EANM Guidelines for Radioiodine Therapy on Differentiated Thyroid Cancer
Dear National Societies,
Dear National Delegates
please
find attached the "EANM Guidelines for Radioiodine Therapy on
Differentiated Thyroid Cancer" which have been submitted for publication
by the EANM Radionuclide Therapy Committee.
These new Guidelines will also replace the 2002 EANM procedure
guidelines for Therapy with Iodine 131.
We
are sending this document to your society with the request to review
the guidelines and to give your comments by May 29, 2008 at the latest
to the Chairman of the EANM Therapy C, Dr. Markus Luster
(luster@nuklearmedizin.uni-wuerzburg.de).
Guidlines
EANM Guidelines, version of 23 April, 2008, Page 1 of 54
GUIDELINES FOR RADIOIODINE THERAPY OF
DIFFERENTIATED THYROID CANCER
M. Luster1, S.E. Clarke2, M. Dietlein3, M. Lassmann1, P. Lind4, W.J.G. Oyen5,
J. Tennvall6, and E. Bombardieri7
Departments of Nuclear Medicine, 1University of Würzburg, Würzburg, Germany;
2Guys and St. Thomas Hospital, London, United Kingdom; 3University of Cologne,
50924 Cologne, Germany; 4Department of Nuclear Medicine and Endocrinology,
Positron Emission Tomography/Computed Tomography Centre, St. Veiterstrasse 47,
9020 Klagenfurt, Austria;5 Radboud University Nijmegen Medical Centre The
Netherlands; 6Department of Oncology, Lund University Hospital, Lund, Sweden;
7National Cancer Institute Foundation, Milan, Italy
Correspondence and reprint requests to:
Markus Luster, MD
Department of Nuclear Medicine
University of Würzburg
Josef-Schneider-Strasse 2
97080 Würzburg GERMANY
+49-931-201-35874 (phone)
+49-931-201-35247 (fax)
luster@nuklearmedizin.uni-wuerzburg.de
EANM Guidelines, version of 23 April, 2008, Page 2 of 54
Table of Contents
I. INTRODUCTION
II. RADIOIODINE THERAPY (RAIT) OF DIFFERENTIATED THYROID
CANCER
A. Definition and Goals
B. Rationale and Indications
1. Ablation
2. Treatment
C. Contraindications
D. Radioiodine Activities and AdministrationE. Patient Preparation
1. Thyroid-Stimulating Hormone (TSH) Stimulation
2. Avoidance of Iodine Excess
3. Other
F. Other Procedural Details
G. Recommended Pre-RAIT History and Examinations
H. Precautions
I. Potential Side Effects of RAIT
J. Alternative or Additional Treatments
1. Cytotoxic Chemotherapy
2. External Beam Radiotherapy (XRT)
3. Local Interventions
4. Molecularly Targeted Therapies
K. Patient Counselling
L. Post-Therapy Scintigraphy
EANM Guidelines, version of 23 April, 2008, Page 3 of 54
M. Issues Requiring Clarification
III. ACKNOWLEDGMENTS
IV. LIST OF ABBREVIATIONS
V. REFERENCES
VI. TABLES
VII. APPENDICES
EANM Guidelines, version of 23 April, 2008, Page 4 of 54
I. INTRODUCTION
Differentiated thyroid cancer (DTC) is defined as carcinoma deriving from the
follicular epithelium and retaining basic biological characteristics of healthy thyroid
tissue, including expression of the sodium iodide symporter (NIS), the key cellular
feature for specific uptake of iodine. DTC is an uncommon disease clinically, but
worldwide, its incidence shows a noticeable increase [1]. Consecutive autopsy studies
have shown that papillary microcarcinoma is frequent in the general population.
Improved detection of some of these subclinical tumours may account for at least part
of the increase in DTC incidence [2].
When appropriate treatment is given, the prognosis of the disease is generally
excellent. Although the 10-year survival rate in cases of distant metastasis is ~25%-
40% [3-5], 10-year overall cause-specific survival for DTC patients as a whole is
estimated at ~85% [6, 7]. However, the lifetime recurrence rate is relatively high,
reaching 10%-30% [7-10] in some series. Therefore lifelong follow-up is needed in
all DTC survivors and subsequent therapy in an appreciable number of patients.
Because DTC survivors number approximately 250,000 in Europe alone [11], DTC
management has notable patient quality-of-life (QOL) and pharmacoeconomic
implications. This state of affairs has driven the elaboration of various national and
international DTC management guidelines from diverse medical specialty
organisations, reflecting the multi-disciplinary approach required for the care of DTC
[12-19].
With the present paper, the European Association of Nuclear Medicine
(EANM) seeks not simply to contribute to the series of publications but to focus on
practical aspects of radioiodine therapy (RAIT) of DTC. Efforts have been made to
harmonise our recommendations with those of the European Thyroid Association
EANM Guidelines, version of 23 April, 2008, Page 5 of 54
guidelines [12], and the lead author of those guidelines has critically reviewed this
article. However, in the area of RAIT, the nuclear medicine specialty can offer
unique experience and perspectives, and as a result, valuable advice to the clinician.
