Side Effects of 131I for Therapy
of Differentiated Thyroid Carcinoma
Douglas Van Nostrand, John E. Freitas, Anna M. Sawka,
and Richard W. Tsang
Introduction
The use of radioactive iodine (131I) for remnant ablation,
adjuvant treatment, and treatment of metastases from dif-
ferentiated thyroid carcinoma may be associated with side
effects in numerous organ systems (Table 62.1). Although
many articles address the side effects of 131I, the character-
izations of these effects vary widely because of a host of
different factors (Table 62.2). This chapter attempts to
consolidate the literature by presenting, where appropri-
ate, (1) the spectrum of signs and symptoms, as well as the
frequency and severity of side effects; (2) a review of
selected articles; (3) a discussion of preventive measures
to reduce the frequency and severity of side effects; and
(4) a discussion of the medical management when selected
side effects do occur.
D. Van Nostrand, MD, FACP, FACNM (*)
Nuclear Medicine Research, MedStar Research Institute
and Washington Hospital Center, Georgetown University
School of Medicine, Washington Hospital Center, 110 Irving
Street, N.W., Suite GB 60F, Washington, DC 20010, USA
e-mail: douglasvannostrand@gmail.com
J.E. Freitas, MD
Department of Radiology, St. Joseph Mercy Health System,
Ypsilanti, MI, USA
e-mail: freitasj@trinity-health.org
A.M. Sawka, MD, PhD
Division of Endocrinology and Metabolism, Department of
Medicine, University Health Network – University of Toronto/
Toronto General Hospital, Toronto, ON, Canada
e-mail: Anna.sawka@uhn.on.ca
R.W. Tsang, MD, FRCP(C)
Department of Radiation Oncology, Princess Margaret Hospital,
University of Toronto, Toronto, ON, Canada
e-mail: Richard.tsang@rmp.uhn.on.ca
© Springer Science+Business Media New York 2016
L. Wartofsky, D. Van Nostrand (eds.), Thyroid Cancer, DOI 10.1007/978-1-4939-3314-3_62
62
Hair
The loss of hair secondary to 131I treatment is an infrequent
complication and has been reported in a patient with an
underlying skull metastasis [1]. Although Alexander et al.
[2] found transient episodes of more generalized alopecia in
28 % (57 of 203) of patients that occurred one to several
weeks after discharge from 131I therapy, this side effect was
not dependent on 131I dosage administered. Because hypo-
thyroid patients suffer from hair loss and cancer patients had
been traditionally hypothyroid when 131I is administered,
hair loss has been generally considered due to the hypothy-
roidism, not 131I per se. As more 131I therapies are performed
after preparation with recombinant human thyrotropin
(rhTSH) with patients euthyroid, it will be of interest to
determine whether there is any associated hair loss.
Brain
Brain metastases diagnosed premortem are rare in patients
with thyroid cancer and most thyroid cancer brain metas-
tases are not iodine avid as determined on diagnostic
whole-body scans (17 % in one series) [3]. Although sur-
gical resection or stereotactic radiosurgery should be
strongly considered first for the treatment (even if iodine
avid) (see Chap. 56), [3] 131I therapy may be considered in
selected patients. If 131I is used, then patients with 131I-avid
brain metastases can experience abrupt and marked dete-
rioration or death secondary to brain metastases swelling,
hemorrhage, and/or cerebral edema in response to 131I
therapy [4–6].
Prior to 131I therapy, such patients should be pretreated
with oral steroids. One approach was the pretreatment for
several hours with 16–32 mg of oral dexamethasone, which
was continued in divided dosages for 5–7 days following 131I
671
672
Table 62.1 Various sites of side effects associated with 131I therapy
Hair
Brain
Spinal cord
Eye
Salivary glands
Taste and smell
Nose
Facial nerve
Vocal cord
Thyroid
Parathyroid
Pulmonary
Gastrointestinal system
Urinary bladder
Bone marrow
Fertility
Second primary neoplasms
Table 62.2 Various factors causing variability of characterizations of
side effects secondary to 131I therapy
Criteria for the presence of side effects
Thoroughness in the search for signs and symptoms of side effects
Various criteria for the grading of severity of side effects
Length of follow-up
Prescribed activities of 131I for remnant ablation, adjuvant treatment,
or treatment of known local regional or distant metastases
Total cumulative prescribed activities of 131I
Time intervals between 131I therapies
Methods implemented or not implemented to prevent side effects
therapy [3]. Of note, elevated thyroid-stimulating hormone
(TSH) from either thyroid hormone withdrawal or injections
of recombinant human TSH may also increase the potential
for enlargement of the metastasis(es), hemorrhage, and/or
cerebral edema, and earlier pretreatment with glucocorti-
coids should again be considered. Although glucocorticoids
have been identified as a cause of reduced 131I uptake in
benign thyroid tissue in euthyroid patients, the rapidity at
which this effect occurs is probably over several days (not
hours) and may not be as marked in hypothyroid individuals
[7]. If an alternative to glucocorticoids is required, 50 % oral
glycerol (1.2–2.0 g/kg) daily has been shown as effective to
reduce cerebral edema in patients undergoing external-beam
therapy of brain metastases and may have similar efficacy in
131
I-treated patients [8].
Spinal Cord
Myelopathy after acute swelling of cord lesions has been
seen after rhTSH-stimulated 131I therapy, but it is difficult to
distinguish whether the etiologic factor was TSH or 131I [9].
D. Van Nostrand et al.
In general, the same precautions for spinal cord metastases
apply for brain metastases. Yevgeniya et al. [10] evaluated
202 patients with spinal metastases, and neural structure
compression (e.g., myelopathy/radiculopathy) was present
in 36 % and 72 % of patients with papillary and follicular
thyroid cancer, respectively.
Eye
The three most important side effects involving the eye area
are inflammation of the lacrimal gland, inflammation and/or
obstruction of the lacrimal duct, and conjunctivitis.
Lacrimal Gland
The proposed mechanism for lacrimal gland inflammation is
similar to sialoadenitis of the salivary glands with uptake of
131
I in the lacrimal gland resulting in radiation damage and
subsequent reduction in the production of tears. However,
the underlying mechanism remains controversial. Although
Spitzweg et al. [11] have reported the presence of the sodium-
iodide symporter in lacrimal ductules and glands,
Morgenstern et al. [12] were unable to demonstrate the pres-
ence of the sodium-iodide symporter in the lacrimal gland,
Wolfring and Krause glands (accessory lacrimal glands),
conjunctiva, or the canaliculus.
Nevertheless, the reduction of tear production has been
studied by Zettinig et al. [13] and appears to occur fre-
quently after 131I therapy. In the evaluation of 88 patients, 81
patients had at least one abnormal result out of a set of three
tests used to assess the quality and quantity of tears. The
Schirmer tear test, which measures the quantity of aqueous
tear production, was positive (decreased tears) in 40 % of
patients in one eye and 20 % in both eyes. The tear film
breakup time (BUT), which measures the tear film’s stabil-
ity, was abnormal in 71 % of patients in at least one eye and
in 57 % of patients in both eyes. The lacrimal lipid layer that
thickens, stabilizes, and retards evaporation of the aqueous
layer underneath was abnormal in 49 % of patients in at
least one eye and in 34 % of patients in both eyes. The lipid
layer is produced by the sebaceous meibomian glands in the
lids as well as by the Zeis and Moll glands along the eyelid
margin and lashes.
Fard-Esfahni et al. [14] evaluated 50 patients treated with
131
I and 50 control patients. In comparing the two groups, no
significant differences in symptoms of xerophthalmia were
observed. However, a lower Schirmer test value was present
in the eyes of patients treated with 131I (14.5 ± 10.8 mm) rela-
tive to the control group (18.2 ± 11.0 mm [p < 0.016]).
The clinical presentation of lacrimal inflammation is
xerophthalmia. Typically, the patient has no initial symptoms
of pain or swelling but subsequently develops reduced pro-
duction of tears, resulting in dry eyes (xerophthalmia). The
frequency of xerophthalmia was 16 % (14 of 88) in patients
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
studied. Seven patients had xerophthalmia and xerostomia,
and seven had only xerophthalmia [13]. Solans et al. [15]
reported xerophthalmia in 33 % (26 of 79), which persisted
for 1 year in 25 %, for 2 years in 17 %, and into the third year
in 14 % of patients. Keratoconjunctivitis sicca persisted in 14
% (11 of 88) of patients into the second year and in 8 % (6 of
88) after the third year. No significant relationship of xeroph-
thalmia was found with cumulative prescribed activity of
131
I. However, changes in tear function tests can be seen with
lower amounts of therapeutic 131I prescribed activity. Koca
et al. [16] reported decreased values of Schirmer test and the
tear breakup time (BUT) in patients receiving prescribed
activities of 131I of ≤30 mCi in patients treated for hyperthy-
roidism. Although one may have expected a significant
decrease in the frequency of xerophthalmia in patients
receiving the lower recommended amounts of 30 mCi of 131I
for remnant ablation for differentiated thyroid cancer, Koca
et al.’s study suggested that significant radiation of the lacri-
mal glands may still occur.
Obstruction of Lacrimal Duct
The mechanism of the obstruction of the lacrimal duct,
which drains the tears to the nasal cavity, is hypothesized to
be the effects of radiation exposure to the duct lining from
131
I in the tears and/or possibly in the cells of the duct lining,
leading to subsequent inflammation, fibrosis, and narrowing.
131
I activity in the tears has been well described with as much
as 0.01 % of the administered 131I dosage secreted in tears in
each eye during the first 4 h after 131I administration [17].
However, an additional and potentially more important
mechanism may be present. Morgenstern et al. [12] have
demonstrated the presence of the Na+/I symporter (NIS) in
the stratified columnar and epithelial cells of the lacrimal sac
and nasolacrimal duct of humans.
The clinical presentation of nasolacrimal duct obstruction
is epiphora (excessive tearing). Zettinig et al. [13] reported
epiphora in 11 % (10 of 88) of patients and epiphora with
photophobia in 1 % of patients. The mechanism of photo-
phobia was not discussed. The exact mechanism of epiphora
was also not discussed but must again relate to the failure of
normal tear drainage to the nasal cavity. Kloos et al. [18]
reported a 2.6 % incidence of epiphora (10 of 390), with
symptoms appearing a mean of 6.5 months after the last 131I
dose (range of 3–16 months). Subsequently, Burns et al. [19]
described a suspected incidence of obstructed nasolacrimal
drainage of 3.4 % and 4.6 %. Fard-Esfahani et al. [20] evalu-
ated 81 patients with dacryoscintigraphy and demonstrated
findings indicative of nasolacrimal obstruction in 18 %
(29/162) of the eyes in patients treated with 1311 relative to 9
% (3/34) in the eyes in patients who were not treated with
131
I. The frequency of complete nasolacrimal obstruction
increased when the cumulative dose of 131I exceed 11.1 GBq
(300 mCi). Orquiza et al. [21] in a prospective survey
673
reported that epiphora was reported on the first day of 131I
treatment in 6 % (5/78) of patients. Between 1 and 10 days
after 131I treatment, 8 % (6/78) of patients reported epiphora.
However, when the frequency of epiphora was adjusted for
patients who reported this symptom within 30 days prior to
131
I treatment, the frequency of epiphora after 131I therapy
was not statistically increased.
Finally, nasolacrimal duct obstruction may not only be
suspected only when the patient complains of epiphora but it
may also be suspected when radioiodine uptake is noted on
radioiodine SPECT-CT images medially in the area of the
lacrimal duct and/or lacrimal sac [22].
Conjunctivitis
The mechanism of conjunctivitis is not well understood but
is most likely the result, at least in part, of documented
changes in the tear quality and quantity. Zettinig et al. [13]
showed changes in the external eye morphology, demonstrat-
ing corneal staining with fluorescein in 42 % (37 of 88) of
patients, and 35 % of patients had abnormal conjunctival
findings on visual inspection. Conjunctivitis typically pres-
ents with pain and erythema. Alexander et al. [2] indicated a
frequency of chronic or recurrent conjunctivitis in 23 % (46
of 203) of patients.
Preventive Management
Currently, no proven method in humans is available to reduce
the radiation exposure to the lacrimal glands, sacs, or ducts;
however, several potential protective options need further
evaluation. Beutel et al. [23] evaluated the protective effects
of amifostine, lidocaine, and pilocarpine on the lacrimal
glands in 25 rabbits. Pre 131I treatment with amifostine
appeared to reduce functional and structural impairment of
the lacrimal glands after exposure to radiation, and lidocaine
had the potential for significant radioprotection. Pilocarpine
had no evidence of radioprotection of the lacrimal glands.
Acar et al. [24] evaluated vitamin E in 24 rats and compared
one group of rats treated with 3 mCi of 131I by gastric lavage
and 1 ml of physiological saline injected intraperitoneally to
a second group of rats that were administered with 131I
through the same route and with the same amount but were
not injected peritoneally with vitamin E (α-tocopherol ace-
tate). Vitamin E was initiated 2 days before and continued 5
days after the administration of 131I. Twenty four hours after
the last dose of vitamin E, the animals were sacrificed.
Histological examination of the rats’ lacrimal glands demon-
strated statistically less frequent periductal and/or periacinar
fibrosis in all lacrimal glands in the rats that received vitamin
E. Koca et al. [25] recently reported histological changes in
the lacrimal glands secondary to 131I therapy and that monte-
lukast (Singular®, Montelo-10®, Monteflo®, Likotas®)
effectively protected against that damage to the lacrimal
glands. Montelukast is a leukotriene D4 receptor antagonist
674
that is administered for the treatment of asthma and relief of
symptoms of seasonal allergies. In the lungs, montelukast
reduces bronchoconstriction otherwise caused by the leukot-
riene and results in less inflammation, and the dose for such
patients is one 10 mg tablet orally per day. However, the effi-
cacy of montelukast in reducing the radiation dose to the lac-
rimal glands, sacs, and ducts needs to be further evaluated.
Management of Xerophthalmia, Lacrimal Duct
Obstruction, Epiphora, and Conjunctivitis
The first and most important aspect regarding the manage-
ment of xerophthalmia, obstruction of the nasolacrimal duct,
or conjunctivitis is for the physician and patient to be aware
of these potential side effects and their presenting signs and
symptoms. Thus, when they do occur, the physician can
implement treatment and/or refer the patient to an ophthal-
mologist. Depending on the severity, the patient may be sim-
ply observed without treatment, treated with artificial tears,
or referred to an ophthalmologist for additional treatments,
such as a dacryocystorhinostomy (surgical creation of com-
munication between the lacrimal sac and nasal cavity) for
patients with severe epiphora. Alexander et al. [2] found that
four of 46 patients underwent dacryocystorhinostomy. More
recently, Ramakrishnan et al. [26] reported on the use of
endoscopic management of nasolacrimal duct obstruction
secondary to 131I treatment in five patients using silicone lac-
rimal stents. Out of ten stents placed, two had to be removed
because of patient discomfort; however, the remaining eight
had resolution or improvement of drainage with no major
intraoperative or postoperative complications.
In summary, side effects of 131I therapy on the lacrimal
glands, lacrimal ducts, and conjunctivae occur frequently,
are often overlooked, may require referral to an ophthalmol-
ogist, and need further study.
Salivary Gland
Significant amounts of 131I can accumulate in the salivary
glands; therefore, 131I therapy can result in significant radia-
tion exposure to the salivary glands that are manifested by
both early and late untoward effects. These have been previ-
ously reviewed, [27] and the untoward effects include sialo-
adenitis, xerostomia, salivary duct obstruction, and tumors of
the salivary gland. The latter are discussed below in this
chapter in a section entitled “Second primary malignancies.”
The terms “sialadenitis” and “sialoadenitis” have been used
interchangeably in the medical literature, and the usage of
either is correct and signifies inflammation of the salivary
gland. For this chapter, “sialoadenitis” will be used.
D. Van Nostrand et al.
Anatomy and Physiology
To discuss the anatomy and physiology of the salivary glands
in depth is beyond the scope of this chapter. However, the
major pairs of salivary glands—the parotid, submandibular,
and sublingual glands—can concentrate iodine as high as
7–700 times the plasma levels [28–31]. The salivary glands
are composed of serous cells and mucous cells. The parotid
glands have predominately serous cells, and its saliva is pre-
dominately serous secretion. The submandibular glands have
a mixture of serous and mucinous cells, and its saliva is pre-
dominately mucinous secretion. The sublingual glands also
have a mixture of cells and make only a small contribution in
volume but affect the viscosity of saliva. The parotid glands
demonstrate a higher frequency of radiation sialoadenitis
than submandibular and sublingual salivary glands, the
hypothetical basis for which is that the serous cells have a
greater ability to concentrate 131I than the mucous cells [32].
An important mechanism of salivary iodide transport is the
same as in the thyroid gland, which is the sodium-iodide
symporter (NIS) in salivary ductal cells. However, despite
the presence of NIS, the salivary accumulation of 131I does
not appear to be affected by the TSH level or the state of
thyroid function [30, 31, 33]. Relating to this, the histopatho-
logic studies of Rice et al. [29] indicate that the parotid acini
and serous cells are severely injured after external radiother-
apy with little discernible change in the mucous cells. The
salivary glands are controlled by the autonomic nervous sys-
tem. The parasympathetic system apparently has a more sig-
nificant impact on saliva production than the sympathetic
system, but the latter still has a role [34].
Radiation-Absorbed Dose
The radiation exposure to the salivary glands has not been
well studied. Donachi et al. [35] reported approximately 250
cGy (250 rad) to the salivary gland from a 185 MBq (5 mCi)
dosagee, and Goolden et al. [36] demonstrated 700 cGy (rad)
during the first 24 h. Liu et al. [37] reported radiation-
absorbed doses of 0.20 ± 0.10 mGy/MBq (range 0.01–0.92
mGy/MBq) and 0.25 ± 0.09 mGy/MBq (range 0.01–1.52
mGy/MBq) for the parotid and submandibular glands,
respectively. However, as noted by Jentzen et al. [38], the
calculated radiation-absorbed doses do not correspond to the
degree of radiation damage, and further investigation is
under way to attempt to take into account the nonuniform
distribution as La Perle et al. has demonstrated that the
sodium-iodide symporter, hence 131I uptake, is located in the
salivary striated ductal cells [39].
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma 675

Salivary Side Effects many months. After employing the usual salivary gland-
protective precautions, the glands of a patient treated for the
Frequency first time with a prescribed activity of 5.55 GBq (150 mCi)
The most frequently reported side effect is acute radiation or less of 131I will most likely be asymptomatic, but this does
sialoadenitis, which has an incidence ranging from 10 to 67 not negate the presence of sialoadenitis. Although an asymp-
% (see Table 62.3) [1, 2, 40–47, 59–62, 70, 198]. As noted tomatic form of sialoadenitis is difficult to confirm histo-
earlier, the variability in frequency and severity are multifac- pathologically, a “silent” sialoadenitis is indirectly or
torial (see Table 62.4), and correlations with both individual retrospectively implicated if there is subsequent develop-
prescribed activity and cumulative prescribed activity of 131I ment of xerostomia. Alexander et al. [2] reported that 56 %
have been reported. Grewal et al. [47] showed a statistically of patients with xerostomia had no prior symptoms of sialo-
significant dose response between administered radioactivity adenitis. However, many patients do develop symptoms. As
and salivary gland swelling but not xerostomia, altered taste, many as one third of patients will report at least mild pain,
or salivary gland pain. with or without tenderness and swelling of the salivary
glands. This pain may begin as early as 6 h or as late as sev-
Signs and Symptoms eral days to even several weeks after 131I treatment. The pain,
tenderness, swelling, or all three signs and symptoms may be
Early Presentation unilateral or bilateral and are more common in the parotid
The spectrum of the signs and symptoms of sialoadenitis glands. However, the submandibular and lingual glands are
range from an asymptomatic sialoadenitis to a very painful, still often involved. Alexander et al. [2] found that in the
tender, and swollen salivary gland, which may persist for group of patients with sialoadenitis (67 of 203), 80.6 % (54
of 67) involved the parotids, and 14 of these were unilateral,
Table 62.3 Incidence of sialoadenitis and 40 were bilateral. Signs and symptoms of sialoadenitis
Author (ref.) Incidence (no. of patients)
in the submandibular glands were seen in 46 % (31 of 67);
Alexander [2] 33 % (67/203)
eight were unilateral and 23 bilateral. Albrecht et al. [42]
Albrecht [42] 59 % (30/51) (parotid) found 59 % (30 of 51) of patients had parotid gland involve-
Alweiss [43] 12 % (10/87) ment, with 25 bilateral and five unilateral, whereas 16 % (8
Benua [1] 2 % (3/122) of 51) had involvement of the submandibular glands. The
Edmonds [198] 10 % (26/258) signs and symptoms may last several weeks and occasionally
Grewal [47] 39 % (102 /262) as long as 1 year. However, Grewal et al. [47] reported per-
Kahn [41] 34 % (17/50) sistent salivary side effects in 5 % or less of patients after a
Kharazi [46] (ThyCa survey) 40 % (640/742) median follow-up of 7 years. Nevertheless, most signs and
Kita [200] 50 % (46/96) symptoms resolve spontaneously within several hours to sev-
Maier [45] 8 % (3/37) eral days with no specific treatment. When treatment was
Nakada [62] 37 % (46/125) to 64 % necessary, symptoms were usually easily controlled with
(67/105) hydration, anti-inflammatory agents (e.g., aspirin and ibu-
Pan [44] 4.6 % (16/342) profen), or an analgesic (e.g., acetaminophen; see discussion
Silberstein [70] 5 % (3/60) below for more details). Sometimes, the symptoms may be
Van Nostrand [40] 67 % (9/15) more severe and chronic, and steroids may be required. If
Walters [59] 24 % (43/176) there is a suppurative parotitis, antibiotics may be required.
In three patients, Allweiss reported a suppurative sialoadeni-
Table 62.4 Multiple factors affecting the frequency and severity of
tis that needed antibiotic treatment [43].
sialoadenitis and xerostomia
Diligence in looking for signs and symptoms of sialoadenitis or
Late Presentation
xerostomia
Individual prescribed activity of 131I Obstruction
Cumulative prescribed activity of 131I Although patients may present with the early signs and
Interval and frequency of 131I symptoms of an acute radiation sialoadenitis, some patients
Amount of 131I uptake in the salivary glands may initially present 1–12 months after 131I therapy or after
Previous history of other salivary gland diseases initial signs of an acute radiation sialoadenitis with new and
Administration of drugs that cause xerostomia different pain, tenderness, and swelling. The process of eat-
Diligence of the patient and physician in reducing the radiation ing or just the sight of appetizing foods often evokes these
exposure to the salivary gland during 131I therapy symptoms, which may resolve within minutes to hours but
676 D. Van Nostrand et al.

