Treatment with 90Y- and
`177Lu-DOTATOC in patients with
`metastatic neuroendocrine tumors
`
`Andrea Frilling, MD, PhD,a Frank Weber, MD,a Fuat Saner, MD,a Andreas Bockisch, MD,b
`Michael Hofmann, MD,c Jan Mueller-Brand, MD,d and Christoph E. Broelsch, MD, PhD,a Essen,
`Germany; Bern, Switzerland; and Basel, Switzerland
`
`Background. Treatment with 90Y- or 177Lu-DOTATOC has recently been introduced in the palliative
`treatment of somatostatin receptor– expressing neuroendocrine tumors (NETs). The aim of the study
`was to present clinical experience with 90Y- and 177Lu-DOTATOC therapy in the management of
`NET.
`Methods. To prove suitability for treatment each patient underwent scanning with 111In–DTPAOC
`or 68Ga-DOTATOC positron emission tomography/computed tomography. All patients received
`[90Y-DOTATOC] as initial treatment. In case of disease relapse the treatment was repeated. To avoid
`side effects of repeated [90Y] applications, a switch to [177Lu-DOTATOC] was carried out. Clinical,
`biochemical, and radioimaging responses were documented.
`Results. Twenty patients with metastatic nonresectable NETs (15 pancreas NETs, 2 midgut NETs, 1
`gastrinoma, 1 paraganglioma, 1 NET of unknown primary origin) were included. In 8 patients the
`treatment was repeated more than once (mean, 3 times; range, 2-5 times). After [90Y] treatment
`moderate toxicity was observed in 8 patients. No serious adverse events were documentable. After
`restaging, a partial remission was found in 5 patients, stable disease in 11 patients, and tumor
`progression in 4 patients.
`Conclusions. Peptide receptor–targeted radionuclide therapy is a promising, safe, and feasible approach
`in the palliative therapy of patients with NET. (Surgery 2006;140:968-77.)
`
`From the Departments of General, Visceral and Transplantation Surgerya and Nuclear Medicine,b University
`Hospital Essen; the Department of Nuclear Medicine,c University Hospital Bern; and the Department of Nuclear
`Medicined University Hospital Basel
`
`Malignant neuroendocrine tumors (NETs) fre-
`quently present with synchronous or metachronous
`metastases. Undoubtedly, aggressive surgical ap-
`proach presents the first treatment of choice even
`in metastasized tumor stage. In the presence of
`nonresectable conditions, various palliative treat-
`ment modalities are available. The unique biologic
`behavior of NETs associated with favorable progno-
`sis, even in the presence of metastases,
`justifies
`their implementation in the therapeutic concept.
`
`Presented at the 27th Annual Meeting of the American Associ-
`ation of Endocrine Surgeons, New York, New York, May, 2006.
`Reprint requests: Andrea Frilling, MD, Professor of Surgery,
`Department of General, Visceral and Tranplantation Surgery,
`University Hospital Essen, Hufelandstr 55, D-45122 Germany.
`E-mail: frilling@uni-essen.de.
`0039-6060/$ - see front matter
`© 2006 Mosby, Inc. All rights reserved.
`doi:10.1016/j.surg.2006.07.030
`
`968 SURGERY
`
`Radiolabeled guanethidine analogue metaiodo-
`benzylguanidine (131I-MIBG), preferably assem-
`bled by the neuroadrenergic tissue was the initial
`targeting pharmaceutical used for radionuclide
`therapy of metastatic NETs other than thyroid car-
`cinoma.1
`Somatostatin receptors (SSTs), expressed by a
`great variety of cell types, offered an alternative prom-
`ising molecular target for radiopharmaceuticals such
`as [indium-111 (111In)-diethylene-triamine-penta-
`acid (DTPA)-D-Phe1]-octreotide
`(111In-
`acetic
`DTPAOC) (OctreoScan; Mallinckrodt, Inc., Petten,
`Switzerland) that have become routinely used ei-
`ther as standard scintigraphy or single photon
`emission computed tomography (SPECT) for ini-
`tial detection and staging of NET, particularly
`those originating from the gut.2 In spite of high
`sensitivity (60%-99%) and specificity (85%-98%),
`the technique is bounded by its poor geometric
`resolution in the presence of deep-seated smaller
`tumors.2
`
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`

`Surgery
`Volume 140, Number 6
`
`Frilling et al 969
`
`In 1996 the chelator somatostatin analogue
`1,4,7,10-tetra-azacyclododedcan-4,7,10-tricar-
`boxy-methyl-1-yl-acetyl-D-Phe1 Try3– octreotide
`(DOTATOC) with high affinity to SSTs and the
`option for stable labeling with ␤-emitting radio-
`isotopes was developed. The labeling of hydro-
`philic peptide vector DOTATOC with the positron
`emitter gallium-68 (68Ga) (68Ga-DOTATOC) en-
`ables positron emission tomography (PET) imag-
`ing that provides diagnostic sensitivity 30% higher
`than that achieved by standard octreotide scan-
`ning.3,4 Precise fusion of functional 68Ga-DOTA-
`TOC PET images with a morphologic image
`technique such as computed tomography (CT)
`(68Ga-DOTATOC PET/CT) offers additional infor-
`mation.