It should be noted that the level of evidence regarding therapy (as well as
diagnosis and follow-up) of DTC patients is low in many instances, as has been
documented in the 2006 American Thyroid Association guidelines [13]. The
relatively low prevalence of the malignancy and the lengthy overall survival of most
patients create the need for large sample sizes and very long-term follow-up to
demonstrate outcome differences between interventions. This, in turn, hinders the
execution of large-scale prospective studies, especially on new therapies. In light of
this dilemma, in developing their recommendations, the authors have relied
significantly on their clinical experience to supplement the observations reported in
the literature. In the interests of simplicity, clarity, and relevance to everyday
practice, the authors have provided citations to key studies underlying their
recommendations rather than formally classifying strength of evidence for proposed
treatment strategies.
II. RAIT OF DTC
A. Definition and Goals
RAIT is defined as the systemic administration of 131-sodium or potassium
iodide (I-131) for selective irradiation of thyroid remnants, microscopic DTC or other
non- or incompletely-resectable DTC, or both purposes. Based on the primary goal of
the RAIT, there are two main forms of the procedure.
The first form, radioiodine ablation, is a post-surgical adjuvant modality. It
seeks to eliminate thyroid remnants to increase the sensitivity and specificity of
follow-up testing for DTC persistence or recurrence, namely, of assays of serum
EANM Guidelines, version of 23 April, 2008, Page 6 of 54
thyroglobulin (Tg) as a tumour marker, and of diagnostic radioiodine whole-body
scintigraphy (dxWBS). Ablation also allows sensitive "post-therapy" whole-body
scintigraphy (rxWBS) that may detect previously occult metastases [15], and serves to
treat any microscopic tumour deposits. Ablation therefore may reduce long term
morbidity and possibly, mortality [15, 20, 21]. Ablation success is evaluated 6-12
months after the ablation procedure, with current definitions of such success including
the following criteria:
- on follow-up dxWBS, negative thyroid bed uptake or thyroid bed uptake
beneath an arbitrarily set, low threshold, e.g. <0.1%
- absence of detectable Tg when interference by anti-Tg antibodies has been
excluded
- absence of suspicious findings on neck ultrasonography (US) [22, 23].
The second form of RAIT, radioiodine treatment of non- or incompletelyresectable
lesions, e.g., macroscopic local tumour or lymph node or distant
metastases, is performed as curative or palliative therapy either as a component of
primary treatment of DTC or to address persistent or recurrent disease.
B. Rationale and Indications
1. Ablation
Due to the generally favourable prognosis of DTC, the impact of radioiodine
ablation on disease-specific mortality and relapse rate is hard to substantiate. Few
randomized studies address this topic, and some of these studies are inconclusive.
However, a recent meta-analysis documented the positive influence of RAIT as an
adjunct to thyroidectomy, namely in retrospective studies with follow-up of 10 years
or more [20]. When thyroid surgery is performed in highly expert hands at selected
EANM Guidelines, version of 23 April, 2008, Page 7 of 54
tertiary referral centres, though, the positive influence of radioiodine ablation may
not be apparent [24].
Radioiodine ablation after total or near-total thyroidectomy is a standard
procedure in patients with DTC. The only exception is patients with unifocal
papillary thyroid carcinoma £1cm in diameter who lack:
- evidence of metastasis
- history of radiation exposure
- unfavourable histology:
o papillary tall-cell, columnar cell or diffuse sclerosing
subtypes.
In these cases, complete thyroidectomy is not the rule and RAIT of larger remnants is
not indicated. However, when such patients have been treated by total or near-total
thyroidectomy, radioiodine ablation may be considered as a means of improving
follow-up and potentially decreasing risk of relapse [25, 26]; potential risk factors for
recurrence or mortality, such as family DTC history, tumour size, history of neck
radiation exposure, histology, closeness of the tumour to the thyroid capsule, presence
of vascular invasion, and, in future, thyroid cancer-related molecular genetic findings,
should be considered when deciding whether to perform radioiodine ablation in these
patients.
2. Treatment
When radioiodine uptake is scintigraphically proven before therapy or after
empiric RAIT, radioiodine treatment of non- or incompletely-resectable tumour, e.g.,
local recurrences, lymph node metastases, or disseminated iodine-avid lung
metastases or other distant lesions, has shown in various investigations to be effective
in eradicating disease, slowing disease progression, or providing symptomatic relief
EANM Guidelines, version of 23 April, 2008, Page 8 of 54
[4]. Indeed, outcome has been shown to be superior in patients with radioiodine-avid
metastases compared to those with radioiodine-negative extra-thyroidal lesions [4].
Furthermore, a recently published study using fluorine-18-fluorodeoxyglucose
positron emission tomography (FDG-PET) suggests that FDG uptake in metastases,
which typically reflects the presence of radioiodine non-avid disease, is itself a
relevant independent unfavourable prognostic indicator [27]. In multivariate analysis,
this study found that greater numbers of FDG-avid lesions or higher maximum
standard uptake values in a patient's tumours correlated significantly with overall
mortality [27].
The results of RAIT are superior for microscopic or small macroscopic
tumours than for larger lesions [4]. Therefore, the feasibility of partial or complete
resection of macroscopic lesions should always be checked as a first treatment option.
Table A provides indications and contraindications for radioiodine treatment.
However, the decision on whether or not to give RAIT should be individualised to the
patient and should consider the following factors:
- operability - except in cases of high risk of important surgical
complications, excision is the preferred first-line treatment for
persistent or recurrent DTC. This preference is based on the
modality's high potential to improve survival, especially in cases of
lesions limited to the thyroid bed or neck lymph nodes, or to palliate
disease and improve quality of life. However, RAIT always should be
offered as an adjuvant to surgery of persistent or recurrent DTC, unless
the disease has been confirmed to be iodine non-avid.
