ATOM INDONESIA JOURNAL
Referee’s Report
Article No. : # 910
Title of Paper :
Evaluation of Kidney Dose In Neuro Endocrine Tumours patients
After Peptide Receptor Radionuclide Therapy using
177Lu-DOTATATE
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[X ] Appropriate [ ] Should be changed
2. Abstract
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Yes[ X] No[ ] Is it an appropriate summary of the content?
3. Main Text
Yes[X ] No[ ] Is there anything new in this work?
Yes[X ] No[ ] Is the relation to previous studies adequately stated?
Yes[ X ] No[ ] Are the assumption(s) and/or method(s) described comprehensively?
Yes[X ] No[ ] Are the new results adequately emphasized?
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13
ABSTRACT
Seventeen patients treated with ……? for metastatic (not clear sentence) administration of ~7.8 GBq of 177Lu-DOTATATE . ( remove space before full stop)
To conclude, estimated radiation dose to the kidneys for PRRT…
Change with
From this study, it can be concluded that estimate……
96
…considered as ideal…..
Change to
…considered as an ideal…..
234
The result of kidney dose from OLINDA/EXM then was investigated between CHANGE TO
The result of kidney dose from OLINDA/EXM was then investigated between
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Evaluation of Kidney Dose In Neuro Endocrine
1
Tumours patients after Peptide Receptor
2
Radionuclide Therapy using 177 Lu-DOTATATE
3 4 5 6 7 8 9 10 11
A R T I C L E I N F O A B S T R A C T 12 13
AIJ use only:
Received date Revised date Accepted date Keywords:
Neuro Endocrine Tumors Kidney radiation dose [Lu-177]-DOTATATE
...
Radiation dose to the kidneys (kidney dose) in 177Lu-DOTATATE - Peptide Receptor Radionuclide Therapy (PRRT) is considered to be the main potential side- effect from the treatment. Prospective assessment of kidney radiation dose can be made with SPECT, however, this requires an intensive imaging regime over a number of days. For this reason, a retrospective investigation of kidney uptake using quantitative SPECT was performed. The aim of the study was to compare the estimated radiation dose to kidneys for each cycle, Seventeen patients treated with for metastatic neuro-endocrine tumours had full imaging for each of their treatment cycles on a Siemens Intevo SPECT/CT gamma camera. One course of treatment consisted of 3 or 4 cycles approximately 8 weeks apart spanning 6 months.
SPECT/CT scans of the abdomen were acquired at 3 time points (4, 24 and 96-120 hours) after administration of ~7.8 GBq of 177Lu-DOTATATE . Nine patients received three cycles in total and eight patients had four cycles. Volumes of interest (VOIs) were defined on a CT scan co-registered with the SPECT images and repeated over all time points, to give the radioactivity in the kidneys. Whole organ dosimetry was estimated using OLINDA/EXM using an exponential clearance model. This gives an estimate of radiation absorbed dose to kidneys (Gy/GBq) for each treatment cycle. The mean of the 3 or 4 cycles and variation can then be determined. The result shows that the average kidney radiation dose was 0.23 Gy/GBq (range: 0.06 – 0.42) and average variation between cycles for all subjects expressed as a percentage was (12.5±7.8)% (median: 11.4%, range: 1.8% – 29.4%).
To conclude, estimated radiation dose to the kidneys for PRRT shows good reproducibility (typically <20% variation) within an individual across all cycles within one course of treatment (up to 4 cycles). The errors introduced by assuming that the dosimetry estimate per unit GBq administered from the initial cycle could be used for subsequent cycles within a course are unlikely to contribute significantly to the overall estimate of radiation burden and are considered to be safe.
INTRODUCTION
14 15
Neuroendocrine tumours (NETs) are
16
heterogeneous neoplasms which are hormonally
17
active with variable natural history and prognosis.
18
These tumors are characterized by their endocrine
19
metabolism, histological pattern, and the presence
20
of secretory granules as well as the ability to
21
produce biogenic amines and polypeptide
22
hormones and originating in the small intestine or
23
in the pancreas, which are often metastatic at
24
the time of initial diagnosis [1-4]. The
25
number of NETs incidence has been reported
26
increasing in the US
27
Corresponding author.
E-mail address:
28
was 1.09 per 100,000 persons in 1973 and
29
increased to 6.98 per 100,000 persons by 2012 [5].