are typically recurrent. The pathogenesis is different from
inflammation of the initial acute radiation sialoadenitis and
is most likely a combination of (1) narrowing of the salivary
ducts secondary to scarring from inflammation and (2)
altered quality and/or quantity of saliva. With normal saliva,
there may be ductal narrowing with acute partial obstruction
upon salivation. With reduced flow and thicker saliva, there
may be stagnation and mucus precipitation, resulting in a
plug (or calculus) with obstruction. Nevertheless, the patho-
genesis is probably a combination of both reduced flow and
narrowing of the duct to varying degrees. Although the natu-
ral history of this side effect has not been well described, in
the experience of one of the authors (dvn), these symptoms
usually, but not always, slowly resolve over several months,
but intermittent signs and symptoms can be persistent.
Xerostomia
Xerostomia (dry mouth) is an important complication of
radiation sialoadenitis. In addition, xerostomia may also be
accompanied by burning oral discomfort, difficulty in eating
dry foods, decreased taste sensitivity, increased production
of viscous mucus or morning expectoration, and mucosal
ulcerations. The reported frequency of xerostomia ranges
from 2 to 55 % (see Table 62.5) [1, 2, 15, 40–43, 48–50, 59,
62, 70, 198], and the frequency and severity are again multi-
factorial. If xerostomia occurs, it may begin within several
weeks after 131I therapy and usually resolves within 3 months
[2, 40, 51]. For the condition to last greater than 1 year is
infrequent but does occur in 4.4–7 % of patients [2, 40, 44,
50]. Xerostomia may even be permanent [52, 53].
Interestingly, Alexander et al. [2] reported one patient whose
xerostomia resolved 7 years after the last 131I therapy.
Currently, there does not appear to be a demonstrable
relationship of xerostomia to an earlier clinically evident
presentation of sialoadenitis. As noted above, Alexander
Table 62.5 Incidence of xerostomia
Author (ref.) Incidence (no. of patients)
Albrecht [42] 22 % (11/51)
Alexander [2] 43 % (87/203)
Alweiss [43] 30 % (3/10)
Benua [1] 2 % (3/122)
Edmonds [198] 10 % (26a/258)
Hall [48] 53 % (1363/2573)
Kahn [41] 18 % (10/55)
Leeper [49] Common
Lin [50] 5.4 % (3/56)
Nakaka [62] 11 % (14/125) to 24 % (25/105)
Silberstein [70] 0 % (0/60)
Solans [15] 33 % (26/79)
Van Nostrand [40] 13 % (2/15)
Walters [59] 44 % (78/176)
a
Calculated
et al. [2] showed that more than half patients (56.1 %; 63 of
96) who were diagnosed with xerostomia did not have clini-
cally evident sialoadenitis, and Malpani et al. [54] also found
no link between significant reduction in the function of the
salivary glands and the symptoms of sialoadenitis.
Regarding the prescribed activity of 131I, Spiegel et al.
[55] evaluated 20 patients with thyroid cancer and reported
a dose-dependent decrease in salivary gland function. The
same group specifically described a 40 % reduction of
parotid gland function after prescribed activities of 9.99 GBq
(270 mCi) [56]. Solans et al. [15] demonstrated no associa-
tion between xerostomia and cumulative prescribed
activity.
Complications of Xerostomia
Salivary gland dysfunction after 131I therapy has been
reviewed previously [57]. A major complication of xerostomia
is significantly increased frequency of dental problems [57,
58]. Walters et al. [59] performed a longitudinal cohort study
of 176 patients evaluating the dental safety profile after treat-
ment with high-dose 131I. The caries risk increased by 99 %
with the presence of xerostomia, and the risk of required
tooth extraction increased 8.14 % per gigabecquerel with
increasing cumulative prescribed activity. They also sug-
gested that salivary gland uptake after 131I therapy predicted
the development of sialoadenitis and xerostomia with an odds
ratio of 1.31 ([1.05–1.63], p < 0.015) and 1.58 ([1.16–2.16],
p < 0.004), respectively. Laupa et al. [58] found that despite
the lower salivary flow rates after 131I therapy, the frequency
of widespread dental caries and demineralization, similar to
that observed in externally irradiated patients, was not evi-
dent. Candidiasis is a rare but possible side effect of xerosto-
mia, which may be severe enough to require treatment (e.g.,
nystatin and clotrimazole) [60]. Recommendations for xero-
stomia management and preventive care to minimize dental
caries are noted in Table 62.6 [61–64].
Although xerostomia is a major complication of radiation
sialoadenitis, it is important to note that xerostomia is a
reported side effect of over 500 medications [65], and the
temporal relationship of 131I ablation or treatment to xerosto-
mia does not prove that the condition is because of prior
radiation. Similarly, in a study of 65-year-old residents in
Maryland, an epidemiological study indicated a 17 % preva-
lence of dry mouth [66]. In a case report, Mandel et al. [67]
further warned against assuming that the presence of xero-
stomia after 131I therapy is secondary to that therapy.
Radiation sialoadenitis may be the most likely cause, but a
thorough evaluation is recommended.
Stomatitis
Stomatitis is rare, but if it occurs, it may be very painful [54].
Its mechanism has not been clarified. If severe, stomatitis
may require treatment with dexamethasone elixir mouthwash
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
Table 62.6 Recommendations for the management of xerostomia and
dental caries
Referral to a dental hygienist, dentist, otolaryngologist, or oral
surgeon
Treatment of causes other than radiation sialoadenitis, such as
changing a drug or drug dosage that is causing xerostomia
Adequate hydration
Impeccable dental hygiene
Artificial saliva swirled in the mouth and swallowed every 3–4 h
Repeated massages of the gland as necessary
Avoidance of anticholinergics
Administration of sialagogues [61]
Pilocarpine (Salagen®), 5–10 mg postoperatively t.i.d. Oral tablet
may need to be taken for 6–12 weeks before full benefit is realized
Cevimeline [62] (Evoxac®), cholinesterase inhibitor, 30 mg
postoperatively TID
Anethole trithione (Hepasulfol®, Mucinol®, Sialor®,
Sonicur®, and Sufralem®). The standard dose is 37.5–75 mg
typically in divided doses before meals. Doses of up to 150 mg
daily have been used
Chewing gum
Trial of saliva-stimulating tablets [63], including such potential
agents as disaccharides and low-dose interferon-α lozenges
Acupuncture [64]
Fluoride therapy in the form of topical fluoride applications,
fluoride mouthwashes, and fluoride toothpastes
Hydrogen peroxide mouthwash diluted with mouthwash (e.g.,
Listerine®) Antibiotics for suppurative sialoadenitis
Table 62.7 Approaches to minimize radiation sialoadenitis and its
consequences
Pre-therapy
• Assessment of salivary glands on pre therapy radioiodine
whole-body scans
• Patient education about prevention
• Patient participation in implementing the preventive measures
• Pretherapy visit and management by dental hygienist or dentist
• Hydration
• Suspension of anticholinergic medications
• Consideration of use of radioprotectants (e.g., amifostine,
reserpine)
Immediately posttherapy
• Hydration
• Sialagogues (see text for discussion)
• Parotid gland massage
Posttherapy
• Anti-inflammatory agents
• Steroids
or mouthwash containing viscous lidocaine, diphenhydramine
and aluminum, and magnesium hydroxides [54]. Referral to
an otolaryngologist is advised.
677
Prevention
Although Grewal et al. [47] reported that after a median of 7
years only 5 % or less of 262 patients had persistent salivary
side effects, the prevention and the management of salivary
complications are very important.
Prevention Prior to 131I Therapy
The most important aspect of treatment to prevent or minimize
sialoadenitis is to begin with preventive measure prior to the
first therapy. However, three factors often undermine our pre-
ventive efforts to aggressively reduce radiation exposure to
the salivary glands on the first therapy. First, the initial signs
or symptoms of radiation sialoadenitis are either silent or
mild and transient after the first 131I therapy, which in turn
discourages future aggressive preventive management with
the first therapy. Second, most patients will never require
another 131I therapy. Third, staging helps predict which group
of patients is at risk for metastasis and thus for additional 131I
therapies. However, neither the relative minor initial signs
and symptoms, the likelihood of not needing another 131I ther-
apy, nor the implication of staging helps the individual patient
who does need additional 131I therapies and is at risk for sialo-
adenitis and its associated consequences. Thus, because the
patient always has the potential of additional 131I therapies
and to reduce the severity and frequency of subsequent sialo-
adenitis and its associated consequences, one author (dvn)
strongly recommends aggressive measures to minimize the
radiation-absorbed dose to the salivary gland beginning with
the first 131I therapy. This will serve to reduce the severity and
frequency of subsequent sialoadenitis and its associated con-
sequences (see Table 62.7).
Assessment of the Salivary Glands
Kulkarni et al. [68] demonstrated that although there was no
significantly statistical difference, the incidence of salivary
gland dysfunction appeared to be higher in patients who
showed moderate and marked salivary uptake of radioiodine
on the diagnostic scans than those patients who had none or
mild salivary gland uptake. Although these preliminary data
should not alter the aggressive management to minimize
radiation dose to the salivary glands, assessment of the
uptake in the salivary glands on such scans still may be pre-
dictive. For example, asymmetric, persistent, relatively
increased uptake in one parotid gland may forewarn of a
problem in that gland. Alternatively, minimal or no radioac-
tivity in any of the salivary glands may suggest a lower radia-
tion dose to the salivary glands from 131I and thus a lower
chance of radiation sialoadenitis in that patient. In patients
considered for high empiric or dosimetrically determined 131I
prescribed activities, marked salivary gland uptake may indi-
cate the need to consider a reduction in prescribed activity to
minimize sialoadenitis. However, as discussed below, the
678
time of imaging after the administration of food or other
sialagogues may affect the uptake of radioiodine in the sali-
vary glands on the diagnostic study. Further research is
warranted to evaluate the utility of the salivary gland uptake
on pretherapy 131I scans, yet until those data are available, a
general assessment of salivary gland uptake may be useful.
Patient Education
Two crucial factors to reducing the radiation-absorbed dose
to the salivary gland are (1) educating the patient about the
importance of minimizing the radiation-absorbed dose to the
salivary gland, along with the techniques to do so, and (2)
encouraging the patient to be part of the treatment team,
thereby promoting compliance with preventive measures.
Prophylactic Dental Hygiene
An important recommendation for the preventive manage-
ment of patients who are going to receive high prescribed
activity of 131I is to see a dental hygienist or dentist prior to
their 131I therapy with proper assessment and, if necessary,
treatment of the patient with preexisting conditions such as
periodontal disease, caries, broken teeth, ill-fitting bridges,
partials, and dentures. The dental hygienist will help ensure
an optimal environment for radiation therapy [69], and den-
tal hygienists are an important part of the treatment team.
Because of the special needs of the thyroid cancer patient,
it is important that dental care is performed in a timely fash-
ion. As already discussed in more detail above, 131I therapy
may result in sialoadenitis and subsequent xerostomia. In
addition to dysgeusia and sialoadenitis, the lack of salivary
flow allows both the oral environment to become more acidic
and oral biofilm to grow out of control, making these patients
more susceptible to periodontal disease, rampant caries,
tooth hypersensitivity, or the worsening of a preexisting
condition.
For the pretreatment stage, the dental hygienist will edu-
cate the patient and reinforce the need for proper oral hygiene
during ALL phases of treatment. The hygienist will instruct
daily brushing, flossing, and rinsing techniques. He/she will
perform scaling and prophylaxis procedures to ensure a
healthy environment and administer a fluoride varnish to
help prevent tooth decay. The fluoride varnish is of particular
importance because it makes the oral cavity less hospitable
to bacteria by making the tooth surface more difficult to
attach to. At a minimum, during the pretreatment stage, a
varnish is suggested because fluoride is only available on the
outer 6 μm of tooth enamel and is quickly eroded in an acidic
environment. Nutritional counseling will typically be offered
and includes recommendations of reducing sugar and refined
carbohydrates in the diet that could augment tooth decay.
Emphasis will be on the use of saliva-stimulating foods such
as sugar-free gum containing xylitol and sugar-free lemon
drops. Chewing hard cheese has been found to raise the pH
level in the mouth and to increase bioavailable calcium in
D. Van Nostrand et al.
saliva to bond to and strengthen the enamel. Home fluoride
treatments have been shown to reduce tooth decay. Custom
trays can even be fabricated for home use to be worn
5–10 min per day.
During the pretreatment stage, the dental hygienist will
also give valuable recommendations to be implemented dur-
ing treatment. The dental hygienist will instruct patients to
continue with optimal oral hygiene. The hygienist will edu-
cate the patient on the possible side effects such as mucositis,
stomatitis, and xerostomia and recommend avoiding denti-
frices containing sodium lauryl sulfates (SLS) and mouth-
washes containing alcohol, which may cause irritation and
dryness of the oral mucosa. To ensure sufficient lubrication
of the lips and mouth, certain products will be recommended.
Over-the-counter mouthwashes containing enzymes and
proteins found naturally in saliva provide temporary relief
for dry mouth. Xylitol-containing products draw moisture
into the mouth naturally, though they should be tried by the
patient prior to the treatment phase. Excessive use of xylitol-
containing products can result in unwanted digestive side
effects. If mucositis occurs, the dentist can prescribe one of
various magic mouthwash mixtures such as mouthwash
solution containing benadryl, bismuth subsalicylate
(Kaopectate®), and lidocaine (Xylocaine®) for short-term
use. The dental hygienist is also valuable in the management
of long-term xerostomia, which is discussed in the section on
the management of xerostomia.
If the patient already has an existing hygienist or dentist
for his or her dental care, the physician administering 131I may
wish to inquire about the patient’s dental health with the treat-
ing hygienist or dentist. The hygienist or dentist can advise
regarding not only how long it has been since dental treatment
has occurred but also if there is current disease that needs to
be addressed prior to 131I therapy or if there are existing condi-
tions that may worsen after 131I therapy. If the patient does not
have an existing hygienist or dentist, several resources can be
used to help facilitate the patient’s access to dental care. The
American Academy for Oral Systemic Health (www.aaosh.
com) will allow the patient to search by location for either a
dentist or dental hygienist with a special interest in oral sys-
temic health. If none is available, the American Dental
Hygienists Association (www.adha.org) is a national organi-
zation with state and local chapters. Searching and contacting
officers via the Internet at the state and local level is recom-
mended to the patient to use as a valuable resource. The
American Dental Association (www.ada.org) is a national
organization for dentists, which also has state and local chap-
ters that may help. If cost is an issue, other options are avail-
able including public health dental clinics, dental hygiene
schools, and dental schools. Some of these facilities treat
patients at reduced or no cost. Nevertheless, good dental
hygiene from a qualified dental hygienist or dentist is impor-
tant care prior to and during 131I therapy. After 131I therapy and
the radiation safety precautions have been terminated, the
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
patient should discard any radioiodine-contaminated tooth-
brush, toothpaste tubes, and floss. The recommendation is for
a dental follow-up visit 3 months posttreatment for consider-
ation of prophylaxis and fluoride varnish application. At this
visit, effects of 131I treatment can be assessed and a treatment
plan, if necessary, developed for the patient.
Hydration
Although there is no direct evidence to demonstrate the
value of hydration to reduce the radiation dose to the sali-
vary glands, hydration is recommended on an intuitive
basis. Dehydration is known to lower saliva production,
thereby increasing stasis of saliva, potentially increasing
stasis of 131I in the salivary glands, and potentially increas-
ing the radiation-absorbed dose to the salivary glands.
Hydration is also important for renal clearance of 131I cir-
culating in the blood, thus reducing the amount and dura-
tion of 131I available in the blood for the salivary gland to
take up.
Cholinergic and Anticholinergic Medications
Although anticholinergic drugs may decrease the initial 131I
uptake in the salivary glands in some patients, as a general
rule, all anticholinergic medications should be discontinued.
Cholinergics (e.g., pilocarpine, cevimeline, anetholetri-
thione, and bromhexine) may be useful to stimulate saliva-
tion and hopefully increase 131I turnover or throughput in the
salivary gland. An empiric treatment plan based on a 5-day
regimen, beginning 2 days prior to 131I treatment, has been
proposed [54]. However, the utility of cholinergic drugs
remains controversial. Alexander et al. [2] and Silberstein
[70] showed no difference in the frequency and severity of
sialoadenitis in those who received pilocarpine compared to
those who did not.
Amifostine
Amifostine (WR-2721, Ethyol) has been shown to protect
the salivary gland from the damaging effects of ionizing
radiation of external radiotherapy for head and neck tumors
[71–73]. Amifostine is an organic thiophosphate and is
dephosphorylated to its active metabolite WR-1065. The
latter is a scavenger of oxygen-free radicals, which are the
primary cause of radiation-induced tissue damage.
Amifostine concentration can be 100 times greater in nor-
mal tissue than tumor tissue [74], and the conversion of
amifostine to WR-1065 is more effective in an alkaline
environment. Normal tissue is more alkaline than tumor tis-
sue. One side effect of amifostine was a temporary drop in
blood pressure that required temporary suspension of the
infusion. However, this is usually not a problem; if it
occurs, it is manageable.
679
Because of its value for external radiotherapy for head
and neck tumors, amifostine has been proposed for use in
patients with thyroid cancer [75]. With salivary gland scin-
tigraphy, Bohuslavizki et al. [76] assessed the influence of
amifostine on the adverse effects of 131I therapies on salivary
gland function and demonstrated that parotid and subman-
dibular function was reduced by approximately 40 % in the
placebo group and remained unchanged in the amifostine
group. However, Kim et al. [77] was unable to demonstrate
any cytoprotective effects of amifostine on the salivary
glands in 42 patients. Nevertheless, even if amifostine has a
protective effect on the salivary glands, amifostine is pres-
ently not widely used in patients receiving 131I therapy
because of concern that amifostine may protect tumors from
the effects of radiation therapy [78].
Reserpine
In addition to the innervation of the salivary glands by the
parasympathetic system, the salivary glands are also inner-
vated by the sympathetic system. Therefore, antisympatho-
mimetic agents may have utility. Levy et al. [79] evaluated
12 patients: nine received reserpine and three did not. Based
on 131I uptake on whole-body images relative to patients not
given reserpine, their data suggested that patients taking
reserpine had a significant decrease in the ratio of parotid-to-
background counts. However, it is uncertain whether the
reduced salivary gland uptake was secondary either to the
reserpine or stunning from a 370 MBq (10 mCi) diagnostic
prescribed activity of 131I or partial treatment of the salivary
gland from the 3.7–5.55 GBq (100–150 mCi) ablative pre-
scribed activities of 131I.
Vitamin E (α-Tocopherol Acetate)
As vitamin E has been evaluated as a radioprotective agent
for the lacrimal glands, it has been evaluated by Bhatriya
et al. [80] as a radioprotective agent for the salivary glands
demonstrating a pronounced decrease in lipid peroxidation
and an increase in endogenous enzymes. Human studies with
vitamin E are warranted.
Ocimum sanctum
Ocimum sanctum (O. sanctum) is a medicinal plant used in
India and is reported to have beneficial effects including
radioprotection against 60Co gamma radiation [81]. Leban
et al. evaluated rats that were presupplemented with O. sanc-
tum or amifostine and then exposed to 131I exposure [81].
Subsequent histology of the parotid glands of the rats pre-
supplemented with O. sanctum or amifostine was compara-
ble to control rats that were not exposed to 131I. However, the
histology of the parotid glands of those rats exposed to 131I
without presupplemented O. sanctum or amifostine demon-
680 D. Van Nostrand et al.

strated multifocal areas of lipomatosis and atrophy. Further

evaluation of this plant extract is warranted.

Montelukast Sodium
Koca et al. [82] evaluated montelukast administration as a
potential preventive agent to reduce the radiation effects of
131
I in the salivary glands. The proposed mechanism of
montelukast was discussed earlier in the section on pre-
venting side effects of the lacrimal glands. They evaluated
99m
technetium pertechnetate scintigraphy and histopatho-
logical examinations in 50 rats after 131I therapy with and
without montelukast administration in various groups. The
pathological changes were more significant in the groups
treated with 131I without montelukast than in the groups
prophylactically treated with montelukast. Additional
potential agents have been evaluated including zinc and
turmeric extract (Curcuma longa), which is a member of
the Zingiberaceae family. An excellent review is available
by Noaparast et al. [83].

Immediate Posttherapy
Hydration
On the day of therapy and immediately afterward, hydration
is again thought to be indicated and valuable. This additional
fluid intake may also be valuable to increase urine flow and
reduce radiation dose to the urinary bladder, the latter dis-
cussed later in this chapter. An alternative to oral intake of
fluid would be continuous intravenous hydration; however, if
the intravenous line is placed after therapy, this may raise
radiation safety issues for the phlebotomist.
Massage
Massage of the parotid glands may also be beneficial, espe-
cially if there is initial partial-flow obstruction (see Fig. 62.1)
[53]. Kim et al. [84] evaluated the effectiveness of parotid
massage. Thirty patients had parotid massage performed 20
times over 1 min, and a Tc-99 m pertechnetate salivary scans
were performed immediately prior to and after the parotid
massage. During the massage, patients contracted their jaw
and masticator muscles. The control group had the same two
salivary scans performed with no parotid massage between
the salivary scans. While patients who received the parotid
massage demonstrated no differences in the mean parotid
gland counts on the pre- and post-massaging images, the
group that had no massage had significantly higher mean
counts (6 %) on the second salivary scan. They concluded
that parotid gland massage could help prevent salivary dam-
age secondary to 131I therapy. Although this study does not
prove that one can reduce damage to the parotid glands sec-
ondary to 131I I therapy and although the authors did not eval-
uate the effectiveness of massage with and without the use of
sialagogues, anything that is easy and can potentially reduce
Fig. 62.1 For antegrade massage, push with the fingers mildly on the
parotid gland cephalad and then anteriorly (Concept from Mandel and
Mandel [57]. Reproduced with permission from Keystone Press from
the book entitled “Thyroid Cancer: A Guide for Patients.”)
the residence time of 131I activity in the salivary glands should
be considered.
Sialagogues
Despite their generally accepted empiric use, some authors
have questioned the utility of sialagogues, and specifically,
the use of sialagogues within the first 24 h after 131I therapy
remains controversial [70, 85–90].
Nakada et al. [86] reported that postponing the use of
sialagogues until 24 h after the administration of 131I thera-
peutic dosage reduced sialoadenitis from 63.8 % (67 of
105) to 36.8 % (46 of 125), hypogeusia (abnormally dimin-
ished acuteness of the sense of taste) or taste loss from 39
% to 25.6 %, and dry mouth from 23.8 % to 11.2 %.
Permanent xerostomia decreased from 14.3 % to 5.6 %.
Based on this data, Nakada et al. recommended that siala-
gogues should not be administered during the first 24-h
period after 131I therapy. As the proposed mechanism for
increased radiation-absorbed dose to the salivary glands
with sialagogues, they report using Doppler flow assess-
ment in several patients demonstrating that salivation
increased blood flow to the salivary glands. They hypothe-
sized that this increased flow increased delivery and uptake
of 131I to the salivary glands, which in turn increased the
radiation-absorbed dose to the salivary glands. Van
Nostrand et al. [27] have referred to this proposed mecha-
nism as a “rebound effect.”
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma 681