EANM Guidelines, version of 23 April, 2008, Page 9 of 54
- iodine avidity - RAIT exerts no benefit in the absence of iodine-avid
tissue. However, lack of iodine avidity only can be confirmed through
an rxWBS performed in the absence of iodine excess.
- disease site - while lymph node, lung, and most soft tissue metastases
have high rates of cure by RAIT with or without surgery, cure of bone
and brain metastases is relatively rare [4, 28].
- tumour characteristics - patients with less differentiated tumour
histotypes such as papillary tall-cell, columnar cell, or diffuse
sclerosing or follicular widely invasive, poorly differentiated or
Hürthle cell have a greater risk of relapse and a reduced survival, yet
despite diminished NIS expression, such tumour may respond well to
RAIT [29]. Metastatic DTC has a highly variable rate of progression,
and in cases of asymptomatic stable disease, particularly when
longstanding, a strategy of "watchful waiting" may be appropriate.
- patient age - patients who are older, e.g., >45 years of age, at thyroid
cancer diagnosis often present with more aggressive tumour and have a
reduced age-adjusted disease-free and overall survival [7]; therefore
older age at diagnosis could be a factor favouring RAIT when the
indication for this intervention is not definite.
- patient health status - inability to tolerate surgery or other potential
therapeutic interventions, e.g. chemotherapy, could make RAIT the
preferred or the only therapeutic option; conversely, where use of
recombinant human thyroid-stimulating hormone (rhTSH) is not
economically feasible, inability to tolerate hypothyroidism could rule
out RAIT(see section II.E.1) [30].
EANM Guidelines, version of 23 April, 2008, Page 10 of 54
- potential risks of the procedure - while RAIT is generally welltolerated,
it is not without potential short- and long-term toxicity
(Table B), which should be weighed against the expected benefits of
the intervention.
C. Contraindications
Absolute:
i. Pregnancy
ii. Breastfeeding
Relative:
Before the potential RAIT, clinically relevant:
i. bone marrow depression, if administration of high I-131 activities is intended.
ii. pulmonary function restriction, if a significant pulmonary I-131 accumulation is
expected in the presence of lung metastases.
iii. salivary gland function restriction, especially if I-131 accumulation in known
lesions is questionable.
iv. presence of neurological symptoms or damage when inflammation and local
oedema caused by the RAIT of the metastases could generate severe compression
effects.
D. Radioiodine Activities and Administration
As a matter of terminology, the amount of radioiodine given in a diagnostic or
therapeutic procedure, expressed in becquerels (Bq) or curies (Ci), should be referred
to as an "activity." The term "absorbed dose" or the shorter version, "dose," should
be reserved to describe the radiation absorbed by an organ, tissue or body
compartment, expressed in Gray (Gy).
EANM Guidelines, version of 23 April, 2008, Page 11 of 54
RAIT activities are generally empirically determined and fixed by a given
institution based on disease characteristics and patient age (see Appendix 1 for
discussion of dosimetry-based activities). The "optimal" activity for radioiodine
ablation in adults without known post-operative macroscopic disease is generally a
single administration of 1 GBq-5 GBq, but within that range, remains controversial,
with different centres advocating use of 1.11 GBq, 1.85 GBq, or 3.7 GBq [31]. A
recent systematic review concluded that current evidence does not yet allow the
determination whether ablation success rates are similar with ablation activities of
1.11 GBq versus 3.7 GBq [31].
For radioiodine ablation in children, some centres adjust the activity by body
weight (e.g., to 1.85-7.4 MBq/kg) or surface area or by age (e.g., to 1/3 the adult
activity in a 5-year-old, 1/2 the adult activity in a 10-year-old, or 5/6 the adult activity
in a 15-year-old) [32]. Another approach, recommended in the German procedure
guidelines for radioiodine therapy in paediatric DTC patients [16], is to adjust the
ablation activity according to the 24-h thyroid bed uptake of a test activity of
radioiodine as well as according to body weight: <5% uptake would warrant an
activity of 50 MBq/kg, 5%-10% uptake, an activity of 25 MBq/kg, and 10%-20%
uptake, an activity of 15 MBq/kg. Because it maximises the degree of
individualisation, flexible ablation dosing according to one or more individual patient
body characteristics, i.e., weight, surface area, thyroid bed radioiodine uptake, appears
to be a preferable strategy to fixed dosing or to flexible dosing based on age.
In general, the rationales for individualising radioiodine activities to a lower than
adult level in paediatric patients are children's longer life expectancy, and hence,
vulnerability to undesired treatment effects, and the greater absorbed dose to bone
EANM Guidelines, version of 23 April, 2008, Page 12 of 54
marrow and extra-thyroidal tissue in children, given the smaller body sizes and the
increased cross-radiation because of the shorter distances between organs [33].
In cases where criteria for ablation success (see section II.A) are not met, one
or more additional ablation activities are recommended. Other options include reoperation
or "watchful waiting."