`It became evident, however, that, because of
`their short-range radiotoxicity, 111 In-coupled
`peptides might be more effectively used for diag-
`nostic than for therapeutic purposes. Labeling of
`DOTATOC with ␤-emitters such as yttrium-90 (90Y)
`or lutetium-177 (177Lu) provided a more favorable
`agent for somatostatin receptor–targeted radionu-
`clide therapy because of their high energy and
`longer range.5-9 In vitro studies confirmed very
`high binding affinity of 90Y-DOTATOC for soma-
`tostatin receptor subtypes 2 and 5, and underlined
`its clinical value in the management of NET.10,11 In
`an initial phase II trial the overall response rate
`after 90Y-DOTATOC treatment was 24% in a group
`of patients with NET originating from the gastro-
`enteropancreatic or bronchopulmonary system.6
`In this study further clinical experience with 90Y-
`and 177Lu-DOTATOC therapy in the palliative
`management of patients with advanced NET will be
`presented.
`
`MATERIAL AND METHODS
`Patients. All patients included in this analysis
`presented with advanced histologically or cytologi-
`cally proven progressive metastatic NET not suitable
`for primary resection. In 2 patients (nos. 1 and 9),
`clinical symptoms caused by excessive hormonal se-
`cretion were evident. Nonresectability, due to either
`technical or oncologic reasons, was confirmed by 2
`experienced surgeons. Further inclusion criteria were
`life expectancy ⬎6 months and World Health Orga-
`nization (WHO) status ⱕ2. The findings of prethera-
`peutic SST scintigraphy were strongly positive in all
`patients. Besides tumor imaging, all patients under-
`went complete blood counts, blood chemistry, deter-
`mination of chromogranin A level in serum, and
`specific hormonal evaluation in case of hormonally
`active tumors. None of the patients had been treated
`with the long-acting somatostatin analogues oct-
`
`reotide or lanreotide during at least the last 6 weeks
`before receiving radiopeptide treatment or with
`short-acting octreotide during the last 3 days before
`therapy. Written informed consent was available for
`each patient. All patients were discussed between a
`surgeon and a therapist from a department of nu-
`clear medicine before the decision for radiotherapy
`was made.
`Tumor imaging. During the initial phase 111In–
`DTPAOC (185-200 MBq) was carried out in planar
`and SPECT standard techniques.3,12 For 68Ga-
`DOTATOC– based imaging introduced more re-
`cently, 68Ga was produced on site by an optimized
`technique as described elsewhere. Patients were
`administrated a bolus intravenous injection of 60-
`150 MBq 68Ga-DOTATOC; then PET dynamic im-
`aging was started immediately and continued for 84
`minutes. Delayed static images were acquired from
`90 minutes up to 180 minutes after injection at
`different bed positions. All scans were carried out
`on a dedicated multislice ring detector scanner
`system (ECAT Exact 922; Siemens/CTI, Knoxville,
`Tenn) in three-dimensional mode.3,6 For 68Ga-
`DOTATOC PET/CT imaging, a dual-modality
`PET/CT (Siemens Medical Solutions, Hoffman Es-
`tates, Ill) composed of 2 components—a full ring
`PET tomography and a dual-slice CT scanner—was
`used.13
`Radiotracer.
