Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy
Aim - radiopeptide therapy with beta emitter labeled ¹⁷⁷Lu/⁹⁰Y- DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) and more recently also alpha emitting ²¹³Bi-DOTATOC are promising new treatments for neuroendocrine tumors. No early predictors for treatment response have been recognized and tumor-shrinkage a...
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| Zitieren: | Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy / F.L. Giesel, P. Flechsig, T. Kuder, L. Schwartz, S. Wulfert, C. Zechmann, F. Bruchertseifer, U. Haberkorn, C. Kratochwil // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 122-126. — Бібліогр.: 9 назв. — англ. |
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Giesel, F.L. Flechsig P. Kuder T. Schwartz L. Wulfert S. Zechmann C. Bruchertseifer F. Haberkorn U. Kratochwil C. 2019-01-19T16:07:01Z 2019-01-19T16:07:01Z 2013 Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy / F.L. Giesel, P. Flechsig, T. Kuder, L. Schwartz, S. Wulfert, C. Zechmann, F. Bruchertseifer, U. Haberkorn, C. Kratochwil // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 122-126. — Бібліогр.: 9 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145224 Aim - radiopeptide therapy with beta emitter labeled ¹⁷⁷Lu/⁹⁰Y- DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) and more recently also alpha emitting ²¹³Bi-DOTATOC are promising new treatments for neuroendocrine tumors. No early predictors for treatment response have been recognized and tumor-shrinkage after radiation therapy appears slowly. In some solid tumors a decline in tumor perfusion was found predictive of final treatment response but the gold standard multiphase computed tomography (CT) has a high radiation burden. Therefore we evaluated the ability of contrast-enhanced ultrasound (CEUS) to evaluate tumor perfusion as a response criteria. 14 patients with hepatic neuroendocrine tumor (NET) metastases were enrolled in the retrospective study. Eleven patients were treated with beta-emitting ¹⁷⁷Lu/⁹⁰Y-DOTATOC, either intravenous (i.v.) (n = 5) or intra-arterial (i.a.) (n = 6) and three patients received alpha-emitting ²¹³Bi-DOTATOC (i.a.). CEUS and contrast-enhanced CT (CE-CT) were performed before and 3 months after treatment. CE-CT and CEUS presented comparable results in the baseline study and in the assessment of perfusion changes due to the different treatment regimes. A therapy related decrease in tumor perfusion is an early predictor of longterm morphologic response. Conclusion: CEUS is available and radiation free technique which showed comparable results for perfusion and diameter of liver metastases compared to CE-CT. Intensity reduction in an arterial phase CEUS can be seen as a positive sign indicating long term tumor response to treatment. Therefore CEUS may be considered as an imaging modality for monitoring early treatment after focal alpha and beta targeted therapy. Key Words: contrast-enhanced ultrasound, radionuclide therapy, treatment response, DOTATOC PET/CT. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy Article published earlier |
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| title |
Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy |
| spellingShingle |
Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy Giesel, F.L. Flechsig P. Kuder T. Schwartz L. Wulfert S. Zechmann C. Bruchertseifer F. Haberkorn U. Kratochwil C. Original contributions |
| title_short |
Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy |
| title_full |
Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy |
| title_fullStr |
Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy |
| title_full_unstemmed |
Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy |
| title_sort |
contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷lu/⁹⁰y-dotatoc and ²¹³bi-dotatoc radiopeptide therapy |
| author |
Giesel, F.L. Flechsig P. Kuder T. Schwartz L. Wulfert S. Zechmann C. Bruchertseifer F. Haberkorn U. Kratochwil C. |
| author_facet |
Giesel, F.L. Flechsig P. Kuder T. Schwartz L. Wulfert S. Zechmann C. Bruchertseifer F. Haberkorn U. Kratochwil C. |
| topic |
Original contributions |
| topic_facet |
Original contributions |
| publishDate |
2013 |
| language |
English |
| container_title |
