Download Update on Recent Developments in the

Update on Recent Developments in the
Therapy of Differentiated Thyroid Cancer
Marcus Middendorp, MD, and Frank Grünwald, MD
In the past decade, the management of differentiated thyroid carcinoma changed significantly and thus contributed to the improvement of the already favorable prognosis of this
malignant disease. Surgical treatment techniques improved and the extent of initial surgery
is more individualized. Radioiodine therapy is an essential part of therapeutic regimens in
almost all cases, and the use of recombinant human thyroid-stimulating hormone has
established for ablation of remnant tissue, treatment of iodine-positive cancer, and sensitive thyroglobulin measurement during follow-up. Risk stratification has become more
important to plan treatment and follow-up individually, particularly to evaluate the need for
thyroid-stimulating hormone suppression therapy. Especially for inoperable and radioiodine-negative thyroid carcinomas, novel treatment options such as tyrosine kinase inhibitor
therapy have emerged. This article deals with the current options of optimal therapy
regimens in differentiated thyroid carcinoma.
Semin Nucl Med 40:145-152 © 2010 Elsevier Inc. All rights reserved.
D
ifferentiated thyroid carcinoma (DTC) is the most common endocrine cancer, representing about 1% of all
malignancies. Excellent prognosis and long-term survival
with a 10-year survival of more than 90% are the main causes
for the lack of relevant prospective randomized controlled
trials.1 Existing guidelines and consensus reports for DTC are
mainly based on large cohort studies, well-designed retrospective studies, and experience of experts in this field.2 In
the last decade, several new therapeutic aspects have arisen,
some of them still being controversially debated (eg, the
adequate therapy of papillary thyroid microcarcinomas
[PTMC]).3 This review will focus on current issues in the therapy of DTC, giving an update on the initial surgical management, the reasonable use of radioiodine therapy (RIT) for
ablation of remnant thyroid tissue and for the treatment of
persistent or recurrent disease, the use of recombinant
human thyroid-stimulating hormone (rhTSH), the role of
external beam radiation therapy (EBRT), the extent of thyrotropin-suppressive therapy, and on options in radioiodinenegative thyroid cancer.
Department of Nuclear Medicine, Johann Wolfgang Goethe University,
Frankfurt/Main, Germany.
Address reprint requests to Frank Grünwald, MD, Department of Nuclear
Medicine, Johann Wolfgang Goethe University Medical School, TheodorStern-Kai 7, 60590, Frankfurt am Main, Germany. E-mail: gruenwald@
em.uni-frankfurt.de
0001-2998/10/$-see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1053/j.semnuclmed.2009.10.006
Current Approach to
Initial Surgical Therapy of DTC
Primary Tumor
In view of the biological heterogeneity of DTC an individualized surgical approach, also considering the postoperative
quality of life, is necessary. The extent of surgery is highly
dependent on an accurate risk stratification of DTC, which is
still not precisely defined. Which initial surgical intervention
is chosen, lobectomy, near-total thyroidectomy, or total thyroidectomy, is mainly determined by preoperative information. In suspicious solitary thyroid nodules smaller than 4
cm, lobectomy is the recommended initial approach.4,5 Completion thyroidectomy is widely accepted in DTC larger than
2 cm but controversially discussed in T1 stage (Union Internationale Contre le Cancer/American Joint Committee on
Cancer 2002).6,7 In case of a preoperatively known DTC,
near-total and total thyroidectomy are mostly performed
with few exceptions.