Liu et al. [87] evaluated 75 patients of which four groups
of patients were administered 100 mg of vitamin C orally at
one hr (18 pts), 5 h (18 pts), 13 h (19 pts), and 25 h (17 pts)
after 131I therapy, and patients received additional vitamin C
every 4 h thereafter for the next 6 days, excluding the hours
between 2 a.m. and 6 a.m. They concluded that “… salivary
stimulation with vitamin C at any time has only a limited
effect on salivary absorbed dose in thyroid cancer patients.”
Jentzen et al. [88] calculated the salivary radiation-
absorbed doses per administered 131I activity in ten patients
based on 124I PET-CT. Patients began chewing lemon slices
20 min after the administration of the 124I. Reportedly, these
patients continuously chewed lemon slice over the first day.
Ten minutes elapsed between stimulation with the lemon
slices and 124I scans. The stimulated patients subsequently
ate lunch 2–4 h later, a snack after 6–7 h, and dinner 9–10 h
later. No comment was stated about continued sialagogues
during the night. The nonstimulated group “… did not chew
lemon slices during the 124I pre-therapy procedure and were
not allowed to have food or drink until after the completion
of the last PET scan on the first day, approximately 4 h after
124
I administration.” Thereafter, patients had lunch after the
first 4-h 124I PET scan and then followed eating a snack and
dinner as the other group. Imaging was performed 0.5, 1, 2,
4, 48, and >96 h after the administration of 124I. They con-
cluded that the radiation-absorbed dose to the salivary glands
was higher when sialagogues were administered. However
and as subsequently discussed below, patients with lemon
stimulation had 10 min to reaccumulate the 124I before imaging,
and patients who were nonstimulated had no lemon or food
for only the first approximately 4 h. In addition, the calcula-
tion of the monoexponential function determined from the
average salivary gland 124I uptake curve only used the data
points from the 4 h time point and later with extrapolation of
the data back to time zero. Thus, no data points were obtained
prior to 4 h with the time between the successive data points
having durations of 20, 24, and 48 h.
Several reports have been published suggested that
sialagogues do decrease sialoadenitis and/or the radiation-
absorbed dose [70, 89].
Silberstein [70] evaluated 60 patients for the effects of
pilocarpine in reducing sialoadenitis. Although he concluded
that pilocarpine was not effective in altering the frequency
or severity of sialoadenitis, his frequency for acute siaload-
enitis was 5 % (3/60), chronic sialoadenitis 1.7 % (1/60),
subjective xerostomia 0 % (0/60), and dysgeusia 5 % (3/60).
These frequencies were significantly less than Nakada et al.’s
reported responses, regardless of whether sialagogues were
used or not (see Table 62.8). Silberstein not only used con-
tinuous sialagogues while awake for a week but also every 3
h throughout the night for three nights. These data strongly
indicated that the continuous use of sialagogues significantly
reduces radiation sialoadenitis. However, of note, Silberstein
also administered dexamethasone to all his patients, and
thus, one cannot determine how much of the lower incidence
of 131I-induced sialoadenitis might have been due to the con-
tinuous administration of sialagogues or the use of steroids.
Van Nostrand et al. [89] evaluated the radiopharmacoki-
netics of radioiodine in 26 patients with preablation salivary
gland scans with the administration of 123I. One-minute
images were obtain every minute for two consecutive phases
of 1 h each with RealLemon® juice administered 5 min into
each phase. These images were initiated 2 h after the admin-
istration of the 123I. A typical time activity curve is shown in
Figure 62.2, and the time activity curves demonstrated that
indeed lemon juice is effective in stimulating the salivary
gland to secrete radioiodine rapidly (mean time to nadir = ~4
min) and effectively (mean washout = ~84 %); however, the
reaccumulation of radioiodine was rapid requiring a mean
time to reaccumulate back to pre-lemon juice radioactivity of
only 21 and 40 min during the first hour and second hour of
the time activity curves, respectively. By analyzing the area
under the time activity curves of all of patients and conserva-
tively assuming that there would have been no further radio-
iodine accumulation had the lemon juice not initially been
given, Van Nostrand et al. [89] calculated that if lemon juice
was readministered at the time the radioactivity had returned
to baseline (i.e., the level prior to the administration of the
RealLemon® juice), one would have potentially reduced the
relative radiation-absorbed dose to the parotid glands by
37–47 %, at least for these two 1-h periods.
In order to determine whether or not a “rebound” effect
may exist, Kulkarni et al. [90] evaluated nine patients who had
both a radioiodine salivary gland performed with and without
the administration of RealLemon® juice on two different
days, thereby allowing the patient to act as his/her own con-

Table 62.8 Comparison of the data from Nakada et al [86] versus Silberstein [70]
Nakada et al. [86] Silberstein [70]
SG every 2–3 h while awake No SG for the first 24 h SG continuously during the day and q3 h during the night
Acute sialoadenitis 63.8 % (67/105) 36.8 % (46/125) 5 % (3/60)
Chronic sialoadenitis Not separated out Not separated out 1.7 % (1/60)
Subjective xerostomia 23.8 % (25/105) 11.2 % (14/125) 0 % (0/60)
Dysgeusia 39.0 % (41/105) 25.6 % (32/125) 5 % (3/60)
682
Fig. 62.2 A typical background-corrected time activity curve (TAC)
demonstrating the response to the oral administration of lemon juice. The
numbers on the X-axis are minutes, and the numbers on the Y-axis are
counts/minute. This figure demonstrates the time points used for the calcu-
lation of the radiopharmacokinetic parameters. A: The peak activity
(counts/min) when lemon juice was administered. B: The nadir (counts/
min) after lemon juice administration. C: The point where activity returned
to activity approximately equal to activity at point A. D: The maximum
activity (counts/min) during the 1 h of imaging. E: The time after the start
Fig. 62.3 This graph demonstrates two curves, which represent two time
activity curves obtain over the parotid glands on two different days after
the administration of 123I. The blue (darker or upper curve) curve repre-
sents the time activity curve obtained 2 h after the administration of 123I
without the administration of any sialagogues. The red (lighter or lower
curve) curve represents the time activity curve that was obtained in the
same patient also 2 h after the administration of 123I, and RealLemon®
juice was administrated 5 min and 65 min after the initiation of the images.
The images demonstrate that there is no “rebound effect” (e.g., the radio-
activity becoming even greater than if lemon juice had not been adminis-
D. Van Nostrand et al.
of imaging (min) to point A. F: The time after start of imaging (min) to
point B. G: The time after start of imaging (min) to point C. H: The time
after start of imaging (min) to point D. Note the prompt response to lemon
juice with subsequent reaccumulation and the similar response following
the second administration of lemon juice at 65 min into the acquisition.
These two phases were initiated 2 h after the administration of 131I (This
figure was originally published in Van Nostrand et al. [89]. Reproduced
with permission from Mary Ann Liebert, Inc. Publishers)
tered) after either the first or second administration of lemon juice. These
images also demonstrate that the percent washout of radioiodine was even
greater after the second administration of lemon juice. Finally, even if
continued imaging had demonstrated that the reaccumulation of radioio-
dine may have exceeded the radioiodine accumulation had a sialagogue
not been administer (e.g., the “rebound effect”), these images suggest that
readministration of lemon juice would have aborted any “rebound effect”
(The above figure is reproduced with permission from Kulkarni [90] and
the publishers, Wolters Kluwer)
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
trol. No rebound effect was observed in any of the nine patients
during the time period imaged (see Fig. 62.3) and the mean
percent reduction in radiation-absorbed dose was 34 ± 17 %.
Kulkarni et al. also observed that spontaneous salivation
occurred 20 times in seven salivary scans that were performed
without the administration of sialagogues.
The reports by Van Nostrand et al. and Kulkarni et al.
raise questions that the time frame of administration of
sialogogues of 2-3h and 4h in Nakada et al.'s and Liu et al's
report, respectively, are too long. Indeed, avoidance of
sialagogues for the first 24 h may be superior to siala-
gogues given every 2–3 h. However, from the reports of
Silberstein, Van Nostrand et al., and Kulkarni et al., the
sialagogues need to be administered more frequently and
preferably continuously. In addition, the sialagogues may
need to be administered not only during the day but fre-
quently during the night. Although Jentzen et al. reported
administering sialagogues continuously, this was only for
4 h before both groups were eating, snacking, and having
dinner. However, more importantly, calculating the radia-
tion-absorbed dose based on measurements of only four
time points beginning at 4 h with periods of 20–48 h
between subsequent time points does not capture what the
continuous lemon slices had achieved during the short 4-h
period prior to the first data point. The radiopharmacoki-
netics of iodine in the salivary gland are in fact “minute by
minute” and are not reflected accurately when measured
by periods of “4 to 24 hours.”
Finally, the recommendation of avoiding sialagogues dur-
ing the first 24 h to avoid salivation is not possible when
patients are eating and drink lunches, snacks, and dinners,
which patients of both Nakada et al. and Jentzen et al. appar-
ently did. Thus, those patients could not avoid salivation
within the first 24 h period. Further, even if one was on NPO
for 24 h, it would appear based on Kulkarni’s preliminary
work—and we would submit based on everyone’s personal
experience - that spontaneous salivation cannot be avoided
during a 24-h period [90]. As a result, spontaneous salivation
defeats, at least in part, the proposed objective of avoidance
of sialagogues for 24 h.
The controversy regarding the use of sialagogues will
continue, but future studies must consider the dynamic min-
ute-by -minute radiopharmacokinetics of iodine in the sali-
vary gland.
Anti-inflammatory Agents
Whether patients should prophylactically take anti-
inflammatory agents to reduce the inflammation and/or the
signs and symptoms of sialoadenitis is not known.
However, Silberstein has report prophylactic use of ste-
roids in all patients [70]. His reported frequency of sialo-
adenitis and/or xerostomia was low and already noted in
683
Table 62.8, but he also administered continuous siala-
gogues as discussed above.
Management of Complications
Sialoadenitis
If signs and symptoms indicating acute sialoadenitis occur,
no guidelines have been evaluated to one author’s (dvn)
knowledge regarding when to begin anti-inflammatory
agents, which anti-inflammatory agents are to be used, and/
or for how long. Van Nostrand [27] has previously proposed
an algorithm based on the National Cancer Institute’s clas-
sification for salivary gland side effects (see Table 62.9), but
as noted by Van Nostrand, no data are available to demon-
strate that these guidelines are any better than any other pro-
posal or even any better than not administering
anti-inflammatory drugs. Further study is needed.
Xerostomia
Multiple recommendations have been proposed for the man-
agement of xerostomia, and a compilation of these recom-
mendations appears in Table 62.10. One caveat regarding
xerostomia is that one should not assume that the presence of
xerostomia is the result of a prior radioiodine therapy. Many
etiologies and combinations of etiologies may exist.
However, a good history of the presence or absence of xero-
stomia prior to 131I therapy and, if present, the severity of the
patient’s xerostomia prior to 131I therapy will be helpful. If
one does not wish to manage persistent xerostomia, then the
patient should be referred to a dentist, oral surgeon, or otolar-
yngologist who does manage such.
Stomatitis
Stomatitis may be treated with dexamethasone elixir mouth-
wash or mouthwash that contains viscous lidocaine, diphen-
hydramine and aluminum, and magnesium hydroxides [53].
Referral of the patient to a dental hygienist, dentist, oral sur-
geon, or otolaryngologist is highly recommended.
Salivary Duct Obstruction
The symptoms of obstruction (as described earlier) should nei-
ther be mistaken as acute or chronic sialoadenitis nor treated as
acute or chronic sialoadenitis. Although a component of
chronic sialoadenitis may be present and warrant treatment,
ductal obstruction should be considered because the manage-
ment is different. If the pain and swelling is mild owing to mild
obstruction from a mucous plug and/or radiation fibrosis, then
increased retrograde or antegrade pressure with massage may
resolve the symptoms by helping the normal or thickened
saliva pass the ductal narrowing or help spontaneously extrude
a mucous plug (see Fig. 62.1). If the symptoms are not mild or
684 D. Van Nostrand et al.

Table 62.9 Proposed guidelines for the management of sialoadenitis, based on the severity of the signs and symptoms1,2
Category Description Treatment
Mild Mild pain (NCI grade I = mild pain not interfering with Nonsteroidal, anti-inflammatory medication for 3 days
function with a duration of <1 h)
No swelling
No tenderness to the touch
Moderate (one Moderate pain (NCI grade II = moderate pain or analgesics Anti-inflammatory medication for 7 days
or more of the for pain interfering with function, but not interfering with
following) activities of daily living of ≥1 h of duration)
Any swelling
Any tenderness to the touch
Severe (one or Severe pain (NCI grade III = pain or analgesics severely Anti-inflammatory medication for 7 days,
more of the interfering with activities of daily living of any duration)
following) Moderate to severe swelling (very subjective)
Moderate to severe tenderness to the touch (very subjective) Methylprednisolone dose pack or equivalent and
Referral to dental hygienist, dentist, oral surgeon, or
otolaryngologist
Extreme Suppurative sialoadenitis Emergency referral to otolaryngologist, oral surgeon, and/or
dentist with special expertise in salivary gland management
Hydration is not listed, because this should already be encouraged and continued
No data are available to suggest that these guidelines are any more or less effective than any other guidelines or even no treatment at all

Table 62.10 Options for the management of xerostomia and dental caries
Maintain good hydration
Refer patient to a dental hygienist, dentist, oral surgeon, or otolaryngologist
Treat causes other than radiation-induced xerostomia such as reducing the dose of a drug or changing a drug that is causing xerostomia
Take frequent sips of sugar-free water or drinks
Drink frequently while eating
Keep a glass of water by one’s bedside for dryness during the night or on awakening
Pause often while speaking to sip some liquids
Avoid coffee, tea, and soft drinks
Chew sugarless gum
Suck sugarless mints or hard sugarless candy allowing them to dissolve in your mouth (cinnamon and mint are often more effective)
Avoid tobacco and alcohol
Avoid spicy, salty, and highly acidic foods that may irritate the mouth
Use a humidifier, particularly at night
Maintain impeccable dental hygiene with regular checkups (3–6 months)
Use fluoride toothpaste routinely
Use nonalcoholic mouth washout such as a nonalcoholic mouthwash mixed with hydrogen peroxide
Consider fluoride therapy in the form of topical fluoride applications, fluoride mouthwashes, and fluoride toothpastes
Artificial saliva swirled in the mouth and swallowed every 3–4 h
Avoidance of anticholinergic medications
Administration of sialagogues [61]
Pilocarpine (Salagen®), 5–10 mg p.o. t.i.d. Oral tablet may need to be taken for 6–12 weeks before full benefit realized
Cevimeline (Evoxac®), cholinesterase inhibitor, 30 mg p.o. t.i.d.
Anethole trithione (Hepasulfol®, Mucinol®, Sialor®, Sonicur®, Sufralem®). The standard dose is 37.5–75 mg typically in divided doses before
meals. Doses of up to 150 mg daily have been used
Trial of saliva-stimulating tablets (SST) [63] including potential agents as disaccharides and low-dose interferon-α lozenges
Acupuncture [64]
Antibiotics for suppurative sialoadenitis
Reproduced with permission from Blackwell Munksgaard
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
transient, then referral to otolaryngologist is strongly recom-
mended. The otolaryngologist can then evaluate for other,
albeit unlikely, etiologies of obstruction, consider ductal dila-
tion of Stensen’s duct with sialoendoscopy, and, in rare cases,
consider tympanic neurectomy or ligation of the duct. Nahlieli
and Nazarian evaluated 15 patients with sialoadenitis after 131I
therapy with sialoendoscopy under local anesthesia. All
patients were reported to be free of swelling and pain in the
parotid glands after one sialoendoscopy for a follow-up period
of 1–4 years. Except for immediate swelling after sialoendos-
copy of the affected salivary gland in all patients, there were no
other complications observed. The swelling resolved spontane-
ously after 12 h [91]. Bomeli et al. [92] have reported on the use
of interventional sialoendoscopy in 32 salivary glands in 12
patients. They were successful in 27 glands (84.4 %) with duc-
tal stenosis in 30 % and mucus plugs removed in 44 %.
Sialoendoscopy improved symptoms in 75 % (9/12) of patients
with no serious complications. Allweiss et al. [43] reported one
patient who required parotidectomy because of intractable sali-
vary gland pain and discomfort, but excision of the gland
should obviously be avoided. Finally, a secondary infection can
occur that may require antibiotics.
In summary, sialoadenitis is an important side effect of
131
I therapy. Awareness of this side effect, its subsequent
complications, and appropriate preventive care and treat-
ment can be very important.
Taste and Smell
Alteration of taste and smell is well documented after 131I ther-
apy [2, 40, 41, 93] and may be described as simply a loss of
taste, loss of smell (2), metallic taste, or chemical taste [93].
Occasionally, these patients may describe a salty taste that
may be secondary to inadequately absorbed sodium and chlo-
ride ions in the saliva [45]. The frequency varies from 2 to 58
% of patients as noted in Table 62.11 [1, 2, 40, 42, 50, 93, 94].
The loss or change in taste or smell may occur as early as 24 h
after 131I ablation and was reported to occur within 168 h [93].
Although transient, the change in taste may persist from 4
weeks to as long as 52 weeks in 37 % of those patients [45].
Alexander et al. [2] found that it occurred up to several weeks
after discharge and persisted for 1–12 weeks. The mechanism
is most likely 131I uptake in von Ebner’s serous gland, located
in the vicinity of the taste buds containing circumvallate
papilla [53, 93]. Albrecht et al. [42] demonstrated a depen-
dence or direct relationship on administered activity of 131I.
Nasal Effects
Pain in the tip of the nose and epistaxis are rare but real
side effects of 131I. Van Nostrand et al. [40] described two
of 15 patients who had received prescribed 131I activities
685
greater than 7.4 GBq (200 mCi) who had nasal complaints.
One patient had dry nasal mucosa at 1 week, followed by
easily controlled epistaxis, and a tender nose with clots
and scabs during the second week. The lining of the nose
has mucous cells that can accumulate 131I. This accumula-
tion can be most prominent in the tip of the nose, which is
frequently seen and confirmed on 131I whole-body scans
(see Chap. 12) [95]. At the present time, little is known
regarding methods to reduce this infrequent side effect of
131
I. However, if performing dosimetry and planning to
administer prescribed 131I activity higher than 7.4 GBq
(200 mCi), the pretherapy scan for nasal uptake can be
assessed to anticipate this potential complication. If there
is facial activity with focal uptake in the nose area, con-
sider a lateral view with appropriate markers. If there is
marked uptake in the tip of the nose and if a high pre-
scribed activity of 131I is being considered, then the pre-
scribed activity can be reduced. Further research is
warranted evaluating drugs that may reduce this nasal
uptake.
Facial Nerve
131
I has been associated as a rare cause of transient facial
nerve paralysis. Levinson et al. [96] reported two patients
who rapidly developed transient facial paralysis after 131I
therapy. The proposed mechanism was the passage of the
affected nerve through the parotid gland, and the paralysis
was attributed to the gland swelling secondary to radiation
sialoadenitis with ischemia of the nerve. After resolution of
the sialoadenitis, the facial nerve palsies resolved.
Thyroid Tissue
Radiation Thyroiditis
Radiation thyroiditis posttherapy is commonly seen in
patients with large benign thyroid remnants (≥10 % neck
uptake), especially when treated with >2.8–3.7 GBq (≥75–
100 mCi) or more of 131I, delivering radiation doses more
than 50,000 rad (cGy). In ten patients studied retrospec-
tively after lobectomy only, more patients demonstrated
neck pain or tenderness (60 %) with 131I ablation of the
residual lobe than with 131I ablation after more extensive
excision (6 %) [97]. Neck and ear pain, dysphagia, painful
swallowing, thyroid tenderness, and even airway compro-
mise requiring intubation can be seen beginning 2–4 days
posttherapy. With more extensive surgery, such as total or
near-total thyroidectomy (<5 % neck uptake), radiation thy-
roiditis is infrequently seen. Cherk et al. [98] demonstrated
that the acute thyroiditis was related to 131I uptake and not
the amount of prescribed activity of 131I.
686
Table 62.11 Incidence of change in taste and/or smell
Author (ref.) Incidence (no. of patients)
Albrecht [42] 58 % (30/51)
Alexander [2] 27 % (55/203)
Benua [1] 2 % (3/122)
Kahn [41] 16 % (8/50)
Kita [200] 9.8 % (9 /92)
Lin [50] 1.8 % (1/56)
Orquiza [94] 44 % (34/78)
Van Nostrand [40] 33 % (5/15)
Varma [93] 48 % (41/85)
However, with extensive neck metastases that are 131I
avid, patients may also demonstrate marked pain and swell-
ing and even hemorrhage following 131I therapy, particularly
if the radiation-absorbed doses exceed 40,000 cGy (rad).
Strong consideration should be given to surgical removal of
all palpable neck metastatic disease to prevent such sequelae.
A less common phenomenon is painless neck swelling that is
manifested by edematous and firm induration of the neck,
typically seen within 1–2 days of 131I therapy of more than
10–15 g of thyroid tissue [99]. This is frequently associated
with a neck-tightening sensation that can be very alarming to
some patients. Although mild symptoms often recede with
just analgesics, an oral prednisone burst and taper may be
both necessary and beneficial in some patients with painful
radiation thyroiditis and most patients with painless neck
edema, using 30–60 mg daily for 3–5 days initially, followed
by a gradual taper over 7–10 days.
Thyrotoxicosis
Thyrotoxicosis has been well documented in patients with
functioning differentiated thyroid carcinoma after 131I ther-
apy [100–103]. Although rare, this is most typical of wide-
spread metastatic follicular thyroid carcinoma. Trunnel et al.
[103] reported that the signs and symptoms of hyperthyroid-
ism appeared within 2 weeks of therapy. Cerletty et al. [104]
described two cases in which the failure to control the thyro-
toxic state led to thyroid storm and death.
Hypoparathyroidism
Therapeutic prescribed activity of 131I can easily deliver
greater than 10,000 cGy (rad) to the thyroid bed with lesser
radiation to adjacent parathyroid tissue at 5–6 weeks post-
thyroidectomy when surgically induced parathyroid injury
may still be present. However, 131I β particles (electrons)
have a range of only 2.5 mm in soft tissue, and parathyroid
irradiation would only be significant for intrathyroidal or
D. Van Nostrand et al.
closely adherent parathyroid glands. Only two cases of
permanent hypoparathyroidism after 131I therapy of thy-
roid cancer have been reported to our knowledge in
patients known to be normocalcemic prior to treatment
[105, 106]. Glazebrook et al. [106] have postulated that
many thyroid cancer patients treated with 131I exhibit
diminished parathyroid reserve, as shown by stress testing
in 53 patients post-thyroidectomy. When salt and water
loaded prior to forced diuresis, 58 % of the 53 patients
treated with 2.96–5.55 GBq (80–150 mCi) demonstrated
transient hypocalcemia. In this prospective study, affected
patients were more likely to have lower prestress serum
calcium levels than unaffected patients. In the absence of
symptoms, routine monitoring of calcemic status does not
appear to be warranted.
Zhu et al. [107] reported in 58 patients that the blood
parathyroid hormone (PTH), blood calcium, and blood phos-
phorus were not significantly affected by 131I therapy with
1.48–3.70 GBq (40–102 mCi). However, in five patients,
PTH levels transiently decreased to below normal levels
returning to normal 4 months after 131I therapy.
Carotid Artery
Cunha et al. [108] have reported a case of a rupture of a
carotid artery following 131I therapy in a patient with dif-
ferentiated thyroid carcinoma. This patient had a large
expansive solid mass with radioiodine uptake that was
located at the base of the skull with tumor invasion of the
left masticatory muscle and adjacent subcutaneous tissue.
However, there was no invasion of the carotid space. As the
authors pointed out, one should be cautious with masses
that have good radioiodine uptake and are adjacent to
important structures.
Vocal Cords
Recurrent laryngeal nerve injury or direct trauma from endo-
tracheal tube placement during thyroidectomy can induce
transient or permanent vocal cord paralysis, manifested by
stridor or hoarseness. In symptomatic patients seen prior to
anticipated 131I therapy, direct laryngoscopy can document
vocal cord dysfunction and should be performed. 131I treat-
ment of residual thyroid bed tissue can cause significant thy-
roid tissue swelling that is associated with laryngeal nerve
compression and dysfunction [109, 110]. As reported by Lee
et al. [109], 5.55 GBq (150 mCi) prescribed activity of 131I
given to treat residual right thyroid bed tissue in a patient
with papillary thyroid cancer was followed by the gradual
development of bilateral vocal cord paresis within 72 h.
As only right thyroid bed irradiation occurred (no significant
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
left-lobe uptake present), it was believed that a partial left
recurrent laryngeal nerve injury had been present since the
surgery, necessitating an emergent tracheostomy. Fortunately,
the bilateral vocal cord dysfunction resolved after 8 weeks.
Pulmonary Effects
Acute radiation pneumonitis (ARP) and pulmonary fibrosis
(PF) are potentially serious complications of 131I treatment in
patients who have pulmonary metastasis from differentiated
thyroid carcinoma. Fortunately, this is very rare; however,
because it is rare, most of the information regarding ARP
and PF secondary to 131I comes from (1) radiation pathology
from external radiotherapy [111, 112], (2) two important
case reports described in 1957 by Rall et al. [113], and (3)
several additional reports in the literature [41, 50, 51, 114–
116, 198]. The occurrence of ARP, PF, or both is directly
related to the extent of pulmonary metastasis, the prescribed
activity of 131I, and its uptake and retention in the lung
lesions. However, based on the information derived from
these resources, radiation pneumonitis and pulmonary fibro-
sis are expected to be infrequent and rare complications of
131
I treatment.
Presentation
Based upon radiation pathology from external radiotherapy
[111, 112], the time of ARP onset is usually 1–20 weeks
after initial therapy. Its clinical presentation includes dys-
pnea, nonproductive cough, possible pleuritic pain, malaise,
occasional fever, and rales. Radiographic changes are simi-
lar to other pneumonitis secondary to other causes, and
computer tomography is more sensitive than chest X-ray in
identifying the radiographic changes. The initial findings
are typically perivascular haziness, which is followed by
alveolar filling densities. Although these changes from
external radiation therapy are typically confined to the field
of irradiation, they may occur outside the field, known as
abscopal effects [117–119]. Morgan et al. [120] suggested
that these changes outside the irradiation field are from
other mechanisms, such as generalized immunologically
mediated lung damage.
The pathologic changes include congestion and intra-
alveolar edema with alveolar macrophages, and the initial
lesions probably occur in the endothelial cells of alveolar
wall capillaries. Protein-rich fluid then leaks through the
damaged capillary wall into the interstitium and alveolar
lumen, with resultant edema in the alveolar septa and
hyperplasia of the alveolar-lining cells. A hyaline mem-
brane may occur, comparable to the pathogenesis of other
etiologies of acute respiratory distress syndromes (ARDS);
687
however, if formed, the hyaline membrane is more prominent
in ARP. This description is similar to the autopsy reports
of the two patients with ARP and PF, as reported by Rall
et al. [113].
PF is a late clinical sequela of ARP. Although PF is
typically present in most individuals who recover from ARP,
PF can develop in patients who never had an initial acute
illness. Most patients who develop PF are symptomatic 1
year later. If PF does occur, it is usually established and sta-
ble by 1 year after exposure and is irreversible. However,
Delanian et al. [ 121 ] reported a decrease in fibrosis
with treatment with a combination of pentoxifylline and
tocopherol, but again, these data involved external radiation
therapy. PF can also be chronic and progressive. The patho-
physiology of PF involves progressive fibrosis of the alveo-
lar septa. The laboratory changes include mildly reduced
pulmonary functions, such as decreased vital capacity,
decreased forced expiratory volume (FEV1), decreased car-
bon monoxide diffusing capacity (DLCO), mild arterial
hypoxia, decreased compliance, and reduced alveolar-capil-
lary membrane integrity. Radiographically, computed
tomography (CT) is again a more sensitive test than chest
radiography and can demonstrate a progressive decrease in
lung volumes, a reduction of pulmonary blood flow, and the
fibrotic changes associated with PF. The pathophysiology
may be the result of multiple agents including transforming
growth factor-beta, interleukins, KL-6, surfactant proteins,
and adhesion molecules [112].
Risk factors for clinical radiation pneumonitis are contro-
versial. Monson [119] demonstrated an increase in clinical
radiation pneumonitis in patients with a low Karnofsky
performance status, a history of smoking, comorbid lung
disease, or low pulmonary function tests (PFTs). In those
patients with an FEV1 of two or less, 24 % (16 of 66) of
patients developed clinical radiation pneumonitis, whereas
in patients with an FEV1 above two, only 6 % (1 of 17) devel-
oped clinical radiation pneumonitis. In those patients with a
forced vital capacity (FVC) of 3 liters or less, 31 % (17 of
54) developed clinical radiation pneumonitis, but no patient
with an FVC more than 3 liters developed clinical radiation
pneumonitis. These patients had received external radiother-
apy for lung carcinoma [119]. However, there is a diversity
of opinions regarding these risk factors such as pulmonary
function [122].
As noted previously, limited reports exist in the literature
regarding ARP and PF secondary to 131I treatment in patients
who have differentiated thyroid carcinoma with pulmonary
metastasis. One of the most detailed reports provides valu-
able descriptions of two patients with documented fatal ARP
and PF. Several salient features about these two patients are
summarized here [113]. First, the initial respiratory symp-
toms occurred approximately 60 and 61 days after their 131I
treatments. For one patient, the presenting symptoms were
688
shortness of breath and substernal pressure during exertion.
For the other patient, symptoms were coldness, fatigue,
shortness of breath, and a slightly nonproductive cough. The
time interval from the initially reported respiratory symp-
toms to death from respiratory failure was 48 and 49 days,
respectively. Rapid deterioration appeared to occur over
the last 23 and 38 days. Steroids were used in one patient,
which produced a significant but only transient improve-
ment. Although other reports of ARP and PF are noted, no
other significant information is available regarding time until
symptoms, course of respiratory failure, the use of steroids,
and so on.
Although these are only two cases and little additional
information is available in the literature, several warnings
appear to be appropriate and prudent. First, the signs or
symptoms of ARP and/or its sequelae do not necessarily
occur immediately after treatment but can be delayed as long
as 8 weeks and possibly longer. Second, the initial symptoms
may appear to be minor and nonspecific but should not be
dismissed as unimportant or owing to other causes. Third,
there may be an initial symptomatic period where early treat-
ment with steroids may possibly alter the patient’s course
before progressive, irreversible respiratory failure begins.
Radiation Dose to the Lung
Estimating the radiation dose to the lung from 131I treatment
is problematic on several counts. There are challenges in
estimating 131I uptake in a pulmonary lesion, inhomogeneous
131
I uptake within the lesion, lesion depth, attenuation of the
radioactivity, radioactivity clearance from the lesion, lesion
volume, and the radiation exposure to adjacent normal pul-
monary tissue. Consequently, the radiation exposure to the
lungs or even a portion of the lungs from 131I is difficult to
accurately determine. Additional studies are underway using
124
I, which are discussed further in Chap. 103. However,
more specific data are available from external radiotherapy
on the relationship between radiation dose and side effects
on the lung (see Tables 62.12, 62.13, and 62.14) [112, 117,
119, 123–130]. The data from external radiotherapy are use-
ful for an overall perspective, but extrapolation of the data to
131
I therapy is again difficult. Similarly, although dosimetric
analysis of radiation exposure to the lungs from 131I with
phantoms has been reported, the information is limited [131].
However, several groups have attempted to define dose-
volume histograms to help predict radiation-induced lung
disease [132, 133]. Gopal et al. [132] demonstrated a signifi-
cant decrease in DLCO with the local lung dose exceeding
13 Gy, but interestingly, the threshold was increased to
36 Gy when the patient was treated with amifostine. Emami
et al. [134] attempted to compile tolerance for normal lung
tissue with estimates of tolerance doses resulting in a 5 %
D. Van Nostrand et al.
Table 62.12 Fractionated radiation dose and side effects on the lung
34.9 Gy (3490 rad), 15 fractions over 19 days = 50 % developed
radiographic evidence of lung damage [123]
40 Gy (4000 rad), 20–30 fractions = 8–15 % severe ARP clinically
[117, 124]
54 Gy (5400 rad; fractionation N/A) = 20 % developed
clinical ARP [119]
Occasionally severe lesions have occurred with lower doses
Of 377 patients treated to the mantle for Hodgkin’s disease, 20
developed ARP; three died with less than 600 cGy (600 rad) to one
whole lung. Five died after 600–1500 cGy (600–1500 rad) [125]
N/A = not available
Table 62.13 Single radiation dose (SD) and side effects on the lung
After 600–1000 cGy (rad) single dose, 17.5 % developed ARP 100
days later and 15 % died of ARP within 2 weeks [126]
820 cGy (rad) for 5 % incidence of ARP
930 cGy (rad) for 50 % incidence of ARP
1100 cGy (rad) for 90 % incidence of ARP [127]
700 cGy (rad) for SD to both lungs is currently proposed limit
[127–129]
Table 62.14 Pulmonary fibrosis
Difficult to establish because it is typically asymptomatic but
probably very frequent [130]
After 3000 cGy over 10–15 days, 30 % had radiographic changes
[123, 127]
After 5000 cGy (rad) over 25 days, 90 % had radiographic changes
[123, 127]
complication rate and a 50 % complication rate, and Burman
et al. [135] further used this model to interpolate clinical data
to provide estimates of radiation pneumonitis to normal lung
tissue based on dose and irradiated volume. Graham et al.
[136] evaluated clinical dose-volume histograms for pneu-
monitis for 3D radiotherapy for non-small cell lung cancer.
They reported that the total lung volume exceeding 20 Gy
(2000 rad), larger effective volume, higher total lung volume
mean dose, and location of the tumor (lower lung) to be sta-
tistically significant for the development of ARP. Wilner
et al. [133] evaluated the relationship of ARP to “a little
(dose) to a lot (of volume) or a lot to a little,” and the risk of
ARP increased significantly with increasing levels of high
radiation dose volume. Reducing high-dose volumes reduced
ARP more than reducing the low-dose volumes. Although
these data are again based on external radiation therapy and
a full discussion is beyond the scope of this chapter, these
data raise the possibility that ARP may be more likely after
131
I therapy in patients with diffuse pulmonary metastases
versus individual areas of pulmonary macronodular disease.
In the literature on ARP and PF secondary to 131I treat-
ment, the most valuable data are again from Rall et al. [113]
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma 689