Experimental Oncology |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| format |
Article |
| description |
Aim - radiopeptide therapy with beta emitter labeled ¹⁷⁷Lu/⁹⁰Y- DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) and more recently also alpha emitting ²¹³Bi-DOTATOC are promising new treatments for neuroendocrine tumors. No early predictors for treatment response have been recognized and tumor-shrinkage after radiation therapy appears slowly. In some solid tumors a decline in tumor perfusion was found predictive of final treatment response but the gold standard multiphase computed tomography (CT) has a high radiation burden. Therefore we evaluated the ability of contrast-enhanced ultrasound (CEUS) to evaluate tumor perfusion as a response criteria. 14 patients with hepatic neuroendocrine tumor (NET) metastases were enrolled in the retrospective study. Eleven patients were treated with beta-emitting ¹⁷⁷Lu/⁹⁰Y-DOTATOC, either intravenous (i.v.) (n = 5) or intra-arterial (i.a.) (n = 6) and three patients received alpha-emitting ²¹³Bi-DOTATOC (i.a.). CEUS and contrast-enhanced CT (CE-CT) were performed before and 3 months after treatment. CE-CT and CEUS presented comparable results in the baseline study and in the assessment of perfusion changes due to the different treatment regimes. A therapy related decrease in tumor perfusion is an early predictor of longterm morphologic response. Conclusion: CEUS is available and radiation free technique which showed comparable results for perfusion and diameter of liver metastases compared to CE-CT. Intensity reduction in an arterial phase CEUS can be seen as a positive sign indicating long term tumor response to treatment. Therefore CEUS may be considered as an imaging modality for monitoring early treatment after focal alpha and beta targeted therapy. Key Words: contrast-enhanced ultrasound, radionuclide therapy, treatment response, DOTATOC PET/CT.
|
| issn |
1812-9269 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/145224 |
| citation_txt |
Contrast-enhanced ultrasound monitoring of perfusion changes in hepatic neuroendocrine metastases after systemic versus selective arterial ¹⁷⁷Lu/⁹⁰Y-DOTATOC and ²¹³Bi-DOTATOC radiopeptide therapy / F.L. Giesel, P. Flechsig, T. Kuder, L. Schwartz, S. Wulfert, C. Zechmann, F. Bruchertseifer, U. Haberkorn, C. Kratochwil // Experimental Oncology. — 2013. — Т. 35, № 2. — С. 122-126. — Бібліогр.: 9 назв. — англ. |
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122 Experimental Oncology 35, 122–126, 2013 (June)
CONTRAST-ENHANCED ULTRASOUND MONITORING
OF PERFUSION CHANGES IN HEPATIC NEUROENDOCRINE
METASTASES AFTER SYSTEMIC VERSUS SELECTIVE ARTERIAL
177LU/90Y-DOTATOC AND 213BI-DOTATOC RADIOPEPTIDE THERAPY
F.L. Giesel1, 4*, P. Flechsig2, T. Kuder3, L.H. Schwartz4, S. Wulfert1,
C.M. Zechmann1, F. Bruchertseifer5, U. Haberkorn1, C. Kratochwil1
1Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany
2Diagnostic and Interventional Radiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg, Germany
3Department of Medical Physics in Radiology, German Cancer Research Center, INF 280, 60120 Heidelberg,
Germany
4Department of Radiology, Columbia University College of Physicians & Surgeons, NewYork-Presbyterian,
New York, NY 10032, USA
5Institute for Transuranium Elements, European Commission, P.O. Box 2340, 76125 Karlsruhe, Germany
Aim: Radiopeptide therapy with beta emitter labeled 177Lu/90Y- DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) and more recently
also alpha emitting 213Bi-DOTATOC are promising new treatments for neuroendocrine tumors. No early predictors for treatment
response have been recognized and tumor-shrinkage after radiation therapy appears slowly. In some solid tumors a decline in tumor
perfusion was found predictive of final treatment response but the gold standard multiphase computed tomography (CT) has a high
radiation burden. Therefore we evaluated the ability of contrast-enhanced ultrasound (CEUS) to evaluate tumor perfusion as a response
criteria. Materials and Methods: 14 patients with hepatic neuroendocrine tumor (NET) metastases were enrolled in the retrospective
study. Eleven patients were treated with beta-emitting 177Lu/90Y-DOTATOC, either intravenous (i.v.) (n = 5) or intra-arterial (i.a.)