PTMC without metastases and invasion of the tumor capsule, with unifocal growth and favorable histology are discussed as indications for less-than-total thyroidectomy. Retrospective data could not show hitherto an advantage for
total thyroidectomy with respect to overall survival.8 Some
surgeons decide in favor of near-total or total thyroidectomy
in case of preoperative diagnosis of PTMC, and on less-thantotal thyroidectomy in incidental finding of PTMC in case of
lobectomy for benign thyroid disease. Completion thyroid145
M. Middendorp and F. Grünwald
146
ectomy and total thyroidectomy, respectively, are recommended in papillary thyroid carcinoma (PTC) larger than 1
cm, in case of multifocal disease, extrathyroidal invasion,
unfavorable histology, or lymph node metastases.9 Some centers always perform near-total or total thyroidectomy arguing
with frequent multifocality of PTC resulting in higher recurrence rates.10,11
In follicular thyroid carcinoma (FTC), extrathyroidal invasion and distant metastases are the most relevant prognostic
factors.12 Follicular microcarcinomas are rather rare. In nonmetastatic minimally invasive FTC without extracapsular extension, less-than-total thyroidectomy is considered as an
adequate therapy. However, in most cases total thyroidectomy is preferred.13 This is attributed to controversial definitions of minimal invasiveness and the suggestion, despite
limited evidence that vascular invasion has a major impact on
the outcome of FTC.14,15
In childhood DTC—mainly PTC—is often associated with
locally aggressive disease and more frequent with distant metastases. With respect to the comparably unfavorable relation
of tumor extension to thyroid volume, total thyroidectomy
and lymph node dissection are suggested to be the optimal
surgical strategy in most cases.16-18 Whether there is an appropriate threshold diameter, below which less-than-total
thyroidectomy is adequate, will have to be evaluated in prospective multicenter trials.
What extent of surgical treatment is necessary in more
aggressive variants of thyroid cancer with intermediate differentiation such as tall cell variant, columnar cell variant,
diffuse sclerosing variant, insular carcinoma, and Hürthle cell
carcinoma? Even though there are only limited data for these
histologic subtypes, evidence-based recommendation mostly
includes total thyroidectomy and neck dissection for node
positivity.19 In poorly differentiated thyroid cancer, lessthan-total thyroidectomy is not recommended.20
Lymph Node Metastases
As overall effect of lymph node metastases on survival is
limited, there are controversial opinions concerning the indication in general (therapeutic/diagnostic/prophylactic purposes), and the extent of lymph node dissection. For PTC less
than 1 cm, no data exist justifying routine lymph node dissection.21 But PTC up to 10 mm is already associated with
lymph node metastases in about 16%, and therefore prophylactic lymph node dissection of bilateral central compartments is mostly recommended for all PTC inclusive of microcarcinomas. Cervical lymph node dissection of the lateral
compartments is considered in case of evident lymph node
metastases in preoperative clinical diagnostics or during operation.5,20,22 In FTC the threshold size for lymph node metastases is greater (⬎ 20 mm) compared to PTC (⬍ 10 mm).
As lymph node metastases are infrequent in FTC, routine
lymph node dissection is not needed, unless there is confirmation of lymph node metastases. Available data on poorly
DTC do not support routine lymph node dissection as well
except for extrathyroidal primary tumor extension.20,22
Reasonable Uses
of Radioiodine Therapy
Radioiodine Ablation
Postoperative RIT aims at destroying of residual microscopic
tumor tissue to reduce the recurrence rate, ablating remaining normal thyroid tissue to optimize follow-up conditions
(eg, thyroglobulin measurement), and completing staging by
a highly sensitive post-therapeutic whole-body scintigraphy
(WBS).
The guidelines for the management of differentiated
thyroid cancer published by the American Thyroid Association (ATA), the European Association of Nuclear Medicine (EANM), and the European Thyroid Association (ETA)
agree in the indication of RIT in high-risk patients and in the
opinion that RIT is not necessary in unifocal thyroid microcarcinomas without metastases, capsule invasion, and lack of
more aggressive histologies such as tall cell, columnar cell,
and diffuse sclerosing variant, the so-called very-low-risk
group.5,23,24 Due to the less precisely defined low-risk group
there are controversies about the adequate management of
these patients. Whatever risk stratification is applied, tumor
diameter, AMES (Age, distant Metastasis, Extent, and Size of
primary cancers), or MACIS (Metastasis, Age, Completeness
of resection, Invasion, and Size) score, most low-risk patients
have excellent prognosis, and thus there remain doubts
about the benefit of RIT. Prospective controlled randomized
trials with an endpoint of specific mortality are rarely realizable.25-29 As no advantage in specific mortality and recurrence rate after RIT of low-risk patients has been proved,
there are significant regional differences in recommendations
of postoperative RIT.27,30 ATA recommends RIT for ablation
of remnants in stages III and IV, in most patients with stage II,
and in selected cases of stage I (American Joint Committee on
Cancer).5 ETA defines probable indications for RIT in the
following circumstances: less-than-total thyroidectomy, no
lymph node dissection, age below 18 years, T1 ⬎ 1 cm and
T2N0M0, or more aggressive histology.23 However, RIT is
often performed to enable a more comfortable follow-up and
with the assumption of lower recurrence rates. Even though
the effect of RIT on low-risk patients is discussed controversially, RIT is an effective therapy to eradicate small residual
tumors and metastases of DTC, which already occur in microcarcinomas. Thus, RIT should be indicated routinely with
only few exceptions.