Fig. 62.4 These data were compiled

from Rall’s original article by one author
(dvn). Changes in pulmonary function
begin to appear after 131I deposited in the
chest at 24 h exceeded 125 mCi. The
effect of pulmonary function was graded
as follows: 0 = none, 1 = minimal X-ray
reaction, 2 = moderate X-ray reaction, 3 =
moderate X-ray reaction + symptoms, 4 =
death from pulmonary insufficiency

Fig. 62.5 The two fatalities from

radiation pneumonitis reported by Rall
et al. each had over 1 Ci-day of 131I
retention in the lung. This was calculated
by summing the calculated lung retention
for each day over 20 days. The amount of
131
I uptake and the amount and duration of
131
I retention appear important, which is
what one would expect. The effect of
pulmonary function was graded as
follows: 0 = none, 1 = minimal X-ray
reaction, 2 = moderate X-ray reaction, 3 =
moderate X-ray reaction + symptoms, 4 =
death from pulmonary insufficiency

and Benua et al. [1]. Rall et al. observed 15 patients with pul-
monary metastasis from differentiated thyroid carcinoma
who were treated with 131I. Four of these patients developed
pulmonary changes, and two subsequently died from the pul-
monary changes as already noted. Figure 62.4 demonstrates
the relationship between the amount of prescribed 131I activ-
ity deposited in the chest and the pulmonary assessment.
When the study was reported in 1957, the pulmonary assess-
ment was made by X-ray and evaluation of symptoms. No
patient who retained less than 4.63 GBq (125 mCi) in the
chest at 24 h developed radiographic changes or symptoms
to suggest pulmonary changes secondary to radiation effects.
In Fig. 62.5, Rall’s data demonstrate an association between
pulmonary assessment and the quantity of 131I deposited in
the chest over the first 20 days following treatment. The
quantity of 131I deposited was expressed in units of “curie-
day,” which represents the sum for each of the 20 days of 131I
estimated quantity deposited in the lungs. Both fatalities had
the highest estimates of 131I exposure to the chest with over 1
Ci-day. Furthermore, no patient with approximately 0.75
Ci-day of 131I deposited in the chest developed radiographic
changes or symptoms to suggest any pulmonary changes
secondary to radiation. In 1961, Benua et al. [1] reported on
an expanded group of patients at Memorial Sloan Kettering
Cancer Center (MSKCC), which included patients of Rall
et al.; 59 patients were treated with 122 doses of 131I. Radiation
pneumonitis occurred in five of these patients. However,
radiation pneumonitis did not occur when the calculated
radiation dose to the blood was less than or equal to 200 cGy
(rad) and the whole-body retention of 131I at 48 h was less
than or equal to 2.96 GBq (80 mCi) (see Chap. 58).
Based on their early experience, Benua and Leeper pro-
posed and implemented the above restrictions for patients with
pulmonary metastasis. In 1982, Leeper reported that no subse-
quent radiation pneumonitis had been observed at MSKCC
over approximately 20 years since the original group of five
690 D. Van Nostrand et al.

Table 62.15 Review of the literature of pneumonitis and pulmonary fibrosis

Pulmonary fibrosis
Author (ref.) Pneumonitis or impairment Fatal Dosimetry Comments
Aldrich [115] 7/35 2/35 No Impairment may have been part of thyroid
cancer or concomitant lung disease
Benua [1] 5/59 1/59 2/59 Yes
Brown [51] 0/31 0/31 0/31 No 1. Dosage typically 150 mCi
2. Maximum dosage 680 mCi
Edmonds [198] 0/5 1/5 0/5 No 1. Dosage typically 150 mCi
2. Range 378–973 mCi
3. Follow-up 8–17 years
4. Progressive impairment, which may have
been part of disease itself
Leeper [201] 0/70 0/70* 0/70* Yes 1. Average dosage of 309 mCi
2. Range 70–654 mCi
Maheshwari [140] 0/53 1/53 0/53 No Dosage typically 50–200 mCi
Menzel [116] 0/23 0/23 0/23 No Used empiric dosages as high as 300 mCi
Pacini [139] 1/86 1/86 No Respiratory failure from thyroid cancer and 131I
therapy, or both could not be differentiated
Samuel [137] 1/35 1/35 0/35 No 1. Highest dosage 270 mCi
2. Highest total dosage 1194 mCi
3. Data based on 99mTc-DTPA clearance
Schlumberger [138] 0/23 0/23 0/23 No Administer repeated dosages of 100 mCi
Van Nostrand [40] 0/6* 0/6* 0/6* Yes Highest dosage 450 mCi
Total 2 % (6/305) 2.8 % (12/426) 1.2 % (5/426)
*After restriction imposed of not exceeding 80 mCi of 131I whole body retention at 48 h

patients [48]. In the intervening years, other institutions have
adopted the Benua and Leeper (MSKCC) dosimetry protocol
with the above restrictions. A review of the literature of those
patients who have had pulmonary metastases and were treated
with a prescribed activity of 131I, either according to dosimetry
with the above restrictions or an empiric formula, is noted in
Table 62.15 [1, 40, 51, 115, 116, 137–140, 198, 201]. The
frequency of observed radiation pneumonitis in the pooled
group of patients was 2 %, PF was 2.8 %, and death secondary
to radiation effects to the lung was 1.2 %.
Thus, despite the absence of prospective data in the litera-
ture and the inability to extrapolate the data from external
radiation therapy, significant empirical data has been accu-
mulated over the last 60 years. These data allow at least one
approach that has a reasonably acceptable risk of ARP and
PF complications.
Thyroid Hormone Withdrawal Versus
Recombinant Human Thyroid-Stimulating
Hormone
The use of thyroid hormone withdrawal (THW) versus
recombinant human thyroid-stimulating hormone (rhTSH)
for the preparation of patients with distant metastases for 131I
has been discussed elsewhere in Chaps. 10, 60 and 103.
However, whether or not the preparation of patient with
either THW or rhTSH for 131I therapies in patients with focal
or diffuse pulmonary metastases could have greater or lesser
complications is not known. However, Goffman et al. [141]
have reported a case with near-lethal respiratory failure after
the use of rhTSH. This case report is a caveat in the use of
rhTSH in patients with pulmonary metastases and indicates
that further study is warranted to evaluate whether or not the
side effects are due to the rapid increase of TSH from the
injection of rhTSH, 131I therapy, or a combination of both and
whether or not pretreatment with steroids is warranted.
Appropriate Time Interval between 131I
Treatments
It is also problematic to determine the appropriate time inter-
val between 131I treatments to minimize the patient’s chance
of developing ARP and PF. Schlumberger et al. [138] found
no ARP or PF in a patient group with pulmonary metastases
who were treated with 131I every 4–6 months, but the pre-
scribed activity used was only ~3.7 GBq (100 mCi). Hindié
et al. [142] also reported no ARP or PF with treatments every
6 months until a cumulative prescribed activity of 18.5 GBq
(500 mCi), at which time the interval was increased to 1 or 2
years. However, Hindié et al. [142] also treated patients with
prescribed activities of 3.7–5.55 GBq (100–150 mCi). Rall
et al. suggested that the recovery from ARP was exponential
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
and that multiple doses should be separated by intervals of 6
months or more [113]. Leeper, who administered much
higher prescribed activities of 131I, empirically recommended
extending the time between treatments to approximately 1
year [48]. Although further study is needed, these studies
will be difficult to perform.
Existence of Prior Pulmonary Disease
Aldrich et al. [115] evaluated pulmonary function in 12 of 35
patients with differentiated thyroid carcinoma metastatic to
the lung. Five patients had other known causes for lung dis-
ease, but no distinctive type of abnormal pulmonary function
(e.g., obstructive, restrictive, or mixed) was identified with
pulmonary metastases. Interestingly, no patient died from
pulmonary complications of 131I treatment if the pretherapy
pulmonary functions tests were normal.
Recommended Pretherapy Management
of Pulmonary Metastases To Minimize
Complications
If a patient has known pulmonary metastases secondary to
differentiated thyroid carcinoma, one author (dvn) recom-
mends the following approach.
1. Obtain a history of any pulmonary disease and the
results of all previous pulmonary function tests, if any.
2. Assess the extent of pulmonary metastases based on chest
X-ray and chest computer tomography (CT) with or with-
out contrast. If CT was performed with contrast, then 131I
therapy can be delayed until the iodine has cleared as mea-
sured by spot urine iodine/creatinine measurements.
3. Examine present pulmonary function using PFTs and
diffuse capacity for the lung to clear carbon monoxide
(DLCO) [143]. (Note: Hughes et al. [143] have sug-
gested that these studies may overestimate the diffusion
limitation by 30 %.)
4. If the patient has a single pulmonary metastasis with no
evidence of distant metastases elsewhere by a thorough
evaluation, consider a pulmonary metastasectomy
[144, 145]. Although the report of Liu et al. report did
not include thyroid cancer, metastasectomy of a solid
pulmonary metastasis may be a reasonable option to
consider [145].
5. Assess the pattern of metastases on chest X-ray, chest
CT scan, and 131I scan. According to the limited litera- 10.
ture (and intuitively), the risk of ARP and PF appears to
be lower when:
(a) The radioactive uptake in the lungs is lower. 11.
(b) The radioactivity in the lungs clears faster.
(c) The disease is a single focus, rather than multiple foci.
691
(d) The disease pattern is more regional than diffuse, such
as one or two macronodular areas of disease in one lobe
instead of diffuse micronodular or miliary disease
throughout both lungs. (However, note that patients
with a micronodular or miliary pattern of metastases
with good 131I uptake may have an improved response
and prognosis after treatment with 131I) [1, 146, 147].
6. Determine the response on clinical exam, chest X-ray,
CT, PFT with DLCOs, 131I scans, and blood thyroglobu-
lin levels after all previous 131I therapies.
7. Recommend dosimetry, and follow the restrictions for
pulmonary metastases as described by Benua and Leeper.
(a) Do not exceed an amount of 131I prescribed activity
that would result in whole-body retention at 48 h of
more than 2.96 GBq (80 mCi).
(b) Do not exceed an amount of 131I prescribed activity
that would result in greater than 200 cGy (rad) to the
blood (bone marrow).
8. If an empiric prescribed activity of 7.4 GBq (200 mCi)
or more is going to be used and the patient has a diffuse
micronodular or miliary pattern of metastases in the
lung, we strongly recommend that a reliable effort be
made to estimate the whole-body retention at 48 h (or
the whole lung retention at 24 h) and adjust the pre-
scribed activity based on Benua’s recommendation of
whole-body retention when lung metastasis are present.
Of note, Esposito et al. [148] reported in 53 patients with
lung metastases that the percentage (number) of patients
who would have received more than 200 cGy (rad) to
the blood (e.g., surrogate for bone marrow) if empiric
dosages of 131I of 100 mCi (3.7 GBq), 150 mCi (5.55
GBq), 200 mCi (7.4 GBq), 250 mCi (9.25 GBq), and
300 mCi (11.1 GBq) had been administered would have
been 0 %(0), 7 %(4), 17 %(9), 24 %(13), and 30 %(16),
respectively. For all patients, regardless if lung metasta-
ses are present or not, Leeper [49] reported that 19 % of
131
I prescribed activities that delivered 200 cGy (rad) to
the blood were below 7.4 GBq (200 mCi). Tuttle et al.
[149] reported that 5 % of patients receiving 200 mCi
(7.5 GBq) of 131I would have received 200 rad (cGy) or
more to the blood. In 127 patients, Kulkarni et al. [150]
reported that if 3.7 GBq (150 mCi), 7.4 GBq (200 mCi),
and 5.55 GBq (300 mCi) of 131I had been administered,
5 %, 11 %, and 17 % of the patient, respectively, would
have received 200 cGy (rad) to the blood (e.g., bone
marrow). This is discussed further later in this chapter.
9. Reduce the amount of prescribed activity of 131I in the
presence of impaired pretherapy PFTs.
With higher empiric or dosimetrically determined pre-
scribed activity, retreat with 131I no sooner than 1 year
from the last 131I therapy.
For patients with changes indicating PF from previous
131
I therapy, consider pulmonary biopsy to assess the
degree of PF.
692
Recommended Posttherapy Management
In follow-up for 131I treatment of patients who have function-
ing pulmonary metastases from well-differentiated thyroid
carcinoma, one author (dvn) recommends the following:
• Educate the patient regarding the signs and symptoms to
carefully monitor, including any cough or shortness of
breath, which may be the initial warning of pulmonary
complications.
• Encourage the patient to seek early evaluation for any
respiratory symptoms.
• Schedule routine follow-up evaluations at 1 and 2 months
posttherapy.
• Recommend PFTs at 1 and/or 2 months. (Until data is
available to demonstrate that there is no value of PFTs at
these time points, one author (dvn) believes these should
be performed as part of the assessment for early pulmo-
nary changes, to assess for both decreases in PFTs that
may be a complication of 1311 or improvement as a thera-
peutic benefit secondary to 131I.
• Repeat PFTs at periodic intervals such as 6 and/or 12 months.
For those patients with possible ARP and PF, we recom-
mend the following:
• Begin treatment as soon as possible. Don’t wait.
• Consider initial therapy with nonsteroidal anti-
inflammatory agents or inhaled steroids, but:
• Consider the early use of oral or intravenous steroids and
antibiotics. For the treatment of ARP secondary to exter-
nal radiation therapy to the lungs, Gomez and Rosenzweig
recommend treatment with at least 60 mg/day of predni-
sone for 2 weeks and then gradually decreasing the dose
over 3–12 weeks [112]. However, no data are available
regarding whether or not this schedule is effective for
ARP secondary to 131I therapy.
• For patients who develop end-stage lung disease due to
131
I-induced pulmonary fibrosis, lung transplantation is
often the only subsequent option.
Summary
In summary, ARP and PF can be serious conditions of 131I
treatment in patients who have functioning pulmonary
metastases from differentiated thyroid cancer. Although sci-
entific data are still limited, evidence is available based on
approximately 60 years of clinical experience that suggests
empiric and dosimetric approaches for 131I treatment of pul-
monary metastases are associated with a minimal risk of
complications of ARP and PF. When the percent 48-h whole-
body retention is obtain and one does not exceed the recom-
mendations of Benua et al. regarding such, this may help
D. Van Nostrand et al.
reduce the risk even further. Nevertheless, additional research
is needed in this area. If ARP does occur, early detection and
treatment are strongly recommended.
Gastrointestinal Effects
131
I ingestion is followed by rapid absorption through the
stomach and small bowel wall into the systemic circulation,
with subsequent active gastric mucosa concentration and
secretion. This direct stomach irradiation engenders no
symptoms in most patients at ingested dosages below
1.11 GBq (30 mCi). However, as the administered 131I dos-
age escalates, nausea is experienced by more patients; 5.35 %
of patients complain of this side effect at a standard dose of
1.48 GBq (40 mCi) [32]. In 78 patients treated with a stan-
dard ablation prescribed activity of 2.78 GBq (75 mCi) for
residual thyroid bed activity, nausea was reported in 12 % of
patients when questioned at 4–5 days post-ablation (jf,
unpublished data). The majority of patients (50–67 %)
treated with prescribed activity of 5.55 GBq (150 mCi) of 131I
will complain of nausea that usually develops after 18–24 h
but can be seen within 2–4 h of therapy and persists for
24–48 h [40, 41. Khorjekar et al. [151] evaluated the
responses of patients to a national survey offered through the
Thyroid Cancer Survivors’ Association, Inc. (ThyCa) regard-
ing the patient’s last 131I outpatient therapy and vomiting. Out
of 801 patients responding, 10 % (81) had vomiting of which
vomiting was described as mild in 25 % (19), moderate in 42
% (32), and severe in 32 % (24) in 75 respondents. In addi-
tion, patients were statistically more likely to vomit if they
were younger and female and/or had a higher level of anxiety
to radiation. Khorjekar et al. [152] reported vomiting with or
without preceding nausea in 7.6 % [30/397] of patients
receiving a prescribed activity of less than 5.55 GBq (<150
mCi) and 15 % [41/274] with amounts of 131I prescribed
activity greater than 5.55 GBq (150 mCi). Whether the fre-
quency of 131I associated nausea is accentuated by the con-
comitant use of sialagogues is not known.
Prior to May 29, 1997, the Nuclear Regulatory
Commission (NRC) guidelines mandated inpatient hospital-
ization for any patient whose whole-body retention exceeded
1.11 GBq (30 mCi) of 131I (equivalent to ≥5 mR at 1 m). If
vomiting occurred in the inpatient setting, 131I in gastric con-
tents was contained within a controlled area [153]. New
NRC guidelines, the so-called Patient Discharge Rules, are
“exposure” based, rather than patient “activity” based.
Patients receiving up to 7.4 GBq (200 mCi) of 131I are now
routinely released by many licensees when the total effective
dose equivalent of a member of the public exposed to the
patient is not likely to exceed 5 mSv (0.5 rem) [154]. Patients
treated with more than 3.7 GBq (>100 mCi) of 131I have
returned to a medical facility after vomiting unknown quan-
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
tities of 131I in an uncontrolled location. The possibility of an
outpatient vomiting over 1.85 GBq (>50 mCi) of 131I in the
home environment (or local motel), significantly contami-
nating family members or the general public, has greatly
heightened the awareness of this issue. Patients with a multi-
plicity of disease processes are at increased risk of vomiting
ingested 131I, including anxiety disorder, cerebral palsy, any
pharyngeal or esophageal motility disorder, gastroesopha-
geal reflux disease, gastroparesis, gastric outlet obstruction,
and other similar entities. To lessen the chance of dealing
with a large quantity of vomited 131I, one patient with a prior
vomiting history shortly after diagnostic 131I ingestion and
another patient with marked diabetic gastroparesis received
their therapy intravenously by sterilization of the commer-
cially available oral formulation with no subsequent nausea,
vomiting, or other sequelae. However, intravenous 131I does
not eliminate the possibility of vomiting 131I entirely because
blood clearance curves of oral and intravenous 131I are simi-
lar and nausea and vomiting may originate centrally rather
than locally in the stomach. Additionally and as noted above,
a significant percentage of the intravenously administered
131
I will be secreted into the stomach within the next 24 h
resulting in a local stimulus of nausea and vomiting.
For most patients, nausea and vomiting can usually be
averted or ameliorated by premedication with antiemetic
preparations, such as ondansetron (Zofran®), prochlorpera-
zine (Compazine®), or triethylperazine (Torecan®).
Emphasizing the possible side effects of nausea and vomit-
ing seems to help precipitate their occurrence, especially in
anxious patients. Our current practice is to provide the
patient with a prescription for six ondansetron 8 mg tablets,
taking one tablet three times daily beginning 30 min prior to
131
I therapy. If necessary, the first 8 mg dose of ondansetron
can be administered intravenously if the patient neglects to
take the medication as prescribed.
Finally, Kinuya et al. [155] reported a Mallory-Weiss syn-
drome caused by 131I therapy for metastatic thyroid carci-
noma. The patient had massive hematemesis secondary to a
tear at the gastroesophageal junction, with only mild nausea
and no initial vomiting.
Radiation Cystitis
Balan et al. [156] and Dobyns et al. [157] each reported one
case of cystitis.
Bone Marrow
Bone marrow suppression, aplastic anemia, and leukemia are
some of the most serious potential untoward affects of 131I
therapy. This section discusses bone marrow suppression
693
and aplastic anemia. Leukemia is discussed later in this
chapter in section “Secondary primary malignancies risk in
thyroid cancer survivors”.
Review of the Literature
Like all side effects of 131I therapy, the variability in the
reported frequency and severity of bone marrow suppression
is multifactorial, and some of these factors are noted in
Table 62.16. A summary of the frequency of occurrence of
bone marrow suppression based on a review of the literature
is presented in Table 62.17 [1, 40, 44, 48, 103, 116, 158–166,
198]. To demonstrate examples of the severity of bone mar-
row suppression according to National Cancer Institute
(NCI) criteria and the typical time courses, two hypothetical
cases are shown in Figs. 62.6 and 62.7. The Common
Terminology Criteria for Adverse Events for hematologic
toxicities are noted in Table 62.18. A review of the literature
on the frequency of reported aplastic anemia or death due to
bone marrow suppression is noted in Table 62.19 [1, 2, 40,
48, 114, 116, 158, 160, 163, 166, 167, 198]. The specifics of
selected articles are subsequently discussed.
Alexander et al. [2] reported that nine out of 203 patients
treated with between 3.7 and 7.4 GBq (100–200 mCi) of 131I
demonstrated hematological abnormalities involving moder-
ate reduction of their leukocytes that ranged from 3200 to
4200 per μL (normal range 4300–10,000/μL). They also
reported no signs of thrombocytopenia or aplastic anemia,
and the total cumulative prescribed activity ranged from 0.1
to 1.9 Ci (3.7–70.3 GBq).
Benua et al. [1] reported bone marrow suppression in 38
of 59 patients who received 122 treatments. Serious bone
marrow depression was observed following these treatments
in eight patients; two patients subsequently died of bone
marrow suppression. Benua has suggested a relationship of
significant bone marrow suppression when the total radiation
Table 62.16 Variability of frequency and severity of bone marrow
suppression
Individual prescribed activity of 131I
Patient’s rate of 131I clearance
Frequency of 131I therapies
Interval between 131I therapies
Total cumulative prescribed activities of 131I
Frequency of prescribed activities delivering greater than 200 or
300 cGy (rad) to the bone marrow determined empirically
Performance of Benua and Leeper dosimetry
Variability in the definition of bone marrow suppression
Variability in the diligence in evaluating bone marrow suppression
Patient bone marrow reserve
Extensive bone metastases
Prior or concomitant radiation therapy to the bone
694 D. Van Nostrand et al.