(n = 6) and three patients received alpha-emitting 213Bi-DOTATOC (i.a.). CEUS and contrast-enhanced CT (CE-CT) were performed
before and 3 months after treatment. Results: CE-CT and CEUS presented comparable results in the baseline study and in the assess-
ment of perfusion changes due to the different treatment regimes. A therapy related decrease in tumor perfusion is an early predictor
of longterm morphologic response. Conclusion: CEUS is available and radiation free technique which showed comparable results for
perfusion and diameter of liver metastases compared to CE-CT. Intensity reduction in an arterial phase CEUS can be seen as a pos-
itive sign indicating long term tumor response to treatment. Therefore CEUS may be considered as an imaging modality for monitor-
ing early treatment after focal alpha and beta targeted therapy.
Key Words: contrast-enhanced ultrasound, radionuclide therapy, treatment response, DOTATOC PET/CT.
Liver metastases are often the life-limiting factors for
patients with gastroenteropancreatic neuroendocrine
tumors (GEP-NET). Most GEP-NETs, as well as their liver
metastases are highly vascularised with a dense intra-
mural vascular network [1]. Hence they show the typical
peripheral contrast enhancement in the arterial phase
of contrast-enhanced computed tomography (CE-CT)
and contrast-enhanced ultrasound (CEUS). Moreover,
they demonstrate an increased somatostatin receptor
expression both in primary and metastatic lesions.
Concerning therapeutic and diagnostic options, the
PET tracer DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTA-
TOC), a 68Ga-labelled somatostatin analog, has been
shown to have high sensitivity and specificity for GEP-NET
detection and staging [2]. Treatment with 90Y- or 177Lu-
DOTATOC (beta emitters) is emerging as a potent therapy
in patients with GEP-NETs. Systemic (i.v.) treatment can
induce partial remission in 25–30% of the patients [3].
Tumor uptake of DOTATOC can be enhanced by loco-
regional (i.a.) administration [4]; however, only patients
with limited tumor extent are eligible for this approach.
In comparison to beta emitters, alpha emitters have
a higher linear energy transfer and potentially can induce
tumor necrosis by structural damage of the targeted cell
rather than radiation-induced apoptosis as occurred with
beta irradiation.
Monitoring structural and functional characterisation
of a tumor during therapy is important to tailor individual
Received: April 26, 2013.
*Correspondence: Fax: 0049 (0)6221-565473
E-mail: frederik.giesel@med.uni-heidelberg.de
Abbreviations used: AASLD — American Association for the
Study of Liver metastases; Bi — Bismut; cc — cubic centimetre;
CE-CT — contrast-enhanced computed tomography; CEUS —
contrast-enhanced ultrasound; CT — computed tomography;
DOTATOC — 177Lu/90Y- DOTA(0)-Phe(1)-Tyr(3)-octreotide; DOTA-
TOC PET — DOTATOC positron emission tomography; EANM —
European Association of Nuclear Medicine; EASL — European
Association for the study of the liver; Fig – Figure; Ga – Gallium;
GBq – Gigabecquerel; GEP-NET — gastroenteropancreatis neu-
roendocrine tumors; HU — Hounsfield units; i.a. — intra-arterial;
i.v. – intravenous; IRB – institutional review board; Lu – Lute-
tium; MBq – Megabecquerel; Met – metastasis; MI — mechani-
cal index; mRECIST — modified Response Evaluation Criteria
in Solid Tumors; MRI – magnetic resonance imaging; n – number;
NET — neuroendocrine tumor; Norm – normal liver parenchyma;
OSEM — ordered subset expectation maximisation; PET – positron
emission tomography; PET/CT — positron emission tomography/
computed tomography; Phe – Phenylalanin; PRRT — peptide
guided radioreceptor therapy; ROI — regions of interest; SNM —
Society of Nuclear Medicine; Tyr – Tyrosin; Y – Yttrium.