In late adolescents and adults, inoperable iodine-avid distant metastases are
typically treated with multiple administrations, each 3.7-7.4 GBq or more, given
every 4-8 months during the first two years following diagnosis of metastatic disease
and at longer intervals thereafter [34-37]. In children, some clinicians use fixed
activities of 1.1 GBq to 11.0 GBq, while others use variable empirical activities
ranging from 37.0 MBq to 92.5 MBq/kg of body weight [16, 32]. In the paediatric
radioiodine treatment setting, a fixed dosing scheme of similar activities to those used
in adult patients appears to be preferable. Such a strategy has the virtue of simplicity,
and may maximise the chances of complete response in a population in whom
persistent tumour cells would have a particularly long time to progress to clinical
recurrence or to de-differentiate.
As an alternative to the administration of fixed RAIT activities in adult or
paediatric patients, pre-therapeutic dosimetry (see Appendix 1) may be used to
calculate an individualised activity projected to deliver a desired amount of
radioactivity to tumour or extra-thyroidal compartments, or both. The generally
accepted absorbed dose thresholds providing high efficacy are ≥ 300 Gy to remnants
or ≥ 80 Gy to tumour deposits [38]. The generally accepted surrogate dose threshold
to avoid serious myelotoxicity is a blood absorbed dose ≤2 Gy [39]. Some centres
combine the lesion- and blood-based dosimetric approaches [40], however larger
patient series are warranted to further support this strategy. The EANM Dosimetry
EANM Guidelines, version of 23 April, 2008, Page 13 of 54
Committee recently published a standard operating procedure guideline on how to
tailor the activity to be administered for systemic treatment of DTC so that the
absorbed dose to blood does not exceed 2 Gy
RAIT should continue until there is no longer evidence of iodine-avid disease,
until intolerable toxicity develops, or until the patient refuses further RAITs. There is
no maximum limit for the cumulative I-131 activity that can be given to patients with
persistent iodine-avid disease. However, most remissions are obtained with
cumulative activities ≤22 GBq [4]; above this threshold, continued RAITs should be
considered on an individual basis. In some cases of iodine-avid disease, in patients
who did not achieve a complete response to several RAITs but have clearly stable
disease (e.g., no clinical signs of progression or increasing Tg levels), RAIT may be
halted in favor of "watchful waiting."
Because of the greater ease to the patient and the superior radiation protection
for caregivers, I-131 generally should be administered orally as a capsule. Before
administration, the actual therapeutic activity should be measured using an
activimeter to confirm that it matches the planned activity.
E. Patient Preparation
1. Thyroid-Stimulating Hormone (TSH) Stimulation
The effectiveness of RAIT depends on the patient's serum TSH level being
sufficiently elevated. A TSH level of >30 mU/L is believed to increase NIS
expression and thereby to optimise radioiodine uptake [13]. Such TSH elevation can
be reached by waiting at least 3 weeks after thyroidectomy, or 4-5 weeks after
discontinuing treatment with levothyroxine (LT4). Triiodothyronine may be
substituted for the LT4 until 2 weeks before RAIT in an attempt to decrease the
EANM Guidelines, version of 23 April, 2008, Page 14 of 54
duration of hypothyroidism. When thyroid hormone is withheld, it should be initiated
or resumed two days after radioiodine administration.
Nonetheless, traditional thyroid hormone withdrawal (THW) has the major
drawback of causing weeks to months of hypothyroid symptoms in most patients [41-
44]. Such physical and psychological morbidity may include fatigue, depression,
impaired ability to concentrate, sleep disturbance, weight gain, constipation, dry skin,
hoarseness, puffy face or hands, cardiovascular abnormalities, impaired renal
function, and exacerbation of dyslipidemia [42, 45-50]. These manifestations in turn
frequently significantly decrease patient QOL, cause absenteeism from or impaired
performance in work or study, or lead to debilitating or even life-threatening
worsening in psychological, cardiovascular, renal or other concomitant conditions
[41-44, 51-54] (Le Clere J, Nunez S, Dejax C, Sohmer V, Schvartz C. Quantitative
and qualitative consequence of LT4 suppressive withdrawal, Satellite Symposium
presentation, EANM Annual Congress, Paris, 3 September 2000).
A few studies suggest that a shorter period of THW may effectively elevate
TSH while mitigating hypothyroid disturbance in adults [55] or children [56];
however, this strategy has the disadvantages with respect to patient adherence and
convenience and to health care costs of requiring multiple physician visits and TSH
determinations. Additionally, a shorter THW fails to elevate TSH in an appreciable
percentage (~10%) of adults [55], and it is not always possible to predict which
individuals will fail to respond to abbreviated THW.
An alternative to THW for attaining TSH elevation is rhTSH administration.
In Europe and elsewhere, this drug has been approved for use in adults as preparation
for serum Tg testing, dxWBS or both or for radioiodine ablation [22, 51, 52, 57]. The
European product labeling specifies an ablation activity of 3.7 GBq I-131 and lowEANM
Guidelines, version of 23 April, 2008, Page 15 of 54
risk status for the patient. rhTSH also has been used "off-label" to aid RAIT of
locally advanced or metastatic DTC or both in several hundred patients,
predominantly adults and predominantly for palliative purposes, with some evident
benefit of the rhTSH-aided treatment reported anecdotally or in retrospective series
[58-60]. In a relatively large retrospective series, rhTSH use appeared to be safe and
effective in promoting Tg production, radioiodine uptake or both in patients ≤18 years
old (Luster, Jarzab, Grossi, Zacharin, Cruz, et al., manuscript on multicentre
paediatric rhTSH in preparation [to be included if in press by time of acceptance of
this manuscript]).