RIT activities are usually determined empirically and given
as a single administration of 1.11 GBq (30 mCi) to 5.5 GBq
(150 mCi). Up to now the most appropriate dose cannot be
derived from evidence-based data.24,31 In children and adolescents, activities are set in consideration of body weight,
body surface, age, or 24-h thyroid bed uptake of an 131I test
activity.32 An alternative to fixed activities is an individualized activity based on pretherapeutic remnant- and lesionbased or bone marrow dosimetry. For this, the EANM
Dosimetry Committee recently published a standard operation procedure. Generally, accepted, absorbed tumor
Developments in therapy of differentiated thyroid cancer
147
doses should exceed 80 Gy and absorbed dose to blood
should be below 2 Gy.33,34
Radioiodine Treatment of
Persistent or Recurrent Disease
In potentially curable patients with persistent or recurrent
disease of DTC, surgical treatment is mostly considered at
first. Radioiodine therapy (RIT) has proved to be an effective
alternative or adjuvant therapy option for tumor eradication,
deceleration of disease progress, or palliation of symptoms.35
The benefit of RIT is crucially dependent on factors such as
radioiodine avidity of the tumor cells, tumor localization,
histology, patient age, and individual health state.24,35 According to EANM guidelines, nonresectable lymph node metastases, pulmonary micrometastases, nonresectable or incompletely operable macrometastases of the lungs, and
nonresectable soft-tissue metastases are definitive indications
for RIT. Further, optional fields of application are recurrent
radioiodine-positive lymph node and distant metastases (adjuvant role), nonresectable small and/or multiple lymph
node metastases, inoperable bone metastases, known or assumed metastases with unknown radioiodine avidity, and
anaplastic or poorly differentiated thyroid cancer with relevant well-differentiated parts and thyroglobulin (Tg) expression, respectively.24 In locoregional relapse and tumor infiltration of the upper airways, adjuvant RIT is performed after
surgery in case of residual tumor tissue—if necessary, in
combination with EBRT. RIT for lung metastases, mostly
with empirically determined 131I activities between 3.7 GBq
(100 mCi) and 11.1 GBq (300 mCi), can be repeated as often
as there is objective therapy response or until complete remission (CR) or serious side effects such as lung fibrosis
occur.5 Overall, if only lung metastases exist—particularly if
they are small and radioiodine-positive—the prognosis is favorable and better than in any other malignant disease with
lung metastases (Fig. 1).36 Therapy management of bone
metastases is influenced by localization, fracture risk, pain,
and radioiodine avidity. Inoperable bone metastases are
treated with EBRT, RIT, intra-arterial embolization, radiofrequency ablation, bone-seeking radiopharmaceuticals,
and bisphosphonates. RIT of 131I storing bone metastases
with most often fixed 131I activities between 5.5 GBq (150
mCi) and 11.1 GBq (300 mCi) is associated with improved
overall survival, even though CR is rarely achieved. In fracture risk and risk of neurological complications, RIT or EBRT
are frequently conducted under medication with corticosteroids to minimize TSH-induced and/or radiation-associated
tumor growth or swelling.37,38 Irrespective of radioiodine
avidity, preferred treatment options for brain metastases are
the complete surgical resection and EBRT.39 Radioiodine can
also be administered in radioiodine-scan-negative cases, supposing only microscopic sites of radiopharmaceutical uptake,
justified by post-therapeutic thyroglobulin decrease.40
The adequate method to determine the 131I activities
remains unclear. Which method, empirically or on the
basis of blood/whole-body dosimetry or tumor dosimetry,
is superior to the others, cannot be assessed conclusively
Figure 1 Case of a 15-year-old female patient with advanced papillary thyroid carcinoma (T3N1bM1). Initially, thyroidectomy and
bilateral selective neck dissection were performed, followed by 2
radioiodine administrations. Computed tomography of the lungs
before RIT (A) with 1 pulmonary nodule visible on this slice (white
arrow). Anterior views of post-therapeutic whole-body scintigraphies (WBS) after the first (B) and second (C) radioiodine administration demonstrate CR of the multiple iodine-positive lung metastases. Additionally, skin contaminations can be observed in both
WBS images.