30
NET incidence also has been reported as a global
31
burden for worldwide cancer incidence [6] which
32
has increased over the past two decades, with the
33
lungs, pancreas, small intestine, rectum, small
34
bowel and colon as the primary sites. Figure 1
35
presents the statistic of NET incidence for last five
36
decades in the US. From the figure, the number of
37
NETs incidence has impeded the incidence of all
38
malignant neoplasms in the US in the end of 2012.
39 40
Atom Indonesia
41
Figure 1. The statistic of NET incidences in the
42
US from 1973 to 2102 [5]
43 44
In 1993, the Erasmus MC hospital in
45
Rotterdam has successfully treated the NET
46
patients with Peptide Receptor Radionuclide
47
Therapy (PRRT) for the first time [7]. Since then,
48
PRRT have been used for treating NET patients.
49
Despite the benefit of PRRT, there were
50
preclinical studies which have shown that kidneys
51
are the main potential side-effect from PRRT [8-
52
9]. Moreover, some clinical studies have reported
53
the similar finding of the effect of PRRT on
54
kidneys [10- 14]
55
To evaluate the effect of PRRT on kidneys,
56
prospective assessment of kidneys can be made
57
with gamma camera and hybrid imaging system
58
such as Single Photon Emission Computed
59
Tomography (SPECT or SPECT/CT) method [15-
60
16]. However this requires an intensive imaging
61
regime over a number of days.
62
For this reason, a retrospective investigation
63
of kidney uptake using quantitative SPECT was
64
performed for evaluating the kidney radiation dose
65
on NET patients who have been treated with
66
177Lu-DOTATATE for 3-4 cycles. The aim of
67
study was to compare the estimated radiation dose
68
to kidneys for each cycles and evaluating the dose
69
during the treatment, so that the kidney dose for
70
next cycles can be predicted and reduce the scan
71
timing.
72 73
PEPTIDE RECEPTOR RADIONUCLIDE
74
THERAPY (PRRT)
75 76
Peptide receptor radionuclide therapy
77
(PRRT) is a targeted radionuclide therapy which
78
specifically uses radiolabeled peptides as
79
biological targeting agent designed to deliver
80
cytotoxic levels of radiation dose to cancer cells.
81
Some radionuclides have been identified as useful
82
for the therapy, such as : 111In, 90Y, 177Lu, 67Cu,
83
47Sc, 161Yb, 225Ac, and 213Bi [17]
84
177Lu emits β electrons with linear energy
85
transfer values of about 0.2 keV/μm, and have a
86
range in tissue of several milimetre. 177Lu decays
87
with a half-life of 6.71 d by emission of β−
88
particles with Emax of 497 keV (78.6%), 384 keV
89
(9.1%) and 176 keV (12.2%) to stable 177Hf. For
90
this reason, 177Lu is the most widely used
91
radioisotope for being used in in-vivo procedures
92
and targeted radionuclide therapy, because of its
93
favorable decay characteristics [18,19].
94
The characteristic of 177Lu penetration has
95
been considered as ideal tools for delivering
96
energy to small volumes and lesion. From the
97
production and labelling aspects, 177Lu has a good
98
possibility to be labelled with peptide and protein
99
radiolabeling of antibodies that have slow
100
targeting kinetics. Moreover, the physical half-life
101
of 177Lu may provide extended time for logistical
102
arrangement from the reactor production to the
103
imaging/therapy facilities [20]. 177Lu-
104
DOTATATE has been considered has better
105
residence time than 177Lu-DOTATATOC
106
[DOTA0, Tyr3]octreotide. Moreover, it has higher
107
ratio of absorbed dose between target (tumors) and
108
non targets, especially for dose limiting organ
109
[15].
110 111
KIDNEY DOSE
112 113
Dosimetry Assessment for Radionuclide
114
Therapy has been a raising concern, especially in
115
PRRT in which the kidneys have been identified
116
as the primary critical organ. This concern is
117
caused by the fact that small peptides are filtered
118
through the glomerular capillaries and are
119
reabsorbed by the proximal tubular cells [21].
120
Since the limiting dose for PRRT has not been
121
standardized, most protocols in radiotherapy have
122
adopted the limiting dose for kidneys from
123
external beam radiation herapy at about 30 Gray
124
(or below) [22-25]. The limiting dose was
125
addressed for protecting the kidneys from the
126
failure due to excessive radiation, called as
127
radiation nephrotoxicity. For this reason, an
128
evaluation of uptake in kidneys need to be
129
performed to optimize the radiation protection to
130
patients in PRRT [26].