The approved regimen of rhTSH is two consecutive daily intramuscular
injections of 0.9 mg. Subcutaneous injection was successfully used in a small case
series (n = 5) of patients on oral anticoagulants and hence at risk of injection site
haematoma [61]. Radioiodine is given 1 day and serum Tg testing is performed 3 or 4
days after the second rhTSH injection. When dxWBS is performed, it takes place 48
to 72 hours after the radioiodine is applied; rxWBS is performed 2-7 days following
radioiodine administration. rhTSH typically is well-tolerated, with short-lived and
generally mild nausea (~10% incidence), headache (~7% incidence) and asthaenia
(~3% incidence) the most common side effects.
In addition, very likely because of improved renal function and, as a
consequence, more rapid excretion of peripheral I-131 under euthyroid versus
hypothyroid conditions, rhTSH appears to decrease radiation exposure of extrathyroidal
tissues and blood after RAIT [62, 63]. This decreased exposure potentially
may reduce length of stay under radioprotection conditions, the long-term risk of
second primary malignancies, or both. rhTSH administration also provides more
rapid and predictable TSH elevation than does THW. This speed and predictability
EANM Guidelines, version of 23 April, 2008, Page 16 of 54
may allow radioiodine ablation to be scheduled sooner after thyroidectomy, with
potential psychological benefits for the patient, and may enhance clinic workflow
management.
Unless economically unfeasible, the use of rhTSH is generally the preferred
TSH stimulation method before radioiodine ablation and before radioiodine treatment
of DTC lesions that has a solely palliative intent. In the absence to date of
prospective studies demonstrating definitive efficacy for rhTSH as an aid to curative
RAIT of metastases, THW remains the preferred TSH stimulation method in
metastatic disease. However, rhTSH is recommended in curative RAIT in patients
who are unable to tolerate hypothyroidism, for example because of significant
medical co-morbidities, or who are unable to raise endogenous TSH [58, 59]. If
completion thyroidectomy is technically impossible or undesired in patients with large
thyroid remnants, e.g., 5-10 mL, endogenous TSH levels <30 mU/L are acceptable
before RAIT, but additional exogenous stimulation with rhTSH is a useful means to
increase the effectiveness of ablative RAIT.
Clinical caution and steroid co-administration are advised when using THW or
rhTSH in patients with known or suspected tumour in confined anatomical spaces,
especially in the central nervous system, lungs, or bones. Such patients are susceptible
to morbid complications of inflammatory tumour expansion or tumour growth under
TSH elevation. Absolute and relative contraindications for glucocorticoids, such as
diabetes mellitus, ulcus ventriculi or duodeni, or electrolyte disorders must be taken
into account when prescribing steroids.
2. Avoidance of Iodine Excess
To avoid competitive handling by NIS of non-radioactive iodine rather than
radioiodine, with a resultant diminution in efficacy of RAIT, patients should be
EANM Guidelines, version of 23 April, 2008, Page 17 of 54
advised to avoid iodine-containing medications, e.g., iodinated contrast agents,
antiseptics, eye drops or amiodarone, and iodine-containing foods, e.g., iodinated
multivitamins or mineral supplements or seafood, for 4-6 weeks prior to RAIT. A
low-iodine diet, when possible, <50 μg/day, starting 1-2 weeks prior to radioiodine
administration is recommended optionally [64, 65]. Written instructions may be
helpful in promoting patient adherence to iodine avoidance measures.
Before every RAIT, patients should be specifically questioned about ingestion
of common iodine-containing medications or foods to rule out iodine excess.
Especially in doubtful cases, urinary stable iodine excretion should be measured.
Urinary stable iodine excretion above an arbitrary institutional cut-off in the range of
150-200 μg/l, is believed to reflect clinically relevant iodine excess and should lead to
postponement of RAIT. After administration of lipophilic iodinated contrast agent,
e.g., for computed tomography (CT), or after amiodarone medication, RAIT should be
postponed for at least 3 months, and in other cases of iodine excess, RAIT should be
postponed for 4-6 weeks.
The literature contains mixed findings as to whether the continued thyroid
hormone ingestion permitted by rhTSH use leads to clinically relevant elevated iodine
levels [22, 66]. Some clinicians favour a "mini-withdrawal" of thyroid hormone for a
short period (e.g., 2 days each) before and after RAIT [67].
3. Other
Large meals may alter the resorption of orally administered radioiodine.
Patients should fast 4 hours prior to and 1 hour after radioiodine administration.
F. Other Procedural Details
Physicians should ensure that national regulations for radioiodine
administration, including those regarding radiation protection, are carefully observed.
EANM Guidelines, version of 23 April, 2008, Page 18 of 54
During hospitalisation, residual whole-body I-131 activity should be quantified at
least daily by measurement using e.g., a gamma probe.