at present. Taking 200 cGy or rad as a basis for a maximum
tolerable doses of the blood/red bone marrow, empirically
set 131I activities between 3.7 GBq (100 mCi) and 11.1
GBq (300 mCi) led to an exceeding of the maximum tolerable doses in up to 22%. By contrast, most patients could
have been treated with higher 131I activities.41 Apart from
148
higher 131I activities, an increase of the tumor dose (about
the 2.3-fold) can be achieved by pharmacotherapy with
lithium. Intake of lithium results in higher 131I retention in
normal thyrocytes and thyroid carcinoma cells. As there
are no trials, which have analyzed the outcome after lithium therapy, a strong recommendation for or against the
use of lithium is not yet possible.42
Extended Fields of
Application for rhTSH
In the USA as well as in Europe, rhTSH was first licensed for
the stimulated Tg measurement with or without radioiodine
imaging and proved its value in the follow-up of DTC for
years.43 Later on, rhTSH was approved for the postoperative
radioiodine ablation in DTC (Europe 2005, USA 2007). Its
use in children and adolescents is not established yet. Several
trials demonstrated comparable radioiodine ablation rates
after administering rhTSH or after withdrawal of thyroid hormone (WTH), but quality of life was higher after use of
rhTSH. In an international randomized controlled trial ablation rates were 100% for both groups by the criterion of
visible 131I uptake in the thyroid bed (3.7 GBq (100 mCi)).
Following rhTSH application, 131I blood dose was one-third
lower compared to WTH. Interestingly, patients treated with
rhTSH had a longer effective radioisotope half-time within
the remnant thyroid tissue.44-47 Retrospective data analysis of
patients with DTC, who recieved postoperative RIT after either rhTSH injection or WTH, revealed similar recurrence
rates after a median follow-up period of 2.5 years.48 The
questions of adequate 131I activity for ablative RIT, 1.1 GBq
(30 mCi), 1.85 GBq (50 mCi) or 3.7 GBq (100 mCi), and of
comparable therapeutic effectivity in high-risk and low-risk
patients are still controversially discussed. A recent multicenter study demonstrated that 1.85 and 3.7 GBq 131I leads to
similar ablation rates. Seventy-two patients were randomly
assigned to receive one of these activities after rhTSH administration. In each group, 88.9% of patients had no visible 131I
uptake in the diagnostic WBS 6-8 months later.49,50
The benefit of rhTSH for RIT of persistent or metastatic disease has not been proven in prospective randomized controlled
trials yet, even though several groups have dealt with this issue.