131 132
EXPERIMENTAL METHOD
133
The work in this study was carried out in
134
Department of Nuclear Medicine , Royal North
135
Hospital Sydney, Australia. The methodology for
136
performing the work was following the method
137
which has been described in previous study by
138
Bailey D.L, et al [27]
139
The investigation was performed for
140
consecutive studies of 17 patients with metastatic
141
neuro-endocrine tumours (8 male, 9 female) who
142
underwent PRRT with 177Lu-DOTATATE. The
143
PRRT was performed by standard protocol with
144
administration of a mean activity of 7.76±0.36
145
GBq (209±9.1 mCi) 177Lu-octreotate per treatment
146
cycle. One course of treatment consisted of 3 or 4
147
cycles approximately 8 weeks apart spanning 6
148
month.
149
The 177Lu that has been used in this work
150
was produced in a nuclear reactor by an (n, γ)
151
reaction (ITG, Isotope Technologies Garching
152
GmbH, Germany and the Australian Nuclear
153
Science and Technology Organisation (ANSTO),
154
Australia). The 177Lu-octreotate is referred to
155
DOTATATE (DOTA0-(Tyr3)-octreotate where
156
DOTA = 1,4,7,10-tetra-azacyclododecane–
157
1,4,7,10- tetraacetic acid) (Auspep, Melbourne,
158
Australia. During the administration of 177Lu-
159
DOTATATE, patients were accompanied by a 3-h
160
amino acid infusion in order to provide protection
161
for the kidneys from radiation.
162
The image acquisition was performed
163
using Siemens Intevo SPECT/CT gamma camera
164
at 3 time points (4, 24 and 96-120 hours) after
165
administration. The images were analysed using
166
in-house developed software using a high-level
167
scientific programming language (IDL, Exelis
168
Visual Information Solutions, Herndon, VA, USA)
169
on a dedicated nuclear medicine workstation
170
(HERMES, Nuclear Diagnostics, Stockholm,
171
Sweden). The Volumes of interest (VOIs) were
172
defined on a CT scan co-registered with the
173
SPECT images and repeated over all time points,
174
to acquire the uptake of 177Lu-DOTATATE in the
175
kidneys.
176
To perform whole organ dosimetry,
177
OLINDA/EXM ver.1 was used by performing
178
biexponential clearance model. OLINDA/EXM is
179
the software which has been approved by US FDA
180
as a tool for internal dosimetry assessment in
181
nuclear medicine [28]. The result of
182
OLINDA/EXM is in the unit of absorbed dose of
183
organ per administered activity (mSv/MBq) or
184
rem/mCi. Hence in this study, the absorbed dose
185
of kidneys for each treatment is given for each
186
treatment cycle. The mean of the 3 or 4 cycles and
187
variation can then be determined.
188 189
RESULTS AND DISCUSSION
190 191
In this study, the evaluation process has
192
been started with acquiring serial scans for 4, 24
193
and 96-120 hours after the administration of 177Lu-
194
DOTATATE. In each time points, the kidneys
195
have been delineated as VOI using the HERMES
196
Workstation, and registering the VOI with CT
197
images. In this step, the VOI of kidneys is
198
presenting as functional (physiological) data,
199
which needs to be registered into CT images. The
200
HERMES work station makes it is possible to
201
combine both functional and anatomical data into
202
quantitative value which are useful for
203
investigating the organ dose in PRRT.
204
Figure 1 has showing the screen shoot of
205
images from HERMES workstation, in which the
206
VOI of kidneys and its registration has been
207
performes as 3D quantification imaging. The result
208
of quantification in this step is the percentage of
209
uptake of 177Lu-DOTATATE in kidneys to be used
210
as the input into OLINDA/EXM.
211 212
213
Figure 1. The screen shoot of HERMES
214
workstation for 177Lu-DOTATATE patients.
215 216
To utilize OLINDA/EXM as a tool for
217
internal dosimetry calculation, it is important that
218
the data consist of at least 3 time points. For this
219
reason, there were some patients data which are
220
excluded from the study, since it has only 2 time
221
points. By using the fitting menu and using the
222
biexponential function, the residence time 177Lu-
223
DOTATATE in the kidneys and the kidney dose
224
for seventeen patients who underwent 3-4
225
treatment cycles has been obtained. Figure 2 has
226
shown the sample screen of OLINDA/EXM in
227
fitting menu.