Exp Oncol 2013
35, 2, 122–126
Experimental Oncology 35, 122–126, 2013 (June)35, 122–126, 2013 (June) (June) 123
patient care and evaluate novel treatment approaches.
Since shrinkage of liver metastases — even with effec-
tive therapy — is rarely observed, modified response
criteria, based on the degree of contrast enhancement,
have been suggested by the American Association for
the Study of Liver diseases (AASLD) and the European
Association for the study of the liver (EASL) (modified
Response Evaluation Criteria in Solid Tumors (mRE-
CIST)). However, multi-phase CE-CT is associated
with high radiation exposure. We investigated the role
of CEUS to detect changes in perfusion as a non-
invasive indicator of therapy response.
MATERIALS AND METHODS
Study design.14 patients with hepatic NET me-
tastases that have been treated with beta-emitting
177Lu/90Y-DOTATOC, either i.v. (n = 5) or i.a. (n = 6)
or alpha-emitting 213Bi-DOTATOC i.a. (n = 3).
According to the Society of Nuclear Medicine (SNM)
and European Association of Nuclear Medicine (EANM)
guideline all patients prior to peptide guided radiorecep-
tor therapy (PRRT) underwent a Somatostatin receptor
(subtype 2 and 5) imaging procedure (68Ga-DOTATOC
or Octreotid-Scan) to elaborate the receptor expression.
Patients who underwent surgery of the primary tumor (for
example pancreatic cancer) and afterwards predomi-
nantly had their tumor load in the liver underwent loco-
regional therapeutic treatment regime (i.a. DOTATOC-
Therapy). In contrast, patients who presented at the first
imaging time point (68Ga-DOTATOC or Ocretotid-Scan)
with an extensive systemic tumor spread underwent the
systemic PRRT approach (i.v. DOTATOC-Therapy).
CEUS and CE-CT were performed as part of our
clinical standard procedures and within the approved
indications before and 3 months after treatment.
A retrospective analysis was done and was approved
by the institutional review board (IRB). Written informed
consent was obtained from all patients. No prospective
experiments with human subjects were performed and
the study was in accordance with the Helsinki Declara-
tion and our national regulations.
Contrast-enhanced ultrasound (CEUS). Prior
to and 3 months after therapy, low-MI CEUS (FR = 19 fps,
mechanical index MI = 0.15; HI VERSION Preirus, Hitachi,
Switzerland) was performed. The examination was car-
ried out with an intermittent breath-holding technique.
One target lesion was identified in each patient by con-
ventional ultrasound. Subsequently, dynamic imaging
of these metastases was performed immediately after
i.v. application of 2.4 cc of the contrast agent SonoVue®
(Bracco S.P.A., Italy) with a duration of two minutes
to monitor early arterial contrast enhancement and late
portal-venous phase. The typical radiological feature
of a liver metastasis of GEP-NETs was arterial phase
hypervascularisation followed by portal-venous wash-
out. Using a self-developed analysis software, regions
Prior to therapy
After therapy
b
a
d
c
Fig. 1. Systemic therapy with 4+4 GBq 90Y-/177Lu-DOTATOC. a, b. CEUS image (a) and corresponding time-intensity curve (b) of a neu-
roendocrine metastasis and normal liver parenchyma before therapy. c, d. CEUS image (c) and corresponding time-intensity curve (d)
of a neuroendocrine metastasis and normal liver parenchyma 3 months after systemic therapy with 4+4 GBq 90Y-/177Lu-DOTATOC. White
arrows indicate metastatic lesion. Undulations in curves are caused by breathing artefacts. An increased uptake in the arterial phase after
therapy (d) was associated with tumor progression in the follow-up. Met — metastasis; Norm — Normal liver parenchyma
124 Experimental Oncology 35, 122–126, 2013 (June)
of interest (ROI) were marked in the liver metastases
and in adjacent normal liver parenchyma, measuring
change in intensity over time. Peak image intensity and
time to peak were recorded for each ROI.