Current data are still insufficient to recommend rhTSH for routine use in RIT of these patients. In certain patient collectives
such as those with hypopituitarism and relevant comorbidities,
in which hypothyroidism after WTH would mean an increased
risk to the patient, TSH stimulation by rhTSH is reasonable and
justifiable.49,51 In a retrospective study, Robbins et al52 showed
that in 112 patients, who could not elevate endogenous thyrotropin or be withdrawn from thyroxine, TSH levels above 25
mU/mL could be achieved. Earlier experienced hypothyroid
complications occurred less frequently. Further potential indications for rhTSH mainly regard diagnostic procedures such as
the 18F-fluorodeoxyglucose-positron emission tomography for
increasing sensitivity.46
M. Middendorp and F. Grünwald
External Beam Radiation Therapy
EBRT plays an adjuvant role in certain patients. For adequate
patient selection, tumor histology, 131I WBS, and 18F-fluorodeoxyglucose-positron emission tomography have to be considered. Generally, accepted indications for EBRT are gross
residual tumor masses, which cannot effectively be eradicated by surgery or RIT, older patients with microscopic
residual tumor after radical resection with high-risk of recurrence and assumed low response to RIT, inoperable and radioiodine-negative relapse, inoperable brain metastases, and
painful bone metastases with or without risk of neurological
complications or fracture. In TNM stages pT1-3 N0M0 no
advantage may be expected after EBRT. In nodal-positive
patients and unfavorable prognostic factors such as poor differentiation, adjuvant EBRT can be indicated in particular
cases without the proof of benefit in study literature. The use
of EBRT in TNM stages pT4pN0/1/x M0 R0 is debatable with
apparently low acceptance for this purpose.5,23,53-55 Schwartz
et al56 presented retrospectively collected data of 131 patients
with locally advanced DTC, partly with gross residual partly
with microscopic tumor disease, who were treated with conformal EBRT or intensity-modulated radiotherapy. Four
years after receiving a median dose of, 60 Gy (range 38-72
Gy) local relapse-free survival was 79%, disease free survival
76%, and overall survival 73%. The use of intensity-modulated radiotherapy (44%) compared to conformal EBRT was
not associated with improved survival but with less frequent
severe late morbidity (12% vs. 2%).
Thyrotropin-Suppressive Therapy
As shown in extensive preclinical and clinical studies, DTC
cells express the TSH receptor on the cell membrane and
react to TSH stimulation with production of specific proteins
and cell proliferation. In addition, a direct triiodothyronine
mediated stimulating effect on cellular growth is discussed.
Herefrom derives the rationale for TSH-suppressive therapy
as a therapeutic strategy of DTC. However, for low-risk patients no benefit in the outcome has been proven hitherto.
Furthermore, TSH-independent proliferation of poorly DTC
is hardly slowed down hereby.57-59 The indication for longterm TSH suppression should be evaluated critically, especially considering the negative impact on bone metabolism,
for example, the increased risk of osteoporosis in postmenopausal women, and potential adverse cardiac events.60,61 Recommendations on adequate risk-adapted TSH ranges remarkably vary between the guidelines and authors. By the
time of CR, ETA suggests TSH suppression irrespective of the
risk stratification, whereas ATA recommends a TSH range of
0.1-0.5 mU/L for low-risk patients and a TSH lower than 0.1
mU/L for high-risk patients and those with persistent disease.
After achievement of CR, ETA and ATA approve TSH values
of 0.5-1.0 mU/L and 0.3-2.0 mU/L, respectively, for low-risk
patients. In the high-risk-group, ETA guidelines schedule the
continuation of TSH suppression for 3-5 years and the ATA
guidelines TSH values between 0.1 and 0.5 mU/L for 5-10
years.5,23 There are several other recommendations with
Developments in therapy of differentiated thyroid cancer
varying TSH ranges, for example, those published by Tuttle
et al62 suggesting a general TSH range of 0.1-0.4 mU/L, except for high-risk patients (⬍ 0.1 mU/L) and for the verylow-risk group (⬍ 1.0 mU/L). Finally, risk stratification has
to be regarded as a dynamic process, which affects the extent
of thyroxine therapy.
Options in Inoperable
Radioiodine-Negative DTC
In particular, in the management of advanced and radioiodine-negative DTC, which may not be treatable with surgery,
RIT, or EBRT, numerous novel therapeutic approaches have
developed in the last decade. The spectrum includes the redifferentiation of thyroid carcinoma tissue, the inhibition of
cell signaling, for example, the mitogen-activated protein kinase pathway, and of angiogenesis, gene therapy, and chemotherapy.