228 229
230
Figure 2. Sample screen from OLINDA/EXM
231
code, fitting data for 177Lu
232
Atom Indonesia
233
The result of kidney dose from
234
OLINDA/EXM then was investigated between
235
cycles and calculated statistically. From the
236
kidney dose variation in Table 1, this study has
237
shown that the variation of kidney dose for
238
seventeen patients who undergo therapy , with
239
the average kidney dose about 0.23 Gy/Bq, and the
240
average variation between cycles for all subjects
241
expressed as a percentage was (12.5±7.8)%
242
(median: 11.4%, range: 1.8% – 29.4%). This
243
means, compared to the number of limiting dose
244
for kidneys in external beam radiation therapy
245
[22], the kidney dose for the patients who undergo
246
3-4 cycles of therapy, are shown in good
247
reproducibility, safe and the dose for next cycles
248
can be predicted.
249 250
Table 1. Variation of kidney dose of NET patients
251
with 177Lu DOTATATE between cycles
252
253
At the moment, there is no standardized
254
model for individualized patient dosimetry, while
255
the evidence is increasing. Performing an
256
individualized patient dosimetry (personalized
257
dosimetry) has been considered to improve the
258
efficacy of therapy and spare the health tissue [29].
259
Recently, the European Association of Nuclear
260
Medicine (EANM), has published internal
261
dosimetry task report and stated that dosimetry-
262
based treatment planning for radionuclide therapy
263
is a mandatory to improve the effectiveness of the
264
radionuclide therapy by predicting the response
265
and toxicity [30]. Beside useful as a treatment
266
planning, there is evidence that dosimetry also can
267
be useful for evaluation of therapy [32]. Likewise,
268
the evaluation kidney dose in this study is a
269
sample how the dosimetry study in PRRT can be
270
performed after the therapy.
271
Since the kidneys are the critical organs as
272
the target of evaluation, for further similar studies,
273
the information of kidney data would be better if
274
the
glomerular filtration rate
(GFR) value of the275
kidneys can be contributed to support the data
276
analysis for the patients, as it has been done in a
277
similar study in which the grading of kidneys has
278
been divided as chronic and acute kidneys with
279
GFR as supporting information [33]. This
280
additional data might be helpful if there are any
281
discrepancies of the data for preparing the
282
investigation of kidneys for next cycles.
283
The utilization of 177Lu-DOTATATE in
284
PRRT for NET patients has been performed
285
worldwide, and the trend seems increasing, while
286
in Indonesia, the data of NET patients who
287
undergo PRRT is hardly to be found. Most of
288
radionuclide therapy in Indonesia was performed
289
for radioiodine therapy [32]. This might be related
290
to the limited availability of 177Lu-DOTATATE
291
for PRRT in Indonesia and not locally provided.
292
Moreover, dosimetry study for
293
radionuclide therapy patients in Indonesia has not
294
been performed yet, while in some countries,
295
dosimetry study has been suggested to be
296
conducted as a tool for implementing radiation
297
protection of patients who undergo radionuclide
298
therapy [33-34]. Hence, this study is important for
299
showing that dosimetry study in PRRT has been
300
performed worldwide because it can improve the
301
efficacy of therapy and protecting critical organs.
302
Moreover, by showing the good reproducibility of
303
kidney doses after the therapy, it will present that
304
the radiation burden in PRRT are considered to be
305
safe. This study may, therefore become a starting
306
point to the urgency of the initialization of
307
dosimetry study for NET patients using PRRT as
308
well as other radionuclide therapies in Indonesia.
309 310
CONCLUSION
311 312
Estimated radiation dose to the kidneys for
313
the patients undergo PRRT with 17Lu-
314
DOTATATE shows good reproducibility
315
(typically <20% variation) within an individual
316
across all cycles within one course of treatment
317
(up to 4 cycles). The errors introduced by
318
assuming that the dosimetry estimate per unit GBq
319
administered from the initial cycle could be used
320
for subsequent cycles within a course are unlikely
321
to contribute significantly to the overall estimate
322
of radiation burden and are considered to be safe.
323 324
ACKNOWLEDGMENT
325 326
The first author gratefully acknowledges
327
the Head of Nuclear Medicine Department of
328
Royal North Shore Hospital Sydney and the staff
329
for the hospitality and assistance during the visits.
330
The acknowledgement also has been gratefully
331
addressed to The Non-Degree Program for
332
Research Innovation in Science and Technology
333
Project (RISET-PRO) from the Ministry of
334
Research, Technology and the Higher Education
335
(Kemenristek Dikti) for the financial support for
336
the activities related to the development of
337
internal dosimetry assessment in nuclear medicine
338
in Indonesia from 2013-2015 and 2017.
339
.
340
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