Contrast-enhanced computed tomography (CE-
CT). Prior to and 3 months after therapy, contrast-en-
hanced CT was performed in each patient using a Siemens
Biograph 6 Positron Emission Tomography/Computed
Prior to therapy
After therapy
ba
dc
100
90
80
70
60
50
40
30
10
20
0
Prior to Therapy
Nom Center of met Periphery of met
100
90
80
70
60
50
40
30
10
20
0
After Therapy
Nom Center of met Periphery of met
Fig. 2. Intra-arterial therapy with 4+4 GBq 90Y-/177Lu-DOTATOC. a, b. CEUS (a) and corresponding time-intensity curves (b) of a neu-
roendocrine metastasis and normal liver parenchyma prior to therapy. c, d. CEUS (c) and corresponding time-intensity curves (d)
of a neuroendocrine metastasis and normal liver parenchyma 3 months after i.a. therapy with 4+4 GBq 90Y-/177Lu-DOTATOC. White
arrows indicate metastatic lesion. A decline in tumor contrast enhancement was observed in CEUS (a, c) and equal to multi-phase
CT (b, d) and was associated with tumor shrinkage in the long term follow-up. Met — metastasis; Norm — Normal liver parenchyma.
ca
d f
b
e
Fig. 3. Intra-arterial therapy with 4+2 GBq 90Y-/177Lu DOTATOC. a, b. CEUS (a) and corresponding time-intensity curves (b) of a neu-
roendocrine metastasis and normal liver parenchyma before therapy. d, e. CEUS (d) and corresponding time-intensity curves (e)
of a neuroendocrine metastasis and normal liver parenchyma 3 months after i.a. therapy. c, f. Sequential hybrid imaging of 68Ga-
DOTATOC PET/CT before (c) and after (f) i.a. therapy also confirm CEUS finding. Met — metastasis; Norm — Normal liver parenchyma
Experimental Oncology 35, 122–126, 2013 (June)35, 122–126, 2013 (June) (June) 125
Tomography (PET/CT). A ROI of 40 pixels was marked
in the center and outer rim of each evaluated metastatic
lesion in the arterial phase of the CE-CT. The ratio of inten-
sity of lesions and normal liver parenchyma was recorded
measuring corresponding Hounsfield units (HU).
DOTATOC positron emission tomography (DOTA-
TOC PET). DOTATOC-PET/CT was also performed on the
Biograph 6 (Siemens, Knoxville, USA). Imaging was initi-
ated about 45 min after i.v. injection of 89–189 MBq 68Ga-
DOTATOC. Static emission scans, corrected for dead
time, scatter and decay were acquired from the vertex
to the proximal legs — requiring eight bed positions, 4 min
each. The low-dose CT without contrast agent was used
for attenuation correction. The images were iteratively
reconstructed with the OSEM (ordered subset expecta-
tion maximisation) algorithm using four iterations with
eight subsets and Gaussian filtering to achieve an in-plane
spatial resolution of 5 mm at full-width half-maximum.
RESULTS
Prior to therapeutic intervention, all liver metas-
tases demonstrated marked enhancement on both
CE-CT and CEUS in all three treatment groups.
For the i.v. group (beta radiation) a significant de-
cline of enhancement was observed in 1/5 patients
3 months after intervention. In 3/5 patients no change
in enhancement was seen and in one patient (Fig. 1)
the lesion progressed.