Chemotherapy and Redifferentiation of DTC
In chemotherapy of advanced and radioiodine-negative
DTC, doxorubicin is mostly the substance of choice for
monotherapy or in combination with other cytotoxic pharmaceuticals. The combination has not yet shown a benefit
over monotherapy. Response rates are usually much below
40% with a time to progression of only a few months. Comparably, promising results with a response rate of 37% and a
median overall survival of 21 months from the beginning of
chemotherapy were achieved by a combination of epirubicin
and carboplatinum under TSH stimulation. To what extent
TSH elevation influenced the chemotherapy effect, has to be
investigated in further studies.63 Chemotherapy of DTC is
generally recommended in progressive disease (PD) after exhausting all surgical treatment options, RIT, and EBRT as
well as considering available novel therapies within trials.5,64-66
Many groups have dealt with inducing radioiodine uptake
in radioiodine-negative DTC. For this, glitazones and retinoid derivates are used. In the latter, signals are transduced by
specific nuclear receptors, the retinoid-X receptors, which
act as transcription factors modulating the activity of retinoic
acid-responsive genes.67 After intake of 13-cis-retinoic acid
(1.5 mg/kg body weight) for 6 weeks, Simon et al68 attained a
moderate or intensive radioiodine uptake in 23 of 50 patients
with PTC, FTC, or Hürthle cell tumors and with afore predominantly negative posttherapeutic 131I WBS. In addition to
an indirect antitumor effect by increased radioiodine uptake,
a direct antiproliferative effect is discussed. With regard to
radioiodine uptake and tumor diameter, objective therapy
response was seen in 10 of 50 patients (20%), stable disease
(SD) in 9 of 50 (18%), and PD in 31 of 50 (62%) patients. In
a small series of 11 patients69 with progressive, metastatic
PTC and FTC increasing 131I uptake was visible in only 2
cases after 8 weeks of medication with 13-cis-retinoic acid.
Authors concluded that redifferentiation therapy has no
benefit in aggressive advanced PTC and FTC. Preliminary
data with comparable results exist for redifferentiation
149
mediated by all-trans-retinoic acid.70 Another study dealt
with the induction of radioiodine uptake by a peroxisome
proliferator-activated receptor-gamma (PPAR-␥) agonist.
Taking rosiglitazone for 6 weeks (8 mg/d), new tumorassociated 131I storage was detected by posttherapeutic
and/or diagnostic 131I WBS in 6 of 23 patients (26%) with
elevated thyroglobulin (⬎ 10 ng/ml). Five of these showed
intense immunohistochemical staining for PPAR-␥.71
Inhibition of Cellular
Signaling and Angiogenesis
In the development of PTC rearrangements of the rearranged
during transfection (RET) oncogene (approximately 30%)
and v-raf murine sarcoma viral oncogene homolog B1
(BRAF) point mutations (approximately 40%) are particularly
involved. In contrast, genetic alterations of FTC are primarily
made up of PAX8-PPAR␥ translocations (25%-60%) and RAS
mutations (40%-50%).72 Further, abnormalities of DTC cells
regard the overexpression of tyrosine kinase receptors, including those for the vascular endothelial growth factor
(VEGF), the epidermal growth factor (EGF), and the insulin
growth factor-1. The basis for molecular targeted therapy of
the DTC is the inhibition of the mitogen-activated protein
kinase and as well the phosphatidylinositol 3-kinase (PI3K)
pathway, and of angiogenesis by kinase inhibitors, monoclonal antibodies, antisense oligonucleotides, and the farnesyl
transferase inhibitor. Small-molecule kinase inhibitors can be
divided in those, which interfere with the adenosine triphosphate-binding domain, from those, which have targets outside this area, for example, at the substrate- or ligand-binding
domain. Such therapies are only reasonable for subgroup of
tumors, which highly express the corresponding target.
Thus, pretherapeutic immunohistochemical screening of the
specific target will become more and more important. It
should be expected that therapy considering several molecular targets and combination with other treatment options
will increase response rates.73,74
Following phase II trials exemplarily represent the molecular targeted therapy of the advanced, inoperable, and radioiodine-negative thyroid carcinoma, mainly PTC and FTC.
The first study examined the outcome after therapy with the
multikinase inhibitor sorafenib (molecular targets: BRAF, vraf-1 murine leukemia viral oncogene homolog 1 [CRAF],
vascular endothelial growth factor receptor [VEGFR], RET,
and platelet-derived growth factor receptor [PDGFR]) in 30
patients (27 with PTC and FTC), of whom 25 were evaluable.
Comprising all histologies, partial response (PR) was
achieved in 23% of patients (7/30), SD in 53% of patients
(16/30), and PD occurred in 7% of patients (2/30). Median
progression free survival (PFS) was 84 weeks for PTC and FTC.