G. Recommended Pre-RAIT History and Examinations
To ensure that it is appropriate to perform the RAIT, and to optimise the
preparation method, I-131 activity and other aspects of the procedure, the following
information should be obtained and the following examinations should be conducted
before each radioiodine ablation or treatment:
- Current patient age and age at DTC diagnosis and, if applicable, age at
metastatic DTC diagnosis
- Tumour pathology:
o staging based on the tumour-nodes-metastases system
o focality, size(s) and diameter(s)
o histology including differentiation
o presence or absence of capsular invasion, involvement of surrounding
tissues or both
o sites and numbers of distant metastases
- Description of prior surgical procedure(s) for DTC, e.g., extent of
thyroidectomy, number and localisation of resected lymph nodes including, if
possible, assignment to cervical compartments
- History including:
o medical and other radiation exposure
o thyroid cancer in relatives
o prior I-131 and other radiopharmaceuticals, including diagnostic
administrations and therapies: number, activities, dates
o toleration of thyroid hormone withholding or withdrawal
EANM Guidelines, version of 23 April, 2008, Page 19 of 54
o exposure to contrast agent or iodinated medication, and adherence to
iodine avoidance recommendations or to any prescribed low-iodine
diet
o significant co-morbidity
- Menstrual history, pregnancy and breastfeeding status in post-pubertal females
and family planning status in all patients
- Physical exam
- Laboratory tests:
o TSH
o Tg including recovery test, quantification of anti-Tg antibodies or both
o urinary stable iodine excretion if there is suspicion of iodine excess
o creatinine
o calcium
o calcitonin (post-surgery, if medullary thyroid cancer has not been ruled
out)
o parathyroid hormone (post-surgery)
o complete blood count with differential
- History of dxWBS: radioisotope, activity, date, results
- Results of prior rxWBS
- Results of neck US and of other imaging procedures, e.g., CT without contrast
or magnetic resonance imaging if applicable, including a rough estimate of
thyroid remnant size
- Results of pulmonary function tests, if necessary
- Results of current laryngeal nerve function tests (post-surgery)
EANM Guidelines, version of 23 April, 2008, Page 20 of 54
H. Precautions
To optimise the safety and efficacy and minimise the negative impact of each
RAIT, the following precautions should be observed:
Avoidance of "stunning": Stunning is defined as diminution of RAIT uptake
and efficacy due to suboptimal therapeutic effects, biological effects, or both, of prior
diagnostic radioiodine administration. In cases where RAIT clearly will be necessary,
pre-therapeutic I-131 dxWBS or thyroid bed uptake measurement should be avoided,
because their results will not modify the indication for the RAIT and these procedures
may induce stunning. To reduce the possibility of stunning when it is not yet known
whether RAIT is indicated, thyroid bed uptake quantification or I-131 dxWBS
performed before the potential RAIT should employ low radioiodine activities.
Recommended quantities are approximately 3-10 MBq for uptake quantification and
10-150 MBq for WBS. Alternatively, use of 40-200 MBq of 123-iodine (I-123) for
diagnostic imaging minimises the risk of stunning. However, the lower imaging
sensitivity and higher cost of I-123 compared with I-131 are disadvantageous. I-123
WBS should employ a gamma camera with a large field of view and a mediumenergy,
high-resolution collimator.
124-iodine (I-124) PET/CT is emerging as an attractive experimental modality
in expert hands for pre-RAIT imaging and dosimetry [40, 68, 69]. The extent of
stunning effects with I-124 is as yet unknown but as a precaution, activities of this
radioisotope should be kept to a minimum.
Minimisation of physiological radioiodine uptake and retention: In the 24
hours following radioiodine administration, liberal oral hydration and use of lemon
juice or sour candy or chewing gum increases salivary flow and reduces radiation
exposure of the salivary glands [70, 71]. It is not evident whether lemon juice may be
EANM Guidelines, version of 23 April, 2008, Page 21 of 54
even more effective 24 hours after than immediately after radioiodine administration
[70].
Adjuvant medication with a mild laxative increases the colonic emptying rate,
decreasing radiation exposure of the intestines and facilitating scan interpretation.
This measure is especially important in cases of constipation. The stomach lining
should be protected by liberal oral hydration, and use of medication, e.g., H2-
blockers, also may be helpful. Liberal oral hydration and frequent urination may
minimise radiation exposure of the urinary bladder and the gonads.
Management of and prophylaxis against neck compression symptoms: Ice
packs should be applied and non-steroidal, anti-inflammatory medication should be
administered if inflammatory reaction occurs in the lower neck. In cases of
radioiodine ablation of larger thyroid remnants, glucocorticoids optionally may be
given for some days as prophylaxis.
Pregnancy, breastfeeding and conception: Pregnancy must be excluded by a
human chorionic gonadotropin-based test (beta-hCG), preferably together with US,
within a few days before each RAIT. Routine urinary pregnancy tests might miss a
late (midterm) pregnancy due to both a decreased production of beta-hCG and a
decreased degree of sialinisation, which results in a shorter half-life of beta-hCG due
to metabolisation in the liver [72]. Patients should be advised to discontinue
breastfeeding for 6-8 weeks before radioiodine administration. Conception should be
avoided by means of effective contraception for 6 months after RAIT, an interval that
allows the replacement of irradiated by non-irradiated spermatozoa and decreases risk
of fetal abnormalities [73]. Avoidance of contraception for 12 months has been
shown to avoid increased risk of miscarriage [73]. If RAIT is expected to involve
high cumulative I-131 activities, e.g., ≥14 GBq, pre-RAIT sperm banking is
EANM Guidelines, version of 23 April, 2008, Page 22 of 54
recommended in men whose family planning is not yet completed [74]. Additionally,
female patients should be advised that an earlier onset of menopause has been
reported after repeated courses of RAIT [75].
I. Potential Side Effects of RAIT
While RAIT is generally well-tolerated if appropriate single and cumulative
activities are used and precautions employed, the procedure does have a number of
potential early and late sequelae. These sequelae and potential prophylactic and
treatment interventions are described in Table B. Characterisation of the sequelae
and risks of RAIT remains ongoing; for example, an overview of the radiation
absorbed dose to normal organs after RAIT was published recently [76].