Table 62.17 Summary of bone marrow suppression

Author (ref.) Year Total Abnormality Hemoglobin WBC Platelets
Alexander [2] 1998 203 4.4 % (9) 0 % (0) 4.4 % (9) No evidence
Benua [1] 1962 122 31 % (38)a – – –
Dorn [158] 2003 25 100 % (25) – – –
Leeper [49] 1982 No permanent bone
marrow suppression
Edmonds [198] 1986 258 1.1 % (3)b – – –
Grunwald [159] 1994 567 1.4 % (8) – – –
Haynie [160] 1963 159 – 34 % (54) 10 % 8.4 % (5)
Keldsen [161] 1988 27 26 % (15) – 33 % in female 30 % in female
(and increased in and 17 in male
male)
Matthies [162] 2004 68 22 % (15) 12 % (8)
Menzel [116] (low 1996 84 3.6 % (3)c 0 % (0) 3.6 % (3) 0 % (0)
prescribed activity;
see text)
Menzel [116] 1996 78 50 % (29)d – – –
(high prescribed
activity; see text)
Molinaro [163] 2009 206 No change 9.7 % decrease 5.8 % decrease
from baseline at from baseline at
1 year 1 year
Pan [44] 2004 – – – 4.00 % 10.40 %
Petrich [164] 2001 107 37.4 % (40/107) – – –
Robeson [165] 2002 12 42 % (5/12) 25 % (3/12) 42 % (5/12) 17 % (2)
Schober [166] 1987 296 24 % (71) 11 % (33) 35 % (104)
Trunnell [103] 1949 9 100 % (9) – – –
Van Nostrand [40] 1986 10 90 % (9) – – –
a
Total of 59 patients and 122 doses. Six of the 122 treatments produced severe bone marrow suppression, with two resulting in death.
b
It isunclear from the article if the asuthor looked for bone marrow suppression other than when it as fatal.
c
Prescribed activites of radioiodine were 1.8-5.5 GBq (49-200 mCi).
d
Prescribed activities of radioiodine were greater than 7.4 GBq (200mCi). Bone marrow suppression was mild in thiryy, grade II in three patients,
and severe in one patient. The data were not fully described.

dose to the blood exceeded 200 cGy (rad). Serious complica-
tions, including bone marrow suppression, were observed in
21 % when total radiation to the blood exceeded 200 cGy
(rad) but in only 3 % when the total radiation to the blood
was less than 200 cGy (rad). Furthermore, bone marrow sup-
pression was also increased when the whole-body retention
at 48 h exceeded 4.44 GBq (120 mCi). Initially, Benua
reported severe and permanent bone marrow suppression in
eight of 59 patients. However, after Benua imposed the
restrictions of (1) a maximum of 200 cGy (rad) to the blood
and (2) 4.44 GBq (120 mCi) whole-body retention at 48 h,
no subsequent cases of permanent bone marrow suppression
have occurred as reported by Leeper [49].
Benua further reported that the mean whole blood radia-
tion dose from 131I therapies in the 59 patients was 267 cGy
(rad), with a range of 45–740 cGy (rad). For the eight patients
with severe bone marrow suppression, the calculated total
radiation dose to the blood from the last 131I therapy ranged
from 170 cGy (rad) to 582 cGy (rad). However, all had been
previously treated. For six of the eight patients with severe
bone marrow suppression in whom total blood radiation dose
could be calculated for the cumulative 131I administered, the
total radiation dose to the blood ranged from 300 to 1100
cGy (rad). Severe bone marrow suppression was not observed
if the total cumulative radiation dose to the blood was less
than 300 cGy (rad).
Dobyns et al. [157] noted that the most likely change in
the blood is a decline in the lymphocytes.
Dorn et al. [158] performed 104 therapies with prescribed
activities determined by a dosimetric MIRD methodology
(see Chap. 59). In 100 % (25/25) of patients who received
absorbed doses of lower than 300 cGy (rad) to the bone mar-
row, transient bone marrow suppression was present.
However, no permanent bone marrow suppression was
observed. The maximum single administered dose was
38.5 GBq (1040 mCi).
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma 695

Fig. 62.6 Hypothetical course of ANC

National Cancer Institute (NCI)
grade I mild to moderate bone Platelet
marrow suppression
4000 250000

Platelet Count
ANC Count
3000 200000
150000
2000
100000
1000 50000
0 0

ar
k

4 k

5 k

6 k
k

th
2 k
e

ee

ee

ee

ee

ee
ee

ye
lin

on
w

w
w
se

1
m
3
1
Ba

3
Time

Fig. 62.7 Hypothetical course of

National Cancer Institute (NCI) ANC
grade IV severe bone marrow Platelet
suppression 300,000
4000

Platelet Count
ANC Count
250,000
3000 200,000
2000 150,000
100,000
1000 50,000
0 0

th
k

ar
k
k

k
e

ee

ee

on
ee
ee

ee

ee

ye
lin

m
w
w

w
se

1
5

6
2
1

3
Ba

Time

Table 62.18 The NCIa common terminology criteria for adverse events
Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Hemoglobin <LLN–10.0 g/dL <10.0–8.0 g/dL <8.0–6.5 g/dL <6.5 g/dL Death
Leukocytes (total WBCs) <LLN–3000 mm3 <3000–2000 mm3 <2000–1000 mm3 <1000 mm3 Death
Neurtophilis/gran/ganluocytes <LLN–1500 mm3 <1500–1000 mm3 <1000–500 mm3 <500 mm3 Death
Platelets <LLN–75,000 mm3 <75,000–50,000 mm3 <50,000–25,000 mm3 <25,000 mm3 Death
<LLN, less than the lower limits of normal for that particular laboratory. Criteria are from v 3.0, December 12, 2003
a
NCI National Cancer Institute

Table 62.19 Aplastic anemia or death attributed to bone marrow Edmonds and Smith found that three patients from a
suppression
group of 258 developed aplastic anemia and died within 4
Author (ref.) Year Aplastic anemia or death years; they had extensive metastases and were treated multi-
Alexander [2] 1998 0 % (0/203) ple times [198]. The total radioactivity was 63 GBq (1700
Benua [1] 1962 1.6 % (2/122) mCi), 40 GBq (1080 mCi), and 31 GBq (850 mCi). In this
Dorn [158] 2003 0 % (25/25) study, patients were initially treated with 2.9 GBq (80 mCi)
Edmonds [198] 1986 1.2 % (3/258) for ablation and, when additional therapies were necessary,
Haynie [160] 1963 0 % (0/159)
with 5.5 GBq (150 mCi) every few months.
Leeper [49] 1982 0 % (0/70)
Grunwald et al. [159] indicated that 1 % (7 of 567) of patients
Menzel [116] 1996 0.5 % (1/167)a
who had 131I therapies had persistent changes in blood counts. In
Petrich [164] 2001 3.7 % (4/107)
patients who received prescribed cumulative activities of less
Schober [166] 1987 1.0 % (3/296)
than 18.5 GBq (500 mCi), only five of 469 had a hemoglobin
Schumichen [167] 1983 0.75 % (3/400)
less than or equal to 9.0, white blood cell count (WBC) 2500 or
Tollefson [114] 1964 0 % (0/70)b
less, and/or platelets 50,000 or less. For prescribed activities of
Van Nostrand [40] 1986 0 % (0/10)
a
18.5 GBq (500 mCi) to less than 37 GBq (<1000 mCi), one of
Patient rejected for additional treatments because of persistent severe
bone marrow suppression 77 patients had changes, and with prescribed activities of
b
In the evaluation of 70 fatalities in patients with thyroid cancer, none 37 GBq (≥1000 mCi), six of 21 patients had blood changes, and
were because of bone marrow suppression four of these patients had pancytopenia.
696
Haynie and Beierwaltes reported their observations in 159
patients who received 131I for the treatment of thyroid cancer
at 3-month intervals (if needed) between 1947 and 1960.
Evaluation of these patients included a baseline and at least
one posttherapy complete blood count (CBC). Patients
received prescribed activities of usually 3.7–11.1 GBq (100–
300 mCi) of 131I with follow-up CBC at 3-month and 1-year
intervals for 10 years after completion of therapy. The most
frequently observed abnormality was a subnormal hemoglo-
bin concentration, which occurred in 34 % (54 of 159).
However, only five of 159 developed a significant anemia
less than 10 g percent. The hemoglobin concentration returned
to the normal range in all but eight patients by 1 year.
Subnormal WBC was observed in about 10 % of these
patients, and the lowest value was 2000 per mm3. No leuko-
penia persisted beyond 1 year. Thrombocytopenia was seen
in only five (3 %) patients, whose levels were only slightly
decreased below the normal limits. If it did occur, thrombocy-
topenia was always transient and returned to normal by 1
year. The degree of suppressed blood counts did appear to
correlate with several factors: total 131I dosage, prior radiation
therapy, and the presence of widely disseminated metastases.
Nevertheless, the authors reported that the suppressed blood
count duration was brief and not associated with symptoms.
They also reported no incidence of aplastic anemia.
Keldsen et al. [161] reported that 26 % (15 of 27) of
their patients’ WBC count dropped below 2500 and/or
platelet count fell less than 150,000 at some point after
treatment. The drop in platelet count was 30 % (305,000–
212,000) in females and 17 % (271,000–224,000) in males.
The WBC decreased 33 % (6000–4400) in women and
increased in men.
In a group of 70 patients treated from 1973 to 1982, Leeper
observed no permanent bone marrow suppression [48]. As
previously noted, the average single therapeutic dose was
11.4 GBq (309 mCi), with a range of 2.59–24.2 GBq (70–654
mCi). No additional data was reported pertaining to the extent
of reversible bone marrow suppression.
Matthias et al. [162] reported on the hematologic toxicity in
68 patients who received cumulative 131I prescribed activities
that ranged from 18.5 to 153.5 GBq (500–4150 mCi).
Thrombocytopenia occurred in five patients with grade I or
II and in three patients with grade III or IV. Grade I com-
prises anemia of 9.5–10.0 g Hgb/100/mL, thrombocytopenia
of 75,000–99,000/mm3, or leukopenia of 3000–3900 mm3.
Grade II is anemia of 8.0–9.4 g Hgb/100 mL, thrombocyto-
penia of 50,000–74,000/mm3, or leukopenia of 2000–2900/
mm3. Grade III is classified as persistent and distinct anemia
of less than 7.9 g Hgb/100 mL, thrombocytopenia of less
than 49,000/mm3, or leukopenia below 1900/mm3.
Leukopenia was observed in 14 patients with grade I or II
and one patient with grade IV. The specific-grading scale
used was not noted.
D. Van Nostrand et al.
Menzel et al. [116] evaluated a group of 26 patients with
167 therapies. He reported that only three of 84 therapies
with a low-131I prescribed activity of less than 1.8–5.55 GBq
(<49–150 mCi) resulted in mild hematological toxicity (leu-
kocytes <3000/nL and/or thrombocytes <75,000/nL). For
patients who received high prescribed activities of 11.1 GBq
[300 mCi] or higher, 38 % (30 of 78) of therapies caused a
mild decline of leukocyte count. Three patients developed
World Health Organization (WHO) grade II hematotoxicity.
One patient had four therapies totaling 44.4 GBq (1200
mCi); one had two therapies that totaled 22.2 GBq (600
mCi), and one patient developed severe leucopenia and
thrombocytopenia (WHO grade III) after three high pre-
scribed activity therapies. Patients in this study were typi-
cally treated at 3-month intervals.
Molinaro et al. [163] evaluated 206 consecutive patients
who had a complete blood count (CBC) before and after 131I
therapy. The median prescribed activity of 131I was 3.7 GBq
(100 mCi) with the CBC performed 1 year later. The total
white blood cell count dropped from 6.7 ± 2.1 × 109 to
6.0 ± 1.8 × 109, which was a decrease of 9.7 % (p < 0.001).
The platelet count drop from 272 ± 67 to 250 ± 655 × 109,
which was a decrease of 5.8 % (p < 0.001).
Pan et al. [44] evaluated 342 patients over approximately
10 years. Transient platelet reduction was noted in 10.4 %,
and transient leukopenia was found in 4 % of patients. The
frequency of abnormalities was higher with cumulative 131I
prescribed activities greater than 18.5 GBq (500 mCi).
Petrich et al. [164] described the side effects of 131I in the
treatment of 107 patients who had bone metastases second-
ary to well-differentiated thyroid carcinoma. Of 107 patients,
40 (37.4 %) had a change in their blood counts. Most of the
changes were WHO grade I or grade II. A total of ten patients
had grade III and four patients had bone marrow aplasia.
With prescribed activities of 131I equal to or exceeding 80
% of the dosimetrically determined dosage, Robeson et al.
[165] found that 42 % (5 of 12) of patients had mild leukope-
nia, 17 % (2 of 12) had mild thrombocytopenia, and 25 % (3
of 12) had anemia. Hypocellular bone marrow biopsy was
noted in one patient. They reported no difference in the
average cumulative prescribed activity in patients with and
without bone marrow suppression.
Schober et al. [166] reported on 296 patients who were
treated with an average cumulative prescribed activity of
19.8 GBq (535 mCi). The observation period was a median
of 65 months. The most frequently observed hematologic
change was thrombocytopenia, occurring in 35 % of patients.
Erythrocytopenia occurred in 24 %, and the leukocytes
decreased in 11 % but increased in 23 %, with a median
decrease of 7 %. The most severe decreased counts occurred
after a high dose of 37 GBq or more (≥1000 mCi).
Pancytopenia was present in 4.4 % of all patients and was
probably a contributing cause of death in three patients.
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
Tollefsen et al. [114] examined the cause of fatalities in
70 patients who had thyroid carcinoma. None of these deaths
were attributed to bone marrow suppression. Notably, some
of these patients were included in earlier reports from
Memorial Sloan Kettering Cancer Center.
Trunnell et al. [103] reported that all patients (nine of
nine) treated for metastatic thyroid cancer had depression of
one or more peripheral blood elements. The greatest drop
occurred in lymphocytes from a level of one third to one
fourth of baseline. They reported one fatality from pancyto-
penia that occurred 1 months after the last treatment, which
was 9.25 GBq (250 mCi) and a total prescribed activity of
638 mCi (23.6 GBq). Bone marrow aspiration biopsies were
performed in seven patients, demonstrating a uniform drop
in total cell count and reversal of the erythroid myeloid ratio.
With the exception of the fatality noted above, peripheral
blood counts recovered in 4–6 months.
Van Nostrand et al. [40] described nine of ten patients
who had bone marrow suppression that was transient and
never required any transfusions. The most severe bone mar-
row suppression was <NCI grade I for hemoglobin, NCI
grade II for leukocytes, and NCI grade I for platelets. 131I
prescribed activities ranged from 1.9 to 16.7 GBq (51–450
mCi), and the total previous cumulative prescribed activity
was 0–25 GBq (0–665 mCi).
Recommendations for Pretherapy
and Posttherapy Management
The difficulty with suggesting recommendations for the pre-
and posttherapy management of possible bone marrow sup-
pression secondary to 131I therapy is that there are no good
studies that have evaluated the efficacy of any specific pre- or
posttherapy plan. However, the physician must still act. In
the absence of good prospective data, the recommendations
must be made upon incomplete retrospective data. Various
suggestions have been proposed by different workers in the
field, but a discussion of all these approaches is beyond the
scope of this chapter. Instead, one proposed set of recom-
mendations is presented below by one author (dvn). These
recommendations should be appropriately modified accord-
ing to the specific clinical situation unique to each patient,
the objectives of the physician, the potential clinical benefit
versus the risk of irreversible bone marrow suppression, and
any new reports in the literature.
General Recommendations for All Patients
Several key methods are proposed for all patients regarding
the pretherapy and posttherapy management of potential
bone marrow suppression:
697
1. Obtain baseline complete blood counts (CBC) with dif-
ferential. If the patient is undergoing thyroid hormone
withdrawal, the baseline CBC with differential should be
obtained when the patient is in both a euthyroid and hypo-
thyroid state. Because the absolute neutrophil count
(ANC) may be reduced in the hypothyroid state [168,
169], a baseline CBC with differentiated obtained under
this condition may not be appropriate to use for long-term
follow-up. However, an additional baseline CBC with dif-
ferential when the patient is hypothyroid just before ther-
apy may be useful for the short-term follow-up. This
information might help identify any initial decline in
blood counts relative to the baseline euthyroid CBC as
secondary to the hypothyroidism and not due to 131I.
2. For any reduction of the baseline CBC values, evaluate
and correct any other cause for the reduced baseline CBC.
3. If the pretherapy scan demonstrates significant 131I uptake
in the bone, lung, and/or other distant metastases, con-
sider dosimetric modification of the prescribed 131I
activity.
4. If distant metastases and “high” prescribed activity of 131I
is selected, recommend CBC with differential at 3, 4, 5,
and 6 weeks after 131I therapy. This is true whether or not
the patient was administered an empirically chosen or
dosimetrically determined prescribed activity. If the
patient has no decrease in any blood counts after therapy,
then discontinue CBCs after 5–6 weeks. If the patient has
a significant drop in blood counts that may place the
patient at risk for infection or bleeding within the first 6
weeks, then continue weekly blood counts until the
patient clearly has a rising ANC and rising platelet count
and is no longer at risk for infection or bleeding.
5. For significant bone marrow suppression, administer
colony-stimulating factor(s) or transfusion as may be
clinically warranted. An oncologist should be part of the
treating team in determining when the bone marrow sup-
pression is significant.
6. Finally, obtain CBC with differential at 1 year after 131I
therapy. Although sequential CBCs with differential after
initial 131I therapy will most likely not affect the clinical
management of these patients at that time because the
counts most likely will not drop significantly enough to
require intervention, one author (dvn) believes these are
prudent to track. These data, and specifically the amount
of suppression, may be important information if a subse-
quent therapy is considered for the treatment of bone
metastases. Sequential CBCs with differential counts
obtained after the initial 131I therapy for bone metastases
may be the only information regarding the response of the
patient’s bone marrow to previous therapeutic prescribed
activities of 131I. Because of the potential value of this
information, and because four to six CBCs are relatively
inexpensive and usually associated with minor inconve-
698 D. Van Nostrand et al.