For the i.a. group (beta radiation) 3/6 patients
demonstrated both a decline of tumor vascularity
as assessed with CEUS and of diameter as assessed
with arterial phase CT (Fig. 2) and also a decline
in SSR2 expression in DOTATOC PET imaging (Fig. 3).
For the i.a. group, treated with 213Bi-DOTATOC
(alpha radiation), CEUS and arterial phase CT demon-
strated a decrease of tumor perfusion (Fig. 4).
Regarding contrast intensity in CEUS in the i.a. group
treated with 213Bi-DOTATOC (relative values), metastases
had a 40% higher contrast intensity than normal liver
parenchyma with an early onset of contrast enhance-
ment before treatment (metastatic liver parenchyma set
as 100% with an early onset of contrast enhancement;
intensity in normal liver parenchyma was measured 60%
of metastatic liver parenchyma (Fig. 4 b)) to almost equi-
librium 3 months after therapy (normal liver parenchyma
and metastases reached the same level of intensity while
metastases still showed an earlier contrast enhancement
than normal liver parenchyma (Fig 4 d)). In CE-CT (ab-
solute values), measuring Hounsfield units in peripheral
regions of metastases, i.a. application of 213Bi-DOTATOC
led to a 50% decrease of density values within 3 months
(800 HU before treatment, 400 HU 3 months later (Fig. 4 b,
d). Simultaneously, i.a. application of 213Bi-DOTATOC
did not lead to a significant shrinkage of metastases
within 3 months. Nevertheless, in the longterm follow up
(9 months) none of these lesions progressed.
The absence of intensity reduction in an arterial
phase CEUS can be seen as a negative sign indicating
unresponsiveness to treatment.
ba
dc
100
90
80
70
60
50
40
30
10
20
0
After Therapy
Nom Center of met Periphery of met
100
90
80
70
60
50
40
30
10
20
0
Prior to Therapy
Nom Center of met Periphery of met
Fig. 4. Intra-arterial therapy with 213Bi-DOTATOC. a, b. CEUS (a) and corresponding time-intensity curves (b) of a neuroendocrine
metastasis and normal liver parenchyma before therapy. c, d. CEUS (c) and corresponding time-intensity curves (d) of a neuroen-
docrine metastasis and normal liver parenchyma 3 months after i.a. therapy with 213Bi-DOTATOC. White arrows indicate metastatic
lesion. Positive contrast in arterial and portal venous phase decline after therapy — this was similar in both CEUS and CT. Met —
metastasis; Norm — Normal liver parenchyma
126 Experimental Oncology 35, 122–126, 2013 (June)
DISCUSSION
As described abovem, patients with systemic
tumor manifestations outside the liver underwent the
systemic PRRT approach (i.v. DOTATOC-Therapy).
Patients without tumor manifestations outside the liver
underwent the loco-regional therapeutic treatment
regime (i.a. DOTATOC-Therapy), irrespective of the
size and number of liver metastases, according to the
SNM- and EANM guidelines.
In patients with liver-metastases from GEP-NETs
i.a. treatment with 177Lu/90Y-DOTATOC lead to a sig-
nificant decrease of tumor vascularity and diameter,
compared to treatment with systemic treatment. The
observed response seen with targeted beta radiation
administered either via i.v. or i.a. was in accordance
with prior results. A decline in lesion perfusion cor-
related with tumor shrinkage on arterial phase CT
[5]. In contrast, high energy alpha radiation produced
marked reduction in tumor vascularity with little
or no change in tumor diameter after several months.
Thus, this data suggests that alpha irradiation leads
to early changes in tumor microcirculation, occurring
prior to tumor shrinkage.