J. Alternative or Additional Treatments
Besides surgery [77], treatments that may be used instead of or in addition to
RAIT include cytotoxic chemotherapy, external beam radiotherapy (XRT), local
interventions, and so-called molecularly targeted therapies. The main settings for
these treatments are late-stage, progressive DTC or symptomatic or progressive
lesions that are unresectable and that have failed to respond to RAIT, or are unlikely
to do so.
1. Cytotoxic Chemotherapy
Cytotoxic chemotherapy has no role in the routine management of DTC but
rather, should be restricted, preferably within controlled clinical trials, to
symptomatic, progressive, end-stage disease uncontrolled by RAIT, surgery, or XRT.
Among cytotoxic chemotherapies studied to date, doxorubicin monotherapy still
provides the best clinical results, even compared with combination regimens, but
attains partial response rates of at most 10%-20% and very rare durable responses [78,
79]. A recent small study [80] showed a 37% response rate (5/16) in patients with
EANM Guidelines, version of 23 April, 2008, Page 23 of 54
non-functioning lung metastases given the combination of carboplatin plus epirubicin
under TSH stimulation (endogenous or rhTSH). The TSH elevation was applied to
foster tumour cell division and hence, vulnerability to chemotherapy; this strategy
merits further study, though molecularly targeted therapies may be a more promising
line of investigation.
2. XRT
The role of XRT of primary tumours, cervical metastases, or both is still
controversial: evidence is available only from retrospective reviews, with sometimes
poorly defined inclusion criteria, inconsistent treatment regimens or obsolete
standards of radiotherapy [81-83]. Traditional indications for XRT in the DTC setting
have been unresectable gross disease, gross tumours left behind after operation, gross
evidence of local invasion, or as postoperative adjuvant therapy.
When neck lesions accumulate I-131, it is recommended to use RAIT and
XRT in combination, since radioiodine can stop the tumour cells in phases (G2, M) in
which the cells are especially sensitive to XRT [84]. Patients with tracheal invasion
by DTC have a high local recurrence rate if they have undergone a "shave" excision
of the tracheal cartilage; if "en bloc surgery" is not feasible, XRT is advocated in such
patients even when only microscopic disease remains [85].
In addition, XRT should be considered in the management of painful bone
metastases or of metastases in critical locations likely to result in fractures or
neurological or compressive symptoms, if these lesions are not amenable to surgery
[81, 86-88]. Use of RAIT in combination with XRT may increase the response,
especially in painful bone lesions [88].
Since there is no evidence that DTC has significantly different radiosensitivity
than do other head and neck carcinomas, total delivered absorbed doses should be 65-
70 Gy to gross disease left behind, 60 Gy to adjacent target volume with risk of
EANM Guidelines, version of 23 April, 2008, Page 24 of 54
microscopic dissemination, and 50 Gy to microscopic disease in a preoperative
setting. For DTC, a 2 Gy/fraction administered 5 days/week is most often used, but
fractionation regimens have not been systematically evaluated.
When possible, XRT of the neck should employ the three-dimensional
conformational or intensity-modulated radiation therapy techniques, which provide
better balance between anti-tumour efficacy and safety of normal adjoining structures
than do traditional delivery methods [83]. Appropriate precautions should be taken to
prevent radiation myelopathy. If possible, salivary glands on the least affected side
should be excluded from the radiation target volume, to prevent xerostomy.
XRT of distant metastases should follow similar practices to those employed
with XRT of the neck, but with special consideration of the frequently slow progress
of metastatic disease. A long expected survival together with a good performance
status speak in favour of a lower fractionation dose (Gy/fraction) to potentially reduce
late toxicity and of a higher total absorbed dose to improve local control.
3. Local Interventions
Local interventions to ameliorate symptoms or slow tumour progression
include chemoembolisation, radiofrequency ablation or cement injection, and as a
systemic therapy, bisphosphonate medication [10].
4. Molecularly Targeted Therapies
With improved understanding of the genetic and molecular bases of DTC,
molecularly targeted therapies for the malignancy have emerged, particularly in the
past decade, as the focus of considerable pre-clinical and clinical research. Present
molecularly targeted therapies can mostly be classified as 1) cell signalling or
angiogenesis inhibitors or as 2) inducers of tumour cell re-differentiation, and hence,
potentially, radioiodine uptake, retention or both [10, 89].
EANM Guidelines, version of 23 April, 2008, Page 25 of 54
A variety of compounds targeting vascular endothelial growth factor receptors,
RET tyrosine kinase, BRAF kinase, or membrane receptor kinases are currently in
Phase II clinical trials or have had preliminary results reported, or both (reviewed in
[10]). The preliminary results have included disease stabilisation or response. Some
of the molecular targets of these compounds occur more frequently or exclusively in
certain DTC histotypes, e.g., somatostatin receptor type 2 in Hürthle cell carcinoma;
few if any of the targets are expressed in all DTC tumours [10]. Hence the future use
of cell signalling agents or angiogenesis inhibitors is likely to entail pre-therapeutic
pharmacogenomic testing to select patients in whom a given medication or
combination of medications is likely to be efficacious.