nience, one author (dvn) again recommends that this be
obtained in every patient treated for distant metastases.
Specific Recommendations for Selected
Patients with Bone Metastases
In selecting the prescribed activity of 131I for a patient with
bone metastases and if the patient’s CBC and differential
counts are abnormal and cannot be corrected, then full or
simplified 131I dosimetry is recommended. However, if an
empiric prescribed activity of 5.55–7.4 GBq (150–200 mCi)
of 131I is to be selected, then reduction of the amount of pre-
scribed activity of 131I should be considered. Unfortunately,
no data are available regarding how much the empirically
chosen or dosimetrically determined prescribed activity of
131
I should be reduced. However, despite the lack of informa-
tion, the physician must again still make a decision, and one
author (dvn) proposes the following guidelines. If the euthy-
roid baseline CBC is reduced to NCI grade I (see Table 62.18)
and the planned prescribed activity of 131I was 5.55–7.4 GBq
(150–200 mCi), then consider a reduction of the prescribed
activity by 15–20 %. For these patients, one author (dvn)
would not recommend an empiric prescribed activity of 131I
of 11.1 GBq (300 mCi). If the prescribed activity of 131I is
determined by dosimetry, then reduction of that calculated
prescribed activity may not be necessary. If the euthyroid
baseline CBC is reduced to NCI grade II (see Table 62.18)
and the planned prescribed activity was again 5.55–7.4 GBq
(150–200 mCi), then consider a reduction of the prescribed
activity by 20–30 %. For patients with NCI grade III, the
benefits and risk should be discussed among the treating
medical team and patients (see Table 62.20). For patients
with NCI grade IV, the benefits and risks must again be
discussed among the treating medical team and patient