Comparing CEUS and CE-CT, results of tumor
perfusion and diameter were equal in both modalities,
regardless of the therapy regimen. One important
point to mention is that the first structural changes
after PRRT are visible about six weeks after therapy
in CEUS and CE-CT. However, morphological changes,
which can be detected with CT and CEUS need at least
a follow up period of 6 months to become visible. This
coincides with findings from evaluations of unclear liver
lesions, where contrast enhanced ultrasound was even
more accurate than multisliced computed tomography
in predicting malignancy and benignity [6]. This applies
especially to lesions in the caudal and ventral parts
of the liver, which can easily be visualized by ultra-
sound. Problems in the evaluation of subdiaphragmatic
lesions are still unchanged, which is a limitation for the
use of ultrasound for follow-up examinations in these
liver segments. Under optimal ultrasound conditions,
when the whole liver can be imaged, CEUS reaches
a diagnostic certainty of > 90% and is as reliable
as contrast-enhanced MRI, and beats CE-CT [7, 8].
Correspondingly high sensitivity rates of CEUS in liver
tumors have been reported in many recent works [9].
A limiting factor of this study is the relatively small
number of 14 patients that has been examined. That
was due to the fact that not all of the patients with liver
metastases of GEP-NETs in our hospital were available
for a comparison of CEUS, CE-CT and DOTATOC-PET/
CT. In each patient we examined no more than one
target lesion due to technical requirements in CEUS.
In summary CEUS is a reliable method to monitor
early changes in metastases even before true volume
shrinkage occurs. After focal alpha targeted therapy
results in CEUS were as valuable as in CE-CT, which
is the common way of examining tumor response.
CEUS is typically available at lower cost and without
additional ionizing radiation compared to CT, and
it is portable. It increases individual patient care and
reduces costs. Therefore, CEUS may be considered
as an additional imaging modality to assess the early
mircovascular tumor environment in follow-up studies
after focal alpha targeted therapy.
CONFLICT OF INTEREST DISCLOSURE
The authors declared no conflicts of interest.
REFERENCES
1. Villaume K, Blanc M, Gouysse G, et al. VEGF secretion
by neuroendocrine tumor cells is inhibited by octreotide and
by inhibitors of the PI3K/AKT/mTOR pathway. Neuroendo-
crinology 2010; 91: 268–78.
2. Ruf J, Heuck F, Schiefer J, et al. Impact of Multiphase
68Ga-DOTATOC-PET/CT on therapy management in pa-
tients with neuroendocrine tumors. Neuroendocrinology 2010;
91: 101–9.
3. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treat-
ment with the radiolabeled somatostatin analog [177Lu-DOTA
0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol
2008; 26: 2124–30.
4. Forner A, Ayuso C, Varela M, et al. Evaluation of tumor
response after locoregional therapies in hepatocellular carci-
noma: are response evaluation criteria in solid tumors reliable?
Cancer 2009; 115: 616–23.
5. Kratochwil C, Lopez-Benitez R, Mier W, et al. Hepatic
arterial infusion enhances DOTATOC radiopeptide therapy
in patients with neuroendocrine liver metastases. Endocr Relat
Cancer 2011; 18: 595–602.
6. Clevert DA, Jung EM, Stock KF, et al. Evaluation
of malignant liver tumors: biphasic MS-CT versus quantita-
tive contrast harmonic imaging ultrasound. Z Gastroenterol
2009; 47: 1195–202.
7. Boozari B, Lotz J, Galanski M, et al. Diagnostic imaging
of liver tumors. Current status. Internist (Berl) 2007; 48: 8–20.
8. Giesel FL, Kratochwil C, Mehndiratta A, et al. Compar-
ison of neuroendocrine tumor detection and characterization
using DOTATOC-PET in correlation with contrast enhanced
CT and delayed contrast enhanced MRI. Eur J Radiol 2012;
81: 2820–5.
9. Celli N, Gaiani S, Piscaglia F, et al. Characterization
of liver lesions by real-time contrast-enhanced ultrasonogra-
phy. Eur J Gastroenterol Hepatol 2007; 19: 3–14.
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