03–1.16) 0.90 (95% CI: 0.82–0.98) 1.29 (95% CI: 1.07–1.57)
● SMR specific: increased mortality due specific: increased mortality specific: increased mortality due
● RR (mortality) to gastro-intestinal due to small bowel to gastro-intestinal (RR 2.49)
(SIR 1.14) and respiratory malignancies (SIR 7.0) tract malignancies
(SIR 1.26) tract malignancies
dose dependency? none not significant none n.a.
latency period cancer mortality only elevated highest risk in the first year after n.a. n.a.
in the first 4 years after 131I exposure → no latency period
therapy → no latency period Risk decreases over time.
conclusion no significantly increased no significantly increased cancer no significantly increased slightly increased mortality due
cancer mortality due to 131I mortality due to 131I therapy overall cancer mortality due to malignant diseases after 131I
therapy to 131I therapy therapy → however data is lack-
ing to judge relationship with 131I
n.a.: not analyzed; SMR: standardized mortality ratio; RR: relative risk; 95% CI: 95 percent confidence interval

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F. A. Verburg et al.: 131I therapy and risk of malignancies 99

be reliably judged whether any of the ob- 13. Holm LE, Hall P, Wiklund K et al. Cancer risk after
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