There were only grade 1 and 2 adverse events. In one case liver
failure resulted in death. Significantly improved overall response rate and PFS were shown compared to chemotherapy.75
Sherman et al76 treated 93 patients with thyroid cancer (82
analyzable) with the multikinase inhibitor motesanib diphosphate (molecular targets: VEGFR, PDGFR, and cellular homolog of the feline sarcoma viral oncogene v-kit [C-KIT])
M. Middendorp and F. Grünwald
150
and demonstrated the following results: PR in 13 of 93 patients (14%), SD in 62 of 93 (67%), and PD in 7 of 93 (8%)
cases. Stable disease outlasted 24 weeks in 33 of 93 patients
(35%). The estimated PFS was 40 weeks. In a third study on
60 patients (36 with PTC and FTC evaluable) treated with the
selective VEGFR inhibitor axitinib, PR was observed in 30%
(18/60), SD in 38% (23/60), PD in 7% (4/60)—the median
PFS was 18.1 months.77 Pennell et al78 evaluated the therapy
effect of the EGFR inhibitor gefitinib in 27 patients with
thyroid cancer, 17 of them with PTC and FTC (63%). Neither
CR nor PR was observed. The rates for SD after 3, 6, and 12
months were 48%, 24%, and 12%, respectively, for all histologies. For DTC, a median PFS of 3.9 months and an overall
survival of 27.4 months were determined.
Gene Therapy
Another future treatment option is gene therapy, which can
be summarized in corrective (eg, p53 restoration), cytoreductive (eg, sodium-iodide symporter [NIS] gene transfer
followed by 131I therapy), and immunomodulatory gene therapies (eg, IL-2 and IL-12 gene transfer). Especially NIS gene
therapy proved as a promising approach in preclinical studies. However, due to lack of integration into thyroid hormone
synthesis, NIS gene transfer led to an only temporarily increased radioiodine uptake of infected tumor cells (in vitro),
and xenografted tumors (in vivo) with consequently low tumor dose due to a short residence time despite initial high
uptake values. Up to now one major problem has been the
inefficiency and lack of safety of the available vector systems,
limited by factors such as a high first-pass effect in the liver,
neutralization by host immunity, and low infectivity. In the
future, replication-selective viral vectors and biodegradable
polymers could be suitable vector systems. Existing data reveal that gene therapy will only be used in a multimodality
treatment approach for the foreseeable future.73,79
Other Treatment Options
Medication or targeted radiotherapy with somatostatin analogues are other potential treatment options. Intramuscular injection of long-acting octreotide for 6 months in 8 patients with
progressive, advanced, and radioiodine-negative but somatostatin receptor-positive thyroid cancer did not result in any objective therapy response, neither PR nor SD.80 For peptide receptor
radionuclide therapy (PRRT) of radioiodine-negative DTC there
are numerous studies with small case numbers, which have
been summarized by Teunissen et al81 in this review objective
therapy response was reported in 5 of 62 of patients (8%) and
SD in 42% with a time to progression of less than 12 months
(not available for all patients). In particular, for the often somatostatin receptor-overexpressing Hürthle cell tumors, PRRT is
an option that has to be evaluated in prospective trials. However,
treatment effect seems to be worse in DTC compared to gastroenteropancreatic neuroendocrine tumors. In a monocenter trial
on yttrium-90 DOTA-TOC ((DOTA(0)-Phe(1)-Tyr(3))octreotid)
therapy in 24 patients with radioiodine-negative DTC, 7 patients
had a decrease in thyroglobulin of 48.9% (range, 0.3%-54.5%)
and 17 had an increase of 36.8% (range, 2.6%-4912.8%). Me-
dian overall survival from the beginning of PRRT was 42.4
months for responders and 13.7 months for nonresponders.82
Cyclo-oxygenase 2 is often overexpressed in malignant tumors as in DTC. In a prospective phase II trial, treatment of
progressive metastatic DTC with the selective Cyclo-oxygenase 2 inhibitor celecoxib resulted in an objective response in
only 1 of 32 patients (3%). Applying RECIST criteria, 12 of
32 cases achieved an SD. Twenty-three of 32 patients (38%)
stopped participation in this study due to PD or toxicity.
Thus, Mrozek et al83 assessed that celecoxib has no benefit in
most patients with advanced DTC.
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