Table 62.20 Recommendations for the evaluation of patients with bone marrow suppression if 131I therapy is being considered
Obtain unilateral or bilateral bone marrow biopsy to assess the bone marrow cellularity and degree of adipose tissue
⚬ Unless the purpose of bone marrow biopsy is to assess a specific area for the presence of metastatic differentiated thyroid carcinoma, bone
marrow biopsy should not be obtained from a bone that is su spected to have metastasis or has had previous external radiotherapy
⚬ Fibrosis of the marrow is not a manifestation of delayed radiation injury of the bone marrow
Assess for the presence and extent of bone metastases such as with a combination of radioiodine whole-body scan, radiographic bone survey,
magnetic resonance, 18F FDG positron emission tomography scan (18F FDG PET), and/or 99mTc MDP or 18F NaF PET-CT bone scan
Review the baseline and subsequent CBCs with differential after previous 131I therapies with specific attention to the nadirs and subsequent
recovery or reduce recovery to baseline
Review the history for extent of any external radiation therapy to the bone marrow
Review the response to previous 131I therapy, such as change in scan, change in thyroglobulin level, and change in size of masses on clinical
exam and/or on other imaging studies
Recommend blood and whole-body dosimetry:
⚬ Do not exceed the prescribed activity calculated by dosimetry
⚬ Do not exceed 4.44 GBq (120 mCi) of 131I whole-body retention at 48 h (In the presence of pulmonary metastases, whole-body retention
at 48 h should not exceed 2.96 GBq [80 mCi]. See section on acute radiation pneumonitis and pulmonary fibrosis in this chapter and
Chap. 58 on dosimetry)
⚬ If only % 48 h whole-body retention is performed(see Chapter 59), do not exceed 70 % of the maximum tolerated prescribed activity
calculated by this method, and follow the other restrictions noted above
If the bone marrow aspiration/biopsy is normal:
⚬ Weigh the potential benefit of 131I therapy vs. other treatments, which will depend on such factors as the degree of radioiodine uptake, size
of tumor, patient desires, etc.
⚬ Consider reduction of the prescribed activity below the maximum tolerated dosimetrically determined prescribed activity as discussed in
the text
⚬ Consider pretreatment with the appropriate colony-stimulating factor(s)
If bone marrow biopsy is abnormal:
⚬ Weigh the potential benefit of 131I therapy vs. other therapies, which will depend on such factors as the bone marrow cellularity and degree
of fat on bone marrow biopsy, degree of radioiodine uptake in the metastases, tumor size, patient desires, and so forth. “Blind treatments”
(treatment when no uptake is seen on radioiodine scan) are not encouraged in these patients
⚬ Prophylactic treatment with granulocyte- or platelet-stimulating factor
⚬ Consider stem cell harvest for rescue bone marrow transplantation. No data are available regarding this option
⚬ If possible, avoid treating within 1 year from previous 131I therapy
⚬ Consider amifostine treatment. Amifostine has been proposed to help protect the bone marrow; however, no data is available regarding
whether the amifostine also protects thyroid cancer. Amifostine has been discussed elsewhere (see section on “Salivary gland side effects”
in this chapter)
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
(see Table 62.20), and additional hematological support
must be strongly considered prior to, during, and after 131I
treatment. Of note, no prospective data are available evaluat-
ing the utility or safety of these guidelines, but the most
important message is consideration of reduction of empiri-
cally chosen or dosimetrically determined prescribed activ-
ity in patients with reduced CBCs and differentials.
For subsequent treatments for metastases in patients
whose baseline CBC, ANC, and platelet count have
remained normal, the empiric prescribed activity should not
exceed 7.4 GBq (200 mCi). If the prescribed activity is
based on dosimetry, then one may consider administering as
much 131I as one’s facility allows up to the dosimetrically
determined maximum tolerated activity. If the percent 48-h
whole-body retention is calculated (see Chap. 59), then no
more than 70 % of the calculated maximum tolerated activ-
ity should be administered. A minimum of 6 months and
preferably 1 year is recommended between therapies in
which the patient received a dosimetrically determined pre-
scribed activity of 131I [170]. At the present time, there is no
evidence whether the total cumulative estimated radiation
dose to the blood (not the total cumulative 131I prescribed
activity) should influence any reduction in dosimetrically
determined prescribed activity. For subsequent therapies of
metastases in patients who had previous 131I treatments with
an uncorrectable abnormal CBC, then again the suggestions
in Table 62.20 should be considered.
Summary
Bone marrow suppression is an important untoward effect
of 131I therapy. Clinically significant bone marrow suppres-
sion as a result of a first 131I therapy is unlikely, especially
if 131I therapy is for remnant ablation with prescribed activi-
ties of 1.1–1.85 GBq (30–50 mCi). However, the overall
data indicate that the frequency and severity of bone mar-
row suppression increases when (1) the individual pre-
scribed activity of 131I increases, (2) the individual
radiation-absorbed dose to the blood exceeds 200 or 300
cGy (rad), (3) the frequency of therapies increases, (4) the
interval between therapies decreases, (5) the total cumula-
tive prescribed activity of 131I increases, (6) the total cumu-
lative radiation dose to the blood increases, and (7) bone
marrow metastases are more extensive.
Routine CBCs with differential counts prior to and at least
1 year after all 131I remnant ablations, 131I adjuvant treat-
ments are encouraged, with more frequent CBCs with dif-
ferential counts within the first 3–6 weeks after 131I treatment
of distant metastases. The latter may be especially helpful in
those patients with distant metastases who may require
additional 131I therapies with high prescribed activity. If
bone marrow suppression does occur, good follow-up, the
699
availability of colony-stimulating factors, and blood transfu-
sions should be sufficient. Infection and hemorrhage are rare.
Fertility
Gonads
131
I therapy irradiates the gonads to a variable extent
depending on the relative radiation contributions received
from multiple sources such as circulating blood, bladder,
gut, and adjacent functioning soft tissue or bone metasta-
ses. Such irradiation raises concerns in regard to transient
or permanent gonadal damage that could be manifest sub-
sequently as decreased fertility or congenital anomalies in
offspring.
Female
Transient ovarian failure following a single 131I therapy
(mean dose 9.99 GBq [270 mCi]) occurred during the first
year posttherapy in 18 of 66 (27 %) older women (mean age
34 years) with regular menstrual cycles prior to therapy
[171]. In this retrospective study, 18 women treated during
thyroid hormone withdrawal demonstrated temporary amen-
orrhea with concomitant “hot flashes” that was delayed for at
least one menstrual cycle posttherapy when patients were not
euthyroid. The amenorrhea persisted for less than 6 months
in 14 of the 18 women. In 23 women with repeatedly mea-
sured serum follicle-stimulating hormone (FSH), luteinizing
hormone (LH), and serum estradiol (E) values, only the nine
amenorrheic women showed elevated serum FSH and LH
with low E levels. No significant differences were noted in
131
I prescribed activity administered, thyroidal uptake, calcu-
lated ovarian doses, or thyroid autoimmunity between the
amenorrheic and non-amenorrheic patients. The estimated
mean ovarian dose in the amenorrheic women was 176 ver-
sus 156 cGy (rad) (p > 0.5) in the menstruating women, but
the amenorrheic group was significantly older (median age
40 vs. 32 years [p < 0.001]). In another retrospective study,
transient ovarian failure occurred in 34 of 409 (8 %) women
(median age 31) and lasted for 4–10 month. The amenorrhea
developed at 1–3 months post 131I therapy associated with
elevated serum FSH and LH levels and was transient in all.
The group of women who developed transient ovarian failure
was older (mean age 36) than their normal menstruating
cohort (mean age 31) [172]. In a prospective study of 50 nor-
mally menstruating women (mean age 29.8 years) treated
with a single dose of 131I (mean dose 4.2 GBq [114 mCi]), ten
(20 %) of the women developed amenorrhea with elevated
serum FSH levels that remitted by 1 year [173]. These stud-
ies consistently demonstrate that the onset of transient amen-
orrhea following 131I therapy is typically delayed for one to
three menstrual cycles, suggesting that the radiation effect
700
predominates in developing oocytes and not on the maturing
follicle. Such ovarian radiation exposure can be reduced by
forced hydration for 24–48 h after 131I administration, fre-
quent urination during the day and night, and laxatives to
prevent constipation and 131I colonic retention.
A few retrospective controlled studies have evaluated the
effect of 131I therapy on the onset of menopause. Ceccarelli
et al. [174] studied 257 women (130 patients, 127 controls
younger than 45 years) to determine age of onset of meno-
pause in 130 women treated with 131I and suppressive doses
of thyroid hormone and 127 control goitrous patients treated
with suppressive doses of thyroid hormone only. 131I-treated
group (median dose 3.7 GBq [100 mCi]) developed meno-
pause (mean age 49.5 years) earlier than the control group
(mean age 51.0 years). In a similar fashion, Rosario et al.
[175] studied 114 women (74 patients, 40 controls) and
found that the onset of menopause occurred earlier in
131
I-treated group than the controls (mean age 46 vs. 50.4
years). The mean radioiodine dose for the 74 patients was
4.8 GBq [130 mCi] with menopause occurring at a younger
age in the women treated with >3.7 GBq [100 mCi] (mean
age 45) than in those women treated with ≤3.7 GBq (mean
age 48). Thus, subclinical persistent ovarian damage induced
by radioiodine therapy appears to manifest itself years later
in a dose-related fashion by the earlier onset of menopause in
treated patients versus controls.
Male
Similarly, transient testicular failure due to germinal cell
injury ensues in male patients treated with even a single dose
of 131I. Wichers et al. [176] studied 25 men prospectively
who were treated with a single or sequential doses of 131I
(mean dose 9.8 GBq [270 mCi]) and then followed over 18
months by serum FSH, LH, inhibin B, and free testosterone
levels. At 6 months, all men demonstrated elevated serum
FSH concentrations and depressed inhibin B levels, the best
markers of germinal cell injury, but these values returned to
normal by 18 months [176]. In a larger group (52 men, mean
age 45 years) treated with a single dose of 131I (mean dose
4.25 GBq [115 mCi]), testicular function was assessed by
serum FSH, LH, and testosterone levels at baseline and 6, 12,
and 18 months after therapy [177]. At 6 months, serum FSH
values were markedly elevated in all patients, but 71 % of
patients showed normal values at 12 months, and all patients
had returned to basal values by 18 months. The mean serum
LH concentration was significantly elevated at 6 months but
normalized subsequently with no significant change in free
testosterone values at any time interval consistent with com-
pensated Leydig cell function. Employing thermolumines-
cent dosimetry in 14 patients, the testicular radiation-absorbed
dose was shown prospectively to be approximately 2.3 cGy/
GBq/testis (0.085 rad/mCi/testis), which should be insuffi-
cient to induce infertility with typical single therapies of pre-
D. Van Nostrand et al.
scribed activity 2.8–5.55 GBq (75–150 mCi) delivering
6.3–12.6 cGy (rad) [177]. Previously, a threshold prescribed
activity of administered 131I of 3.7 GBq (100 mCi) has been
suggested since testicular damage manifested as serum FSH
elevation was not seen at such prescribed activity [178]. As
the mean administered cumulative prescribed activity of 131I
increases, there is a corresponding posttherapy rise in mean
peak serum FSH values reflecting progressively greater ger-
minal cell damage [139]. At the same time, there was no sig-
nificant change in mean serum testosterone levels in men
grouped by increasing cumulative administered 131I thresh-
olds. Repetitive semen analysis has confirmed a decreased
sperm count from baseline in 35.8 % of men (19/53) 2–6
months after 131I therapy that persisted in 36.8 % (7/19) at 1
year [179]. Moreover, studies have shown that each subse-
quent 131I therapy magnifies the initial germinal cell insult
and leads to a gradual persistent elevation of baseline serum
FSH levels (measured prior to subsequent 131I therapy). In 22
men with lung metastases treated with mean cumulative 131I
dose of 20.3 GBq (548 mCi), serum FSH values were persis-
tently high in 12 of the 22 (54.5 %) men who received a
cumulative prescribed activity of ≥13 GBq (≥351 mCi), and
oligospermia (on repeated posttherapy sperm analysis) was
present in 36.3 % [179]. Similarly, in four patients treated
with repetitive doses of 3.7–5.55 GBq (100–150 mCi) for
resistant functioning metastatic disease, serum FSH values
progressively peaked at higher values and became persis-
tently elevated indicating permanent germinal cell damage.
Infertility
Fertility of the patient and health of subsequent offspring
remains a concern, expressed by patients referred for 131I
therapy following appropriate surgery for differentiated thy-
roid cancer. This concern has been addressed in several
recent studies. In 1126 women treated surgically for thyroid
cancer, a total of 2673 pregnancies had occurred: 2078 preg-
nancies prior to thyroid cancer therapy, 112 pregnancies fol-
lowing surgery alone, and 483 pregnancies following surgery
and 131I therapy [180]. In pregnancies that occurred prior to
thyroid cancer therapy, 10.4 % of these pregnancies resulted
in miscarriage as compared to 19 % pregnancies after sur-
gery alone and 20.7 % of pregnancies that occurred after sur-
gery and 131I therapy. The incidence of stillbirths, preterm
births, and congenital malformations was not different prior
to or following 131I therapy. Forty-three percent of the post
131
I therapy cohort of patients received ≥3.7 GBq (100 mCi)
of 131I for metastatic disease with estimated radiation-
absorbed dose to the ovaries of up to 1 Gy (100 rad). Two
subsequent reviews including other smaller patient groups
confirmed these findings [181, 182]. Similarly, in 224 men
treated surgically for thyroid cancer, a total of 493 pregnan-
cies had occurred: 356 pregnancies prior to thyroid cancer
therapy, 23 pregnancies following surgery only, and 114
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
pregnancies following surgery and 131I therapy [183].
Miscarriages occurred in 7.5 % of pregnancies fathered, and
this was not statistically different in frequency prior to or fol-
lowing 131I therapy. In those pregnancies conceived after
paternal exposure to 131I, the estimated average radiation-
absorbed dose to the testis was 9.2 cGy (rad). There was no
increase in untoward events in offspring fathered after 131I
therapy than prior to 131I therapy. This study was underpow-
ered to determine if there was a decrease in male fertility in
those fathers receiving >3.7 GBq (100 mCi) of 131I, who are
most likely at risk for decreasing fertility with increasing
cumulative 131I exposure. A review of available studies dem-
onstrated that the evidence of permanent germinal cell injury
manifested by decreased sperm count and elevated serum
FSH levels is common as cumulative doses of 131I exceed
13 GBq (350 mCi), and the majority of men receiving
>22 GBq (>593 mCi) show persistent serum FSH levels
[184]. There are no prospective studies that compare fertility
rates and clinical outcomes in men with thyroid cancer
treated with 131I versus men treated surgically only.
When Should a Pregnancy Be Conceived?
Following 131I therapy for differentiated thyroid cancer, when
should a pregnancy be conceived? Clinical practice guidelines
recommend that prospective parents should wait until their
thyroid hormone status is stable and women should delay con-
ception until 6–12 months and men should delay fathering a
child for 3–4 months following 131I therapy [185–187]. In
males with extensive or resistant thyroid cancer likely to
receive cumulative prescribed 131I therapy of >14.8 GBq (400
mCi), family planning should be addressed. The possibility of
storage of sperm or fertilized ova should be discussed if future
offspring are desired. Reducing testicular radiation exposure
from each 131I therapy should be encouraged by optimizing 131I
clearance through forced hydration, frequent urination, and
prevention of constipation.
Second Primary Malignancies
Second primary malignancies due to radiation therapy for
cancer have been a major concern for cancers that have a
high survival rate such as differentiated thyroid cancer.
Second primary malignancies may include solid cancers or
hematologic malignancies such as leukemia. Solid cancers
have long latency periods of development, typically in excess
of 10 years and often over 20 years, whereas myeloid leuke-
mias secondary to radiation have shorter latency periods
[188]. Ionizing radiation is carcinogenic chiefly through its
damaging effects on cellular DNA. Experimental data would
suggest a “two-step” process with radiation producing DNA
breaks causing chromosomal aberrations and genomic insta-
bility of the exposed cells, and this can be passed onto many
cell divisions [188]. Much later, a second step occurs that
usually involves a mutation that may result in the activation
of an oncogene or deactivation of a tumor suppressor gene,
701
which in turn may result in the second malignancy. Radiation
carcinogenesis is a stochastic effect [188]. This means that
there is no threshold radiation-absorbed dose, and the prob-
ability of developing a second malignancy depends on the
radiation-absorbed dose, either in a linear or linear quadratic
relationship, down to zero radiation-absorbed dose. The car-
cinogenic risk of very low radiation-absorbed dose exposure
(<1 cGy [10 mGy]) is controversial, but in general, 131I ther-
apy for thyroid cancer results in radiation-absorbed doses to
many tissues and organs that are significant such as in the 10
cGy to 10 Gy range and not considered to be in the very low
range [188]. The main beta component of 131I has an energy
of 0.6 MeV with a maximum range in tissue of approximate
2.5 mm, and thus through physiological distribution of 131I,
the beta component exposes the salivary gland, gastrointesti-
nal tract, and urinary epithelium as well as the bone marrow
to significant radiation-absorbed doses [188]. Thus, theoreti-
cally, such organs would be at especially high risk for devel-
opment of 131I treatment-associated second primary
malignancies. Furthermore, the gamma component exposure
of all bodily tissues could pose additional general carcino-
genic risks.
Second Primary Malignancy Risk in Thyroid
Cancer Survivors
It is important to consider epidemiologic studies examining
second primary malignancy risk in thyroid cancer survivors.
It is known that thyroid cancer survivors compared to the
general population are at increased risk of developing a sec-
ond primary malignancy [189]. In a recent meta-analysis
based on pooled data from six studies of 70,844 thyroid can-
cer survivors, the incidence of second primary malignancies
in thyroid cancer survivors was increased compared to the
general population with an age-standardized incidence ratio
of 1.20 (95 % confidence interval [CI] 1.17–1.24) [189]. The
risk of the following second primary malignancies was sig-
nificantly increased in thyroid cancer survivors compared to
the general population: salivary gland, stomach, colon/
colorectal, breast, prostate, kidney, brain/central nervous
system, bone/joints, and adrenal cancer; soft tissue sarcoma;
non-Hodgkin’s lymphoma; multiple myeloma; and leukemia
[189]. Conversely, significantly reduced risks of lung and
cervical cancers were observed in thyroid cancer survivors
compared to the general population [189]. The observed
elevated second primary malignancy risk in thyroid cancer
survivors could be explained by a number of factors includ-
ing genetic predisposition, environmental exposures, surveil-
lance bias, or thyroid cancer therapy (such as 131I therapy or
external-beam radiation therapy). In determining whether
131
I therapy may be associated with an increased risk of sec-
ond primary malignancies in thyroid cancer survivors,
Brown et al. examined data from the cancer registry records
of the Surveillance, Epidemiology, and End Results (SEER)
program of the National Cancer Institute in North America
702
[190]. Brown et al. reported that the risk of second primary
malignancies was significantly higher for irradiated thyroid
cancer survivors versus nonirradiated patients (relative risk
1.16, 95 % CI 1.05–1.27, p < 0.05) [190]. In this study, 7.1 %
of thyroid cancer survivors developed a second primary
malignancy at a median of 8.1 years after their initial thyroid
cancer diagnosis [190]. Furthermore, the rate of observed/
expected (O/E) second primary cancers was significantly
elevated at 1.23 (95 % CI 1.04–1.45) in thyroid cancer survi-
vors treated with 131I compared to thyroid cancer patients not
treated with 131I. Of note, this study had a 36-month latency
exclusion in order to exclude cancers that may have been
unrelated to the therapy [190]. Brown et al. reported that the
risk of the following types of second primary malignancies
was significantly elevated in 131I-treated patients compared to
those who did not receive iodine: second cancers at all sites,
all solid tumors, stomach, prostate, lymphatic and hemato-
poietic diseases, and leukemia [190]. In a European cohort
study including data from clinical centers in France, Italy,
and Sweden, Rubino et al. [191] reported that the relative
risk of second primary malignancy was significantly elevated
at 1.2 (95 % CI 1.0–1.4) in patients treated with 131I com-
pared to those not treated with 131I with a 2-year latency
exclusion. In the European study, 8.4 % of individuals devel-
oped one or more second primary malignancies, and the
mean time from diagnosis of thyroid cancer to second pri-
mary malignancy was 15 years [191]. Rubino et al. [191]
further reported that the risk of the following types of second
primary malignancies was significantly elevated in
131
I-treated patients compared to those thyroid cancer patients
who did not receive 131I: cancer at all sites, salivary glands,
bone and soft tissue, uterus, female genital organs, and leu-
kemia. Data from the SEER study [190] and the European
cohort study [191] were pooled in a meta-analysis, and the
overall relative risk of second primary malignancies in thy-
roid cancer survivors treated with 131I was found to be signifi-
cantly elevated at 1.19 (95 % CI 1.04–1.36, p = 0.010),
relative to thyroid cancer survivors not treated with 131I. These
data were from 16,502 individuals using a minimum latency
period of 2 years after thyroid cancer diagnosis [192]. The
pooled risk of leukemia was also significantly increased in
thyroid cancer survivors treated with 131I with a relative risk
of 2.5 (95 % CI 1.13–5.53, p = 0.024) [192]. Pooling of data
on respective types of malignancies was limited in this meta-
analysis due to differences in categorization of some malig-
nancies between SEER and European studies [192].
However, a recent report by Gandhi et al. [193] suggested
that no significant risk for second primary malignancy occurs
after radioactive iodine treatment in patients with differenti-
ated thyroid cancer.
In summary, the controversy continues, but thyroid can-
cer survivors appear to have an increased risk of develop-
D. Van Nostrand et al.
ing second primary malignancies compared to the general
population, and thyroid cancer patients treated with 131I
appear to have an increased risk of second primary cancer
compared to thyroid cancer survivors not exposed to 131I.
Factors That May Modulate Second Primary
Malignancy Risk in Patients Treated with 131I
It is important to consider factors that may modulate second
primary malignancy risk in thyroid cancer survivors treated
with 131I. In considering the impact of cumulative prescribed
activity of 131I, Rubino et al. [191] reported that the risk of
both solid tumors and leukemia significantly increased in a
linear fashion with increasing cumulative prescribed activity.
An excess absolute risk of 14.4 solid cancers and 0.8 leuke-
mias per GBq (i.e., 27 mCi) of 131I and 105 person-years of
follow-up were reported in this study [191]. Furthermore, in
a recent study of 1106 thyroid cancer survivors from China,
a cumulative 131I prescribed activity of 3.0–8.9 GBq (81–240
mCi) was independently associated with an increased risk of
developing a nonsynchronous second primary malignancy
(relative risk 2.38, 95 % CI 1.04–5.26, p = 0.040) [194]. A
retrospective study from Iran suggested that the risk of sec-
ond primary malignancy was dramatically increased after a
cumulative prescribed activity of 40 GBq (1081 mCi) [195];
however this study was limited by a very low number of
observed second primary malignancies, so it may have been
underpowered for meaningful prescribed activity analysis. A
recent reanalysis of SEER data suggested that age may mod-
ulate the risk of second primary malignancy because indi-
viduals younger than 45 years who were treated with 131I
were more likely to develop a second cancer compared to
older individuals [196]. However, this observation needs fur-
ther validation. There is some recent evidence that the total
body effective half-life and radiation-absorbed dose of 131I in
the large intestine, breasts, ovaries, and bone marrow may be
lower in individuals pretreated with recombinant human thy-
rotropin compared to preparation with thyroid hormone
withdrawal prior to 131I therapy [197]. Although such data
are relevant to consider, it is currently not known whether the
preparation with recombinant human thyrotropin rather than
preparation with thyroid hormone withdrawal may signifi-
cantly impact the risk of second primary malignancies after
131
I therapy. In summary, there appears to be a relationship
between cumulative prescribed activity of 131I and second
primary malignancy risk, but there are some conflicting find-
ings in the literature as to an exact threshold at which the risk
significantly escalates. More research is needed to validate
whether young age is associated with an increased risk of
second primary malignancy after 131I therapy. Also, the
impact of the preparation using recombinant human thyro-
tropin prior to 131I therapy on second primary malignancy
risk deserves careful study.
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
The Risk of Dying from a Second Primary
Malignancy after 131I Therapy for Thyroid Cancer
Another important consideration is whether or not 131I ther-
apy of thyroid cancer increases the risk of dying of a second
primary malignancy. Currently, there is a paucity of studies
examining the risk of mortality due to second primary cancer
in thyroid cancer survivors, and the available studies have
relatively small sample sizes, potentially underpowering
their analyses. Edmonds et al. [199] reported that the stan-
dardized mortality risk was significantly elevated for leuke-
mia (p = 0.0013) and bladder cancer (p = 0.024) in thyroid
cancer survivors treated with 131I compared to the general
population. This relatively small study was limited by the
lack of a thyroid cancer control group that was not treated
with 131I. Ishikawa et al. [199] reported that the standardized
mortality risk due to second primary malignancies was sig-
nificantly elevated in thyroid cancer survivors compared to
the general population but that the risk did not appear to be
attributed to radiotherapy. More recently, Lang et al. [194]
reported that the risk of death due to nonsynchronous second
primary cancer did not appear to be significantly impacted
by cumulative prescribed activity of 131I. To summarize,
there is currently insufficient evidence to know whether 131I
therapy increases the risk of death due to second primary
malignancy, and this is a result of the limited number and
size of studies examining this topic.
Summary
In summary, thyroid cancer survivors appear to have an
increased risk of developing second primary malignancies
compared to the general population. Moreover, thyroid cancer
patients treated with 131I may have an increased risk of second
primary cancers compared to those not exposed to 131I. The
risk of second primary cancer appears to be related to cumula-
tive prescribed activity of 131I. It is important to note that the
excess risk of second cancers attributable to 131I is not suffi-
cient to warrant special screening procedures for second can-
cers, and established age-appropriate cancer screening
programs are recommended for all thyroid cancer survivors.
Acknowledgments My deepest thanks go to the many patients who
have given generous donation to help underwrite the research studies
that have been performed at the MedStar Washington Hospital Center
regarding the side effects of 131I therapy.
In addition, my personal gratitude also goes to Kristen L. Blair,
RDH (Registered Dental Hygienist), and Janice Falvo, BS, RDH
(Registered Dental Hygienist), for not only their input to this chapter
regarding the value of a dental hygienist but also for managing some of
my post 131I therapy patients.
703
References
1. Benua RS, Cicale NR, Sonenberg M, Rawson RW. The relation of
131
I dosimetry to results and complications in the treatment of
metastatic thyroid cancer. Am J Roentgenol Radium Ther Nucl
Med. 1962;87:171–82.
2. Alexander C, Bader JB, Schaefer A, et al. Intermediate and long-
term side effects of high-dose 131I therapy for thyroid carcinoma.
J Nucl Med. 1998;39:1551–4.
3. Chiu AC, Delpass ES, Sherman SI. Prognosis and treatment of
brain metastases in thyroid carcinoma. J Clin Endocrinol Metab.
1997;82:3637–42.
4. Holmquest DL, Lake P. Sudden hemorrhage in metastatic thyroid
carcinoma of the brain during treatment with iodine-I31. J Nucl
Med. 1976;17:307–9.
5. Datz FL. Cerebral edema following iodine-131 therapy for thyroid
carcinoma metastatic to the brain. J Nucl Med. 1986;27:637–40.
6. Hurley JR, Becker DV. The use of 131I in the management of thy-
roid cancer. In: Freeman LM, Weissman HS, editors. Nuclear
medicine annual 1983. New York: Raven Press; 1983. p. 329–84.
7. Grayson RR. Factors which influence the radioactive iodine thy-
roidal uptake test. Am J Med. 1960;24:397–415.
8. Bedikian AY, Valdivieso M, Heilbrun LK, et al. Glycerol: a suc-
cessful alternative to dexamethasone for patients receiving brain
irradiation for metastatic disease. Cancer Treat Rep.
1978;62:1081–3.
9. Murakami H, Kawahara N, Yahata T, et al. Radiation myelopathy
after radioactive iodine therapy for spine metastasis. Br J Radiol.
2008;79:e45–9.
10. Yevgeniya SK, Sergiy VK, Caroll NM, Felger E, Links TP,
Bonichon F, Preul MC, Sonntag VKH, Van Nostrand D, Burman
KD, Boyle LM. Spinal metastases due to thyroid carcinoma: an
analysis of 202 patients. Thyroid. 2014;24:1443-55.
11. Spitzweg C, Joba W, Schriever IK, Goellner JR, Morris JC,
Heufelder AE. Analysis of human sodium iodide symporter
immunoreactivity in human exocrine glands. J Clin Endocrinol
Metab. 1999;84:4178–84.
12. Morgenstern KE, Vadysirisack DD, Zhang Z, et al. Express of
sodium iodide symporter in the lacrimal drainage system: implica-
tion for the mechanism underlying nasolacrimal duct obstruction
in 131I treated patients. Ophthalmic Plast Reconstr Surg.
2005;21:337–44.
13. Zettinig G, Hanselmayer G, Fueger B, et al. Long-term impair-
ment of the lacrimal glands after 131I therapy: a cross-sectional
study. Eur J Nucl Med. 2002;29:1428–32.
14. Fard-Esfahni A, Mirshekarpour H, Fallahi B, et al. The effect of
high-dose radioiodine treatment on lacrimal gland function in
patients with differentiated thyroid carcinoma. Clin Nucl Med.
2007;32:696–9.
15. Solans R, Bosch JA, Galofre P, et al. Salivary and lacrimal gland
dysfunction (sicca syndrome) after 131I therapy. J Nucl Med.
2001;42:738–43.