The most widely investigated re-differentiation therapies have been the vitamin
A analogues, the retinoids [90, 91], which by binding to their receptors, increase NIS
expression and radioiodine uptake in tumour cells [10, 92-94]. However, dedifferentiated
DTC cells have numerous metabolic defects other than deficient NIS
expression, and these defects may, for example, impair radioiodine retention,
decreasing the tumour dose and RAIT efficacy [10]. This phenomenon may partially
account for the relatively low response rates - 20%-30% -- to retinoid redifferentiation
therapy in clinical trials to date [10, 89]. Another explanation for the
low response rates may be that studies till now have not screened patients for retinoid
receptor expression; use of such screening might increase response rates even as it
narrows the treated population [10, 89]. Of interest, a recent case report suggests that
retinoids may exert therapeutic biological effects independent of enhancing RAIT
[95].
K. Patient Counselling
Before receiving RAIT, patients should be informed about:
EANM Guidelines, version of 23 April, 2008, Page 26 of 54
- Additional or alternative therapeutic and management options, as appropriate,
including "watchful waiting"
- Potential benefits of RAIT
- Potential adverse effects and risks of RAIT (Table B)
- Advantages and disadvantages of THW and rhTSH and regulatory status of
the latter
- The need and methods to avoid iodine excess
- The need for hospitalisation during RAIT
- Radiation protection recommendations during hospitalisation and after
discharge
- The need to avoid pregnancy and breastfeeding and the need for both female
and male patients to use effective contraception for 6-12 months after RAIT
- The need for lifelong, risk-adapted follow-up care for DTC patients, and the
importance of adherence to suppressive doses of LT4 in cases where such
doses are indicated
- Local, regional and national support groups and other resources for DTC
patients and their families.
It can be helpful to reiterate the above information in written handouts that patients
and families can refer to at home. Clinicians should document the pre-RAIT
counselling and should obtain written informed consent as required by institutional,
regional or national regulations.
L. Post-Therapy Scintigraphy
Because of its high sensitivity for localising and characterising the extent of
thyroid remnant and tumour and detecting previously occult lesions, whole-body
gamma scintigraphy, with spot imaging of regions of interest (ROIs) as applicable,
EANM Guidelines, version of 23 April, 2008, Page 27 of 54
should be performed following every RAIT. rxWBS should not take place sooner
than 72 hours after radioiodine administration during THW, or sooner than 48 h after
the second injection of rhTSH. Appendix 2 presents additional considerations for
rxWBS.
Whenever possible, single photon emission computed tomography (SPECT),
or, if available, SPECT/CT, of the neck and other anatomical regions as appropriate
and feasible, should be performed at the time of rxWBS. By providing a threedimensional
image of involved lymph nodes, SPECT is an excellent means of
visualising DTC lymph node lesions and SPECT/CT adds morphological information
to the functional data furnished by SPECT alone [96].
M. Issues Requiring Clarification
- Role of outpatient RAIT
- Optimal I-131 activities for safe and effective radioiodine ablation
- Optimal definition of ablation success
- Value of radioiodine therapy in patients with measurable or increasing Tg
levels, e.g., >10 ng/mL under TSH stimulation, but no evidence of tumour in
morphological or functional imaging, e.g., negative I-131 dxWBS
- Optimal I-131 activities and number/schedule of therapies to treat
incompletely- or non-operable tumour
- Value of dosimetrically determined versus fixed empirical activities for RAIT
- Role of rhTSH as preparation for RAIT to treat incompletely or non-resectable
local recurrence or metastases, especially for RAIT with curative as opposed
to palliative intent
- Value of low-iodine diet in light of an increasing alimentary iodine supply
EANM Guidelines, version of 23 April, 2008, Page 28 of 54
- Correlation between urinary stable iodine excretion values and extent of iodine
interference with radioiodine uptake and efficacy; optimal cut-off urinary
stable iodine excretion level predicting clinically relevant iodine interference
- Role of pre-RAIT retinoids (vitamin A derivatives) for tumour cell redifferentiation
and improvement of I-131 uptake into metastases
- Role of redifferentiation therapy with peroxisome-proliferator activated
receptor gamma agonists, an experimental modality that in animal models, has
been shown to induce tumour cell apoptosis and to slow tumour growth
- Value of lithium therapy to improve radioiodine retention by tumour cells
III. ACKNOWLEDGMENTS
The authors thank Professor Furio Pacini of the University of Siena and
Robert J. Marlowe for their critical reviews of the manuscript. Development of this
paper was supported by a grant from Genzyme Europe B.V.
IV. LIST OF ABBREVIATIONS
hCG - beta human chorionic gonadotropin
Bq - becquerel
Ci - curie
CT - computed tomography
DTC - differentiated thyroid carcinoma
dxWBS - diagnostic whole-body scan
EANM - European Association of Nuclear Medicine
Gy - Gray
I-123 - 123-iodine
I-124 - 124-iodine
I-131 - 131-sodium or potassium iodide
EANM Guidelines, version of 23 April, 2008, Page 29 of 54
LT4 - levothyroxine
NIS - sodium iodine symporter
PET - positron emission tomography
QOL - quality-of-life
rhTSH - recombinant human thyroid-stimulating hormone
RAIT - radioiodine therapy
ROI - region of interest
rxWBS - post-therapy whole-body scan
SPECT - single photon emission computed tomography
Tg - serum thyroglobulin
THW - thyroid hormone withdrawal
TSH - thyroid-stimulating hormone
US - ultrasonography
WBS - whole-body scan
XRT - external beam radiotherapy
EANM Guidelines, version of 23 April, 2008, Page 30 of 54
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