16. Koca G, Acar U, Atilgan HI, Acar DE, Altiparmak UE, Demirel
K, Yalnizi-Akkay Z, Ustun H, Korkmas M, Ornek F. Changes
in conjunctival cytology and tear function tests with radioio-
dine treatment for hyperthyroidism. Ann Nucl Med.
2013;27:694–9.
17. Bakheet SMB, Hammami MM, Hemidan A, et al. 131I secretion in
tears. J Nucl Med. 1998;39:1452–4.
704
18. Kloos RT, Duvuri V, Jhiang SM, et al. Nasolacrimal drainage sys-
tem obstruction from radioactive iodine therapy for thyroid carci-
noma. J Clin Endocrinol Metab. 2002;87:5817–20.
19. Burns JA, Morgenstern KE, Cahill KV, et al. Nasolacrimal
obstruction secondary to I-131 therapy. Ophthal Plast Reconstr
Surg. 2004;20:1126–9.
20. Fard-Esfahani A, Farzanefar S, Fallahi B, Beiki D, Saghari M,
Emami-Ardekani A, Majdi M, Eftekhari M. Nasolacrimal duct
obstruction as a complication of iodine-131 therapy in patients
with thyroid cancer. Nucl Med Commun. 2012;33:1077–80.
21. Orquiza M, Khorjekar G, Schneider M, Kulkarni K, Garcia C, Acio
E, Burman K, Wartofsky L, Van Nostrand D. Epiphora and xeroph-
thalmia after 131I therapy: the frequency, time of onset, severity, and
duration. J Nucl Med. 2014;55:1933 (abstract).
22. Yuoness S, Rachinsky I, Driedger AA, et al. Differentiated thyroid
cancer with epiphora: detection of nasolacrimal duct obstruction
on I-131 SPECT/CT. Clin Nucl Med. 2011;36:1149–50.
23. Beutel J, Schroder C, von Hof K, Rades D, et al. Pharmacological
prevention of radiation-induced dry eye: an experimental study in
a rabbit model. Arch Clin Exp Ophthalmol. 2007;245:1347–55.
24. Acar U, Atilgan HI, Acar DE, Yalniz-Akkaya Z, Yumusak N,
Korkmaz M, Koca G. The effect of short-term vitamin E against
radioiodine-induced early lacrimal gland damage. Ann Nucl Med.
2013;27:886–91.
25. Koca G, Yalniz-Akkaya Z, Gultekin SS, Yumuksak N, Demirel K,
Korkmas M, et al. Radioprotective effect of montelukast sodium
in rat lacrimal glands after radioiodine treatment. Rev Esp Med
Nucl Imagen Mol. 2013;32:294–300.
26. Ramakrishnan VR, Durairaj VD, Kingdom TT. Endoscopic man-
agement of acquired nasolacrimal duct obstruction secondary to
radioactive radioiodine treatment for thyroid malignancy.
J Allergy Ther. 2011;2:2–6.
27. Van Nostrand D. Sialoadenitis secondary to 131I therapy for well-
differentiated thyroid cancer. Oral Dis. 2011;17:154–61.
28. Schiff L, Stevens CD, Molle WE, et al. Gastric (and salivary)
excretion of 131I in man (preliminary report). J Natl Cancer Inst.
1947;7:349–54.
29. Rice DH. Advances in diagnosis and management of salivary
gland diseases. West J Med. 1984;140:238–49.
30. Myant NB. Iodine metabolism of salivary glands. Ann N Y Acad
Sci. 1960;85:208.
31. Freinkel N, Ingbar SH. Concentration gradients for inorganic
I-131 and chloride in mixed human saliva. J Clin Invest.
1953;32:1077–84.
32. Honour AJ, Myant NB, Rowlands EN. Secretion of 131I in diges-
tive juices and milk in man. Clin Sci. 1952;11:449–62.
33. Jhiang SM, Cho JY, Ryu KY, et al. An immunohistochemical
study of Na+/I−symporter in human thyroid tissues and salivary
gland tissues. Endocrinology. 1998;139:4416–9.
34. Batsakis JG. Physiology. In: Cummings CW, Schuller DE, editors.
Otolaryngology-head and neck surgery, vol. 2. St. Louis: Mosby-
Year Book; 1998. p. 1210–22.
35. Donachi I. Biologic effects of radiation on the thyroid. In: Werner
SC, Ingbar SH, editors. The thyroid. New York: Harper & Row;
1978. p. 274–83.
36. Goolden AWG, Mallard JR, Farran HEA. Radiation sialitis fol-
lowing 131I therapy. Br J Radiol. 1957;30:210–2.
37. Liu B, Huang R, Kuang A, Zhao Z, Zeng Y, Wang J, Tian R. Iodine
kinetics and dosimetry in the salivary glands during repeated
courses of radioiodine therapy for thyroid cancer. Med Phys.
2011;38:5412–9.
38. Jentzen W, Hobbs RF, Stahl A, Knust J, Sgouros G, Bockisch
A. Pre-therapeutic 124I PET(/CT) dosimetry confirms low average
absorbed doses per administered 131I activity to the salivary glands
in radioiodine therapy of differentiated thyroid cancer. Eur J Nucl
Med Mol Imaging. 2010;37:884–95.
D. Van Nostrand et al.
39. La Perle KMD, Kim DC, Hall NC, Bobbey A, Shen DH, Nagy
RS, Wakely PE, Lehman A, Jarjoura D, Jhiang SM. Modulation of
sodium/iodide symporter expression in the salivary gland.
Thyroid. 2001;23:1029–35.
40. Van Nostrand DV, Neutze J, Atkins F. Side effects of “rational
dose” iodine-131 therapy for metastatic well differentiated thyroid
carcinoma. J Nucl Med. 1986;27:1519–27.
41. Kahn S, Waxman A, Ramanna L, et al. Transient radiation effects
following high dose I-131 therapy for differentiated thyroid can-
cer (DTC). J Nucl Med. 1994;35:15P.
42. Albrecht HH, Creutzig H. Salivary gland scintigraphy after radio-
iodine therapy. Functional scintigraphy of the salivary gland after
high dose 131I therapy. Fortschr Rontgenstr. 1976;125:546–51.
43. Allweiss P, Braunstein GD, Katz A, Waxman A. Sialoadenitis fol-
lowing I-131 therapy for thyroid carcinoma: concise communica-
tion. J Nucl Med. 1984;25:755–8.
44. Pan MS. Follow-up study of side effects for iodine-131 treatment
in patients with differentiated thyroid cancer. J Nucl Med.
2004;5S:386P.
45. Maier H, Bihl H. Effect of radioactive iodine therapy on parotid
gland function. Acta Otolaryngol. 1987;103:318–24.
46. Kharazi P, Van Nostrand D, Khorjekar G, Brennan M, McIver G,
Mete M, Bloom G. Characterization of salivary gland side effects
secondary to 131I therapy in patients with differentiated thyroid
cancer: a national ThyCa: Thyroid Cancer Survivors’ Association,
Inc. Survey. J Nucl Med. 2011;52S:1759 (abstract).
47. Grewal RK, Larson SM, Pentlow CE, et al. Salivary gland side
effects commonly develop several weeks after initial radioactive
iodine ablation. J Nucl Med. 2009;50:1605–10.
48. Hall J, Kharazi P, Van Nostrand D, Khorjekar G, Brennan M,
McIver B, Mete M, Bloom G. Characterization of salivary gland
side effects Up to 7 days after 131I therapy: updated report of the
Thyroid Cancer Survivors’ Association, Inc. (ThyCa) National
Survey. J Nucl Med. 2012;53(Suppl1):306.
49. Leeper R. Controversies in the treatment of thyroid carcinoma: the
New York Memorial Hospital approach. Thyroid Today.
1982;4:1–6.
50. Lin WY, Shen YY, Wang SJ. Short-term hazards of low-dose 131I
ablation therapy in postsurgical thyroid cancer patients. Clin Nucl
Med. 1996;21:780–2.
51. Brown AP, Greening WP, McCready VR, et al. 131I treatment of
metastatic thyroid carcinoma: the Royal Marsden hospital experi-
ence. Br J Radiol. 1984;57:323–7.
52. Schneyer LH, Tanchester D. Some oral aspects of radioactive
iodine therapy for thyroid disease. N Y J Dent. 1954;24:308–9.
53. Mandel S, Mandel L. Persistent sialoadenitis after radioactive
iodine therapy: report of two cases. J Oral Maxillofac Surg.
1999;57:738–41.
54. Malpani BL, Samuel AM, Ray S. Quantification of salivary gland
function in thyroid cancer patients treated with 131I. Int J Radiat
Oncol Biol Phys. 1996;35:535–40.
55. Spiegel W, Reiners C, Borner W. Sialoadenitis following iodine-131
therapy for thyroid carcinoma. J Nucl Med. 1985;26:816.
56. Reiners C, Eichner R, Eilles C, et al. Kamera-funktionsszintigraphie
der kopfspeicheldrusen nach hoch-dosierter radiojodtherapie bei
schilddrusenkarzinoma patienten. In: Nuklearmedizin, Schmidt
HAE, Riccabona G, editors. Stuttgart: Schattauer 1980. p. 477–81.
57. Mandel SJ, Mandel L. Radioactive iodine and the salivary glands.
Thyroid. 2003;13:265–71.
58. Laupa MS, Toth BB, Keene HJ. Effect of radioactive iodine ther-
apy on salivary flow rates and oral streptococcus mutants preva-
lence in patients with thyroid cancer. Oral Surg Oral Med Oral
Pathol. 1993;75:312–7.
59. Walters MA, Turtschi CP, Schindler C. The dental safety profile of
high-dose radioiodine therapy for thyroid cancer: long-term results
of a longitudinal cohort study. J Nucl Med. 2007;48:1620–5.
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
60. Busnell DL, Boles MA, Kaufman GE, et al. Complications,
sequela and dosimetry of iodine-131 therapy for thyroid carci-
noma. J Nucl Med. 1992;33:2214–21.
61. Davies AN. The management of xerostomia: a review. Eur
J Cancer Care. 1997;6:209–14.
62. Nakada K, Hirata K, Ishibashi T, et al. Cevimeline hydrochloride
hydrate in treating salivary gland dysfunction following 131I ther-
apy for thyroid cancer. J Nucl Med. 2004;45S:17P.
63. Ericson T, Lindberg A. Clinical trial of a saliva stimulating tablet
SST. Tandjakartidningen. 1982;74:713–6.
64. Blom M, Lunderberg T. Long term follow up of patients treated
with acupuncture for xerostomia and the influence of additional
treatment. Oral Dis. 2000;6:15–24.
65. Sreebny LM, Schwartz SS. A reference guide to drugs and dry
mouth. Gerodontology. 1986;5:75–99.
66. Hochberg MC, Tielsch J, Munoz B, et al. Prevalence of symptoms
of dry mouth and their relationship to saliva production in com-
munity dwelling elderly; the SEE project. J Rheumatol.
1998;25:486–91.
67. Mandel SJ, Mandel L. False-positive xerostomia following radio-
active iodine treatment: case report. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod. 2007;103:e43–7.
68. Kulkarni K, Kim SM, Intenzo C. Can salivary gland uptakes on a
diagnostic I-131 scan predict acute salivary gland dysfunction in
patients receiving 131I therapy for thyroid cancer? J Nucl Med.
2004;5S:291P.
69. Personal communications with Kristen L. Blair, Registered Dental
Hygienist (RDH) and Janice Falvo, RDH, BS.
70. Silberstein E. Reducing the incidence of 131I-induced sialadenitis:
the role of pilocarpine. J Nucl Med. 2008;49:546–9.
71. Shaw LM, Bonner HS, Schuchter L, et al. Pharmacokinetics of
amifostine: effects of dose and method of administration. Semin
Oncol. 1999;26:34–6.
72. Werner-Wasik M. Future development of amifostine as a radio-
protectant. Semin Oncol. 1999;26:129–1234.
73. Dorr RT, Holmes BC. Dosing considerations with amifostine: a
review of the literature and clinical experience. Semin Oncol.
1999;26:108–19.
74. Hall P, Holm LE, Lundell G, Ruden BI. Tumors after radiotherapy
for thyroid cancer. Acta Oncol. 1992;31:403–7.
75. Sasse AD, Clark LG, Sasse EC, et al. Amifostine reduced side
effects and improves complete response rate during radiotherapy:
results of a meta-analysis. Int J Radiat Oncol Biol Phys.
2006;64:784–91.
76. Bohuslavizki KH, Klutmann S, Jenicke L, et al. Salivary gland
protection by S–2-(3-amiopropylamino)-ethylphosphorothioic
acid (amifostine) in high-dose 131I treatment: results obtained in a
rabbit animal model and in a double blind multi-arm trial. Cancer
Biother Radiopharm. 1999;13:337–47.
77. Kim SJ, Choi HY, Kim IJ, et al. Limited cytoprotective effects of
amifostine in high-dose radioactive iodine 131I-treated well-
differentiated thyroid cancer patients: analysis of quantitative sali-
vary scan. Thyroid. 2008;18:325–31.
78. Schuchter L, Meropol NJ, Winer EP, et al. Amifostine and chemo-
radiation therapy: ASCO responds. Lancet Oncol. 2003;4:593.
79. Levy HA, Park CH. Effect of reserpine on salivary gland 131I
uptake in thyroid cancer. Clin Nucl Med. 1987;12:303–7.
80. Bhartiya US, Raut YS, Joseph LJ, Hawaldar RW, Rao
BS. Evaluation of the radioprotective effect of turmeric extract
and vitamin E in mice exposed to therapeutic dose of radioiodine.
Indian J Clin Biochem. 2008;23:382–6.
81. Leban JJ, Bhartiya U, Raut YS, et al. Radioprotective effect of
Ocimum sanctum and amifostine on the salivary gland of rats after
therapeutic radioiodine exposure. Cancer Biother Radiopharm.
2011;26:737–43.
705
82. Koca G, Gültekin SS, Han Ü, Kuru S, Demirel K, Korkmaz
M. The efficacy of montelukast as a protective agent against
131I-induced salivary gland damage in rats: scintigraphic and his-
topathological findings. Nucl Med Commun. 2013;34:507–17.
83. Noaparast Z, Hosseinimehr J. Radioprotective agents for the pre-
vention of side effects induced by radioiodine-131 therapy. Futur
Oncol. 2013;9:1145–59.
84. Kim HW, Ahn BY, Lee SW, Lee J. Effect of parotid gland massage
on parotid gland Tc-99m pertechnetate uptake. Thyroid.
2012;22:611–6.
85. Freitas JE, Gross MD, Ripley S, Shapiro B. Radionuclide diagno-
sis and therapy of thyroid cancer; current status report. Semin
Nucl Med. 1985;15:106–31.
86. Nakada K, Ishibashi T, Takei K, et al. Does lemon candy decrease
salivary gland damage following 131I therapy for thyroid cancer?
J Nucl Med. 2005;46:261–6.
87. Liu B, Kuang A, Huang R, et al. Influence of vitamin C on salivary
absorbed dose of 131I in thyroid cancer patients; a prospective, random-
ized, single-blind, controlled trial. J Nucl Med. 2010;51:618–23.
88. Jentzen W, Balschuweit D, Schmitz J, et al. The influence of sali-
vary flow stimulation on the absorbed radiation dose to the sali-
vary glands during radioiodine therapy of thyroid cancer using
124
I PET/CT imaging. Eur J Nucl Med Mol Imaging.
2010;37:2298–306.
89. Van Nostrand D, Bandaru V, Chennupati V, Kulkarni K, Wexler J,
Atkins F, Mete M, Gadwale G. Radiopharmacokinetics of
radioiodine in the parotid glands after the administration of lemon
juice. Thyroid. 2010;20:1113–9.
90. Kulkarni K, Van Nostrand D, Atkins F, Mete M, Wexler J,
Wartofsky L. Does lemon juice increase radioiodine re-
accumulation within the parotid glands more than if lemon juice is
not administered? Nucl Med Commun. 2014;35:210–6.
91. Nahlieli O, Nazarian Y. Sialadenitis following radioiodine ther-
apy—a new diagnostic and treatment modality. Oral Dis.
2006;12:476–9.
92. Bomeli ST, Schaitkin B, Carrau RL, et al. Interventional sialen-
doscopy for treatment of radioiodine-induced sialadenitis.
Laryngoscope. 2009;119:864–7.
93. Varma VM, Dai WL, Henkin RI. Taste dysfunction in patients
with thyroid cancer following treat with I-131. J Nucl Med.
1992;33:996.
94. Orquiza M, Khorjekar G, Schneider M, Kulkarni K, Garcia C,
Acio E, Burman K, Wartofsky L, Van Nostrand D. Altered and/or
loss of taste after 131I therapy: the frequency, time of onset, sever-
ity, and duration. J Nucl Med. 2014;55:1933.
95. Norby EH, Neutze JH, Van Nostrand D, et al. Nasal radioactive
iodine uptake: a prospective study of frequency, intensity and pat-
tern. J Nucl Med. 1990;31:52–4.
96. Levenson D, Coulec S, Sonnenberg M, et al. Peripheral facial
nerve palsy after high-dose 131I therapy in patients with papillary
thyroid carcinoma. Ann Intern Med. 1994;120:576–8.
97. Burmeister LA, du Cret RP, Mariash CN. Local reaction to 131I in
the treatment of thyroid cancer. Am J Med. 1991;90:217–22.
98. Cherk MH, Yap KV, Topliss BM, et al. Acute radiation thyroiditis
that sometimes occurs with post-thyroidectomy remnant ablation
is directly related to thyroidal 131I uptake and not to the amount of
131
I used for ablation. Clin Thyroidology. 2009;21:24–6.
99. Goolden AWG, Kam KC, Fitzpatrick ML, Munro AJ. Oedema of
the neck after ablation of the thyroid with radioactive iodine. Br
J Radiol. 1986;59:583–6.
100. Cooper DS, Ridgway EC, Maloof F. Unusual types of hyperthy-
roidism. Clin Endocrinol Metab. 1978;7:199–220.
101. Smith R, Blum C, Benua RS, Fawwaz R. Radioactive iodine treat-
ment of metastatic thyroid carcinoma with clinical thyrotoxicosis.
Clin Nucl Med. 1985;10:874–5.
706
102. Ikejiri K, Furuyama M, Muranaka T, et al. Carcinoma of the thy-
roid manifested as hyperthyroidism caused by functional bone
metastasis. Clin Nucl Med. 1997;22:227–30.
103. Trunnell JB, Marinelli LD, Duffy Jr BJ, et al. The treatment of
metastatic thyroid cancer with radioactive iodine: credits and deb-
its. J Clin Endocrinol. 1949;9:1138–52.
104. Cerletty JM, Listwan WJ. Hyperthyroidism due to functioning
metastatic thyroid carcinoma. Precipitation of thyroid storm with
therapeutic radioactive iodine. JAMA. 1979;242:269–70.
105. Winslow CP, Meyers AD. Hypocalcemia as a complication of 131I
therapy. Am J Otolaryngol. 1998;19:401–3.
106. Glazebrook GA. Effect of decicurie prescribed activity of radioac-
tive I-131 on parathyroid function. Am J Surg. 1987;154:368–73.
107. Zhu R, Yu Y, Lu H. Clinical study of 312 cases with metastatic
differentiated thyroid cancer treated with large doses of 131I. Chin
Med J. 2005;118:425–8.
108. Cunha DDS, Izilda MI, Simōes P, et al. Carotid artery rupture fol-
lowing radioiodine therapy for differentiated thyroid carcinoma.
Arq Bras Endocrinol Metab. 2011;55:419–25.
109. Lee TC, Harbert JC, Dejter SW, et al. Vocal cord paralysis follow-
ing I-131 ablation of a postthyroidectomy remnant. J Nucl Med.
1985;26:49–50.
110. Pochin EE. 131I treatment of thyroid cancer. In: Hahn PF, editor.
Therapeutic use of artificial radioisotopes. New York: Wiley;
1956. p. 195.
111. Fajardo L-GLF, Berthrong M, Anderson RE, editors. Radiation
pathology. Oxford: University Press; 2001.
112. Gomez D, Rosenzweig KE. Lung. In: Shrieve DC, Loeffler JS,
editors. Human radiation injury. Philadelphia: Wolters Kluwer;
2011. p. 306–15.
113. Rall JE, Alpers JB, Lewallen CG, et al. Radiation pneumonitis and
fibrosis: a complication of 131I treatment of pulmonary metastases
from cancer of the thyroid. J Clin Endocrinol Metab.
1957;17:1263–76.
114. Tollefsen HR, DeCosse JJ, Hutter RVP. Papillary carcinoma of the
thyroid. A clinical and pathological study of 70 fatal cases. Cancer.
1964;17:1035–43.
115. Aldrich LB, Sisson JC, Grum CM. Pulmonary function in thyroid
carcinoma metastatic to the lung. J Endocrinol Invest.
1987;10:111–6.
116. Menzel C, Grunwald F, Schomburg A, et al. “High-dose” 131I ther-
apy in advanced differentiated thyroid carcinoma. J Nucl Med.
1996;37:1496–503.
117. Bennett DE, Million RR, Ackerman LV. Bilateral radiation pneu-
monitis. A complication of the radiotherapy of bronchogenic car-
cinoma. Cancer. 1969;23:1001–18.
118. Fulkerson WJ, McLendon RE, Prosnitz LR. Adult respiratory
distress syndrome after limited radiotherapy. Cancer. 1986;57:
1941–6.
119. Monson JM, Stark P, Reily JJ, et al. Clinical radiation pneumonitis
and radiographic changes after thoracic radiation therapy for lung
carcinoma. Cancer. 1998;82:842–50.
120. Morgan GW, Pharm B, Breit SN. Radiation and the lung. Int
J Radiat Oncol Biol Phys. 1995;31:361–9.
121. Delanian S, Porcher R, Rudant J, et al. Kinetics of response to
long-term treatments combining pentoxifylline, and tocopherol in
patients with superficial radiation-induced fibrosis. J Clin Oncol.
2005;23:8570–9.
122. Choi NC, Kanarek DJ, Kazemi H. Physiologic changes in pulmo-
nary function after thoracic radiotherapy for patients with lung
cancer and role of regional pulmonary function studies predicting
postradio-therapy pulmonary function before radiotherapy.
Cancer Treat Symp. 1985;2:119–30.
123. Mah K, Van Dyk J, Keane T, Poon PY. Acute radiation-induced
pulmonary damage: a clinical study on the response to fractionated
radiation therapy. Int J Radiat Oncol Biol Phys. 1987;13:179–88.
D. Van Nostrand et al.
124. Smith JC. Radiation pneumonitis. A review. Am Rev Respir Dis.
1963;87:647–65.
125. Carmel RJ, Kaplan HS. Mantle irradiation for Hodgkin’s disease.
An analysis of technique, tumor eradication and complications.
Cancer. 1976;37:2813–25.
126. Fryer CJH, Fitzpatrick PJ, Rider WD, et al. Radiation pneumoni-
tis: experience following a large single dose of radiation. Int
J Radiat Oncol Biol Phys. 1978;4:931–6.
127. McDonald S, Rubin P, Philips TL, Marks LB. Injury to the lung
from cancer therapy: clinical syndromes, measurable endpoints,
and potential scoring systems. Int J Radiat Oncol Biol Phys.
1995;31:1187–203.
128. Fowler JF, Travis EL. The radiation pneumonitis syndrome in
half-body radiation therapy. Int J Radiat Oncol Biol Phys.
1978;4:1111–3.
129. Keane T, Van Dyk J, Rider WD. Idiopathic interstitial pneumonia
following bone marrow transplantation. The relationship with total
body irradiation. Int J Radiat Oncol Biol Phys. 1981;7:1365–70.
130. Gross NJ. Pulmonary effects of radiation therapy. Ann Intern
Med. 1977;86:81–92.
131. Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary
metastasis of differentiated thyroid carcinoma: treatment results in
101 patients. J Clin Endocrinol Metab. 1985;60:376–80.
132. Gopal R, Tucker SI, Komaki R, et al. The relationship between
local dose and loss of function for irradiated lung. Int J Radiat
Oncol Biol Phys. 2003;56:106–13.
133. Wilner J, Jost A, Baier K, et al. A little to a lot or a lot to a little?
An analysis of pneumonitis risk from dose-volume histogram
parameter. Strahlenther Onkol. 2003;179:548–56.
134. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider
JE, Shank B, Solin LJ, Wesson M. Tolerance of normal tissue to
therapeutic irradiation. Int J Radiat Oncol Biol Phys.
1991;21:109–22.
135. Burman C, Kutcher GJ, Emami B, Goitein M. Fitting of normal
tissue tolerance data to an analytic function. Int J Radiat Oncol
Biol Phys. 1991;21:123–35.
136. Graham MV, Purdy JA, Emami B, Harms W, Bosch W, Lockett
MA, Perez CA. Clinical dose-volume histogram analysis for
pneumonitis after 3D treatment for non-small cell lung cancer.
J Radiat Oncol Biol Phys. 1999;45:323–9.
137. Samuel AM, Unnikrishnan TP, Baghel NS, Rajashekharrao
B. Effect of 131I therapy on pulmonary alveolar-capillary mem-
brane integrity. J Nucl Med. 1995;36:783–7.
138. Schlumberger M, Arcangioli O, Piekarski JD, et al. Detection of
and treatment of lung metastases of differentiated thyroid carci-
noma in patients with normal chest x-rays. J Nucl Med.
1988;29:1790–4.
139. Pacini F, Gasperi M, Fugazzola L, et al. Testicular function in
patients with differentiated thyroid carcinoma treated with 131I. J
Nucl Med. 1994;35:1418–22.
140. Maheshwari YK, Strattton Hill C, Haynie TP, et al. Iodine-131
therapy in differentiated thyroid carcinoma: M.D. Anderson
Hospital experience. Cancer. 1981;47:664–71.
141. Goffman T, Loff V, Tuttle M, et al. Near-lethal respiratory failure
after recombinant human thyroid-stimulation hormone use in a
patient with metastatic thyroid carcinoma. Thyroid.
2003;13:827–30.
142. Hindiè E, Melliere D, Lange F, et al. Functioning pulmonary
metastases of thyroid cancer: does 131I influence the prognosis?
J Nucl Med. 2003;30:974–81.
143. Hughes JM, Lockwood DN, Jones HA, et al. DLCO/Q and diffu-
sion limitation at rest and on exercise in patients with interstitial
fibrosis. Respir Physiol. 1991;83:155–66.
144. Khan JH, McElhinney DB, Rahman SB, et al. Pulmonary metas-
tases of endocrine origin: the role of surgery. Chest.
1998;114:526–34.
62 Side Effects of 131I for Therapy of Differentiated Thyroid Carcinoma
145. Liu D, Labow D, Dang N, et al. Pulmonary metastasectomy for
head and neck cancers. Ann Surg Oncol. 1999;6:572–8.
146. Nemec J, Zamrazil V, Pohunkova D, Roohling S. Radioiodide
treatment of pulmonary metastases of differentiated thyroid can-
cer; results and prognostic factors. Nuklearmedizin.
1979;18:86–90.
147. Massin JP, Savoie JC, Garnier H, et al. Pulmonary metastases in
differentiated thyroid carcinoma: study of 58 cases with implica-
tions for the primary tumor treatment. Cancer. 1984;53:982–92.
148. Esposito G, Van Nostrand D, Atkins F, Burman K, Wartofsky L,
Kulkarni K. Frequency of “over” and “under” treatment with
empiric dosage of I-131 in patients with and without lung metas-
tasis secondary to well-differentiated thyroid cancer. J Nucl Med.
2006;47(1):238P. abstract.
149. Tuttle RM, Leboeuf R, Robbins RJ, Qualey R, Pentlow K, Larson
SM, Chan CY. Empiric radioactive iodine dosing regimens fre-
quently exceed maximum tolerated activity levels in elderly
patients with thyroid cancer. J Nucl Med. 2006;47:1587–91.
150. Kulkarni K, Van Nostrand D, Atkins F, Aiken M, Burman K,
Wartofsky L. The relative frequency in which empiric dosages of
radioiodine would potentially overtreat or undertreat patients who
have metastatic well-differentiated thyroid cancer. Thyroid.
2006;16:1019–23.
151. Khorjekar G, Van Nostrand D, Vetter R, Ringel M, Carter E,
Bloom G. The frequency of vomiting after outpatient I-131 ther-
apy in patients with well-differentiated thyroid cancer. J Nucl
Med. 2010;51S:1580. abstract.
152. Khorjekar G, Van Nostrand D, Vetter R, Ringel M, Carter E,
Bloom G. The relationship of several factors and vomiting after
outpatient I-131 treatment in pts with well-differentiated thyroid
cancer. J Nucl Med. 2010;51S:1570. abstract.
153. Quimby ES, Feitelberg S, Laughlin JS, et al. NCRP report 37:
precautions in the management of patients who have received
therapeutic amounts of radionuclides. Washington, DC: National
Council on Radiation Protection; 1970.
154. US Nuclear Regulatory Commission. Criteria for release of indi-
viduals administered radioactive materials. Fed Regist.
1997;62:4120.
155. Kinuya S, Hwang E, Ikeda E, et al. Mallory-Weiss Syndrome
caused by iodine-131 therapy for metastatic thyroid carcinoma.
J Nucl Med. 1997;38:1831–2.
156. Balan KK, Raouf AH, Critchley M. Outcome of 249 patients
attending a nuclear medicine department with well-differentiated
thyroid cancer; a 23 year review. Br J Radiol. 1994;67:283–91.
157. Dobyns BM, Maloof F. The study and treatment of 119 cases of
carcinoma of the thyroid with radioactive iodine. J Clin
Endocrinol. 1951;11:1323–60.
158. Dorn R, Kopp J, Vogt H, et al. Dosimetry-guided radioactive
iodine treatment in patients with metastatic differentiated thyroid
cancer: largest safe dose using a risk—adapted approach. J Nucl
Med. 2003;44:451–6.
159. Grunwald F, Schomburg A, Menzel C, et al. Blood count changes
after 131I treatment in thyroid carcinoma. Med Klin. 1994;89:522–8.
160. Haynie T, Beierwaltes W. Hematologic changes observed follow-
ing therapy for thyroid carcinoma. J Nucl Med. 1963;4:85–91.
161. Keldsen N, Mortensen BT, Hansen HS. Bone marrow depression
due to I-131 treatment of thyroid cancer. Ugeskr Laeger.
1988;50:2817–9.
162. Matthies A, Bender H, Distelmaier M, et al. Efficacy and side
effects of high dose iodine-131 therapy in metastatic thyroid car-
cinoma. Eur J Nucl Med. 2004;45S:189P.
163. Molinaro E, Leboeuf R, Shue B, et al. Mild decreases in white
blood cell and platelet counts are present one year after radioac-
tive iodine remnant ablation. Thyroid. 2009;19:1035–41.
164. Petrich T, Widjaja A, Musholt TJ, et al. Outcome after 131I therapy
in 107 patients with differentiated thyroid carcinoma and initial
707
bone metastases: side effects and influence of age. Eur J Nucl
Med. 2001;28:203–8.
165. Robeson WR, Ellwood JE, Margulies P, Margouleff D. Outcome
and toxicity associated with maximum safe dose 131I treatment of
metastatic thyroid cancer. Clin Nucl Med. 2002;27:556–666.
166. Schober O, Gunter HH, Schwarzrock R, Hundeshagen
H. Hamatologische langzeitveranderungen bei der
Radiojodtherapie des Schilddrusenkarzinoms. Strahlenther
Onkol. 1987;163:464–74.
167. Schumichen C, Schmitt E, Scheuffele C. Influence of the therapy
concept onto the prognosis of thyroid carcinoma. Nuklearmedizin.
1983;22:97–105.
168. Kuhn JM, Rieu M, Wolf LM, et al. Hematologic repercussions of
disorders of thyroid secretion. Presse Med. 1984;13:421–5.
169. Donate RM, Gallagher NI. Hematologic alteration associated with
endocrine disease. MedClin N Am. 1968;52:231–41.
170. Leeper 1980. Personal communication.
171. Raymond JP, Izembart M, Marliac V, et al. Temporary ovarian
failure in thyroid cancer patients after thyroid remnant ablation
with radioactive iodine. J Clin Endocrinol Metab.
1989;69:186–90.
172. Vini L, Hyer S, Al-Saadi A, et al. Prognosis for fertility and ovar-
ian function after treatment with 131I for thyroid cancer. Postgrad
Med J. 2002;78:92–3.
173. Souza Rosario PW, Alvarenga Fagundes T, Villa-Boas Fagundes
AS, et al. Ovarian function after 131I therapy in patients with thy-
roid cancer. Exp Clin Endocrinol Diabetes. 2005;113:331–3.
174. Ceccarelli C, Bencivelli W, Morciano D, et al. I-131 therapy for
differentiated thyroid cancer leads to an earlier onset of meno-
pause; results of a retrospective study. J Clin Endocrinol Metab.
2001;86:3512–5.
175. Rosario PW, Fagundes TA, Fagundes AV, et al. 131I therapy and
age at menopause in patients with thyroid cancer. Clin Endocrinol
(Oxf). 2006;64:225–6.
176. Wichers M, Benz E, Palmedo H, et al. Testicular function after 131I
therapy for thyroid carcinoma. Eur J Nucl Med. 2000;27:503–7.
177. Hyer S, Vini L, O’Connell M, et al. Testicular dose and fertility in
mean following I-131 therapy for thyroid can. Clin Endocrinol.
2002;56:755–8.
178. Handelsman DJ, Turtle JR. Testicular damage after radioactive iodine
therapy for thyroid cancer. Clin Endocrinol. 1983;18:465–72.
179. Rosario PW, Barroso AL, Rezende LL, et al. Testicular function
after 131I therapy in patients with thyroid cancer. Thyroid.
2006;16:667–70.
180. Esfahani AF, Eftekhari M, Zenooz N, et al. Gonadal function in
patients with differentiated thyroid cancer treated with I-131. Hell
J Nucl Med. 2004;7:52–5.
181. Garsi J-P, Schlumberger M, Rubino C, et al. Therapeutic adminis-
tration of I-131 for differentiated thyroid cancer: radiation dose to
ovaries and outcome of pregnancies. J Nucl Med.
2008;49:845–52.
182. Sawka AM, Lakra DC, Lea J, et al. A systematic review examin-
ing the effects of therapeutic radioactive iodine on ovarian func-
tion and future pregnancies in female cancer survivors. Clin
Endocrinol. 2008;69:479–90.
183. Sioka C, Fotopoulos A. Effects of I-131 therapy on gonads and
pregnancy outcome in patients with thyroid cancer. Fertil Steril.
2011;95:1552–9.
184. Garsi J-P, Schlumberger M, Ricard M, et al. Health outcomes of
children fathered by patients treated with 131I for thyroid cancer.
Clin Endocrinol. 2009;71:880–3.
185. Sawka AM, Lea J, Alshehri B, et al. A systematic review of the
gonadal effects of therapeutic radioactive iodine in male thyroid
cancer survivors. Clin Endocrinol. 2008;68:610–7.
186. Cooper DS, Doherty GM, Haugen BR, et al. Revised American
Thyroid Association management guidelines for patients with
708
thyroid nodules and differentiated thyroid cancer. Thyroid.
2009;19:1167–214.
187. Sisson JC, Freitas J, McDougall IR, et al. Radiation safety in the
treatment of patients with thyroid diseases by 131I I-131: practice
recommendations of the American Thyroid Association. Thyroid.
2011;21:335–46.
188. Hall EJ, Giaccia AJ. Radiobiology for the radiologist. 6th ed.
Philadelphia: Lippincott William & Wilkins; 2006.
189. Subramanian S, Goldstein DP, Parlea L, et al. Second primary
malignancy risk in thyroid cancer survivors: a systematic review
and meta-analysis. Thyroid. 2007;17:1277–88.
190. Brown AP, Chen J, Hitchcock YJ, Szabo A, Shrieve DC, Tward
JD. The risk of second primary malignancies up to three decades
after the treatment of differentiated thyroid cancer. J Clin
Endocrinol Metab. 2008;93:504–15.
191. Rubino C, de Vathaire F, Dottorini ME, et al. Second primary
malignancies in thyroid cancer patients. Br J Cancer.
2003;89:1638–44.
192. Sawka AM, Thabane L, Parlea L, et al. Second primary malig-
nancy risk after 131I treatment for thyroid cancer: a systematic
review and meta-analysis. Thyroid. 2009;19:451–7.
193. Gandhi S, Abhyankar A, Basu S. Dual malignancies in the setting
of differentiated thyroid carcinoma: their synchronous or meta-
chronous nature, impact of radioiodine treatment on occurrence of
second malignancy and other associated variables. Nucl Med
Commun. 2014;35:205–9.
D. Van Nostrand et al.
194. Lang BH, Wong KP. Risk factors for nonsynchronous second
primary malignancy and related death in patients with differenti-
ated thyroid carcinoma. Ann Surg Oncol. 2011;18:3559–65.
195. Fallahi B, Adabi K, Majidi M, et al. Incidence of second primary
malignancies during a long-term surveillance of patients with dif-
ferentiated thyroid carcinoma in relation to 131I treatment. Clin
Nucl Med. 2011;36:277–82.
196. Iyer NG, Morris LG, Tuttle RM, Shaha AR, Ganly I. Rising inci-
dence of second cancers in patients with low-risk (T1N0) thyroid
cancer who receive 131I therapy. Cancer. 2011;117:4439–46.
197. Taïeb D, Sebag F, Farman-Ara B, et al. Iodine biokinetics and 131I
exposure after recombinant human thyrotropin-assisted remnant
ablation in comparison with thyroid hormone withdrawal. J Clin
Endocrinol Metab. 2010;95:3283–90.
198. Edmonds CJ, Smith T. The long-term hazards of the treatment of
thyroid cancer with 131I. Br J Radiol. 1986;59(697):45–51.
199. Ishikawa K, Noguchi S, Tanaka K, Fukuda A, Hirohata T. Second
primary neoplasms in thyroid cancer patients. Jpn J Cancer Res.
1996;87:232–9.
200. Kita T, Yokoyama K, Higuchi T, Kinuya S, Taki J, Nakajima K,
Michigishi T, Tonami N. Multifactorial analysis on the short-term
side effects occurring within 96 hours after radioiodine-131 for dif-
ferentiated thyroid carcinoma. Ann Nucl Med. 2004;18:345–9.
201. Leeper RD. The effect of I-131 therapy on survival of patients
with metastatic papillary or follicular thyroid carcinoma. J Clin
Endocrinol Metab. 1973;36:1143–52.