`analogue
`somatostatin
`The
`synthesized as previously de-
`DOTATOC was
`scribed.6 For radiolabeling, 90YCl3 or 177LuCl3 was
`added to DOTATOC lyophilized kits according to the
`protocol reported by Forrer et al14 and Waldherr et
`al.6,15
`Treatment. For each treatment session, the pa-
`tients were hospitalized in the Department of Nu-
`clear Medicine at the University Hospital Basel for
`3 days in accordance with the legal requirements
`for radioactivity control. For the initial treatment, 2
`applications of 90Y-DOTATOC (cumulative dose of
`7.4 GBq/m2 90Y-DOTATOC) were used. During
`each 90Y-DOTATOC application, 37 to 111 MBq of
`111In-DOTATOC was injected simultaneously with
`an aim to control the DOTATOC binding. Static
`images were acquired 1 hour, 24 hours, 48 hours
`and, in some cases, 72 hours after injection of the
`radionuclide. All patients received at least 2 treat-
`ment sessions. The treatments were repeated in
`intervals of 8 to 10 weeks. In case of the necessity of
`multiple treatments due to tumor relapse or for
`biophysical reasons (small size of the lesion), a
`switch to 177Lu-DOTATOC (fixed activity, 7400
`MBq of 177Lu-DOTATOC) was attempted to avoid
`toxicity that can occur after treatment with 90Y-
`DOTATOC. An infusion of 2000 mL of an amino
`
`Evergeen Ex. 1036
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`
`

`

`970 Frilling et al
`
`Table I. Patient characteristics
`
`Patient
`no.
`
`Gender
`
`Age
`(y)
`
`Primary tumor
`
`History of
`tumor
`(mo)
`
`Tumor manifestation
`before first
`90Y-DOTATOC
`treatment
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`F
`F
`M
`M
`M
`M
`M
`F
`M
`M
`F
`M
`M
`M
`F
`M
`M
`M
`M
`F
`
`76 NET-ileum
`45 NET-pancreas
`29
`Paraganglioma-neck
`62 NET-pancreas
`52 NET-pancreas
`47 NET-pancreas
`65 NET-pancreas
`54 NET-pancreas
`42 Gastrinoma-pancreas
`46 NET-unknown origin
`58 NET-ileum
`63 NET-pancreas
`49 NET-pancreas
`43 NET-pancreas
`60 NET-pancreas
`58 NET-pancreas
`55 NET-pancreas
`65 NET-pancreas
`50 NET-pancreas
`56 NET-pancreas
`
`15
`72
`70
`24
`26
`18
`26
`49
`12
`15
`35
`60
`16
`21
`26
`18
`14
`18
`22
`16
`
`L
`L, LN
`L, M, PR
`L, LN
`L
`L
`L
`L, LN, LU
`L
`L
`L, LN
`L
`L
`L, LN
`L
`L, LN
`L, LN
`L
`L
`L
`
`Previous therapy
`
`S, RFA,TACE, Oct
`S
`S
`S, Oct
`S, TACE, Oct
`Oct
`TACE, Oct
`LTX, Oct
`S, Oct
`TACE, Oct
`TACE
`CT, IFN
`Oct
`S, CT
`CT, IFN,Oct
`TACE, Oct
`S, CT, Oct
`Oct
`S, Oct
`TACE, Oct
`
`Surgery
`December 2006
`
`No. of
`90Y- DOTATOC
`treatments
`
`2
`1
`1
`2
`2
`2
`1
`2
`4
`2
`2
`2
`2
`3
`2
`2
`3
`2
`2
`2
`
`90Y-DOTATOC, Yttrium-90 1,4,7,10-tetra-azacyclododedcan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1 Try3 – octreotide;
`177Lu-DOTATOC, lutetium-177 1,4,7,10-tetra-azacyclododedcan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1 Try3 – octreotide;
`IFN, alpha-interferon; L, liver; LN, lymph nodes; LTX, liver transplantation; LU, lung; M, mediastinum; NET, neuroendocrine tumor;
`Oct, octreotide; PR, paravertebral; RFA, radiofrequency ablation; S, surgery; TACE, transarterial chemoembolisation.
`*After treatment initiation.
`†No change in response 3 mo after last DOTATOC treatment.
`
`acid solution (Ringer lactated Hartmann solution
`[Proteinsteril; B. Braun Medical AG, Sempach,
`Germany], HEPA 8%, Mg 5-Sulfat [B. Braun Med-
`ical AG]) was given to inhibit tubular reabsorption
`of the radiopeptide started 30 minutes before ad-
`ministration of the radiopharmaceutical and con-
`tinued until up to 4 hours after administration.
`Imaging and dosimetry were performed in accor-
`dance with the protocols as previously report-
`ed.14,15 After demission, complete blood cell and
`platelet counts were measured every 2 weeks for at
`least 8 weeks.
`Evaluation of tumor response and measurement
`of quality of life. Eight to 12 weeks after radiopep-
`tide therapy, response to treatment was assessed by
`CT. For evaluation of tumor growth, WHO stan-
`dard criteria were used. Blood counts and chemis-
`try, chromogranin A measurement, and tumor-
`specific hormonal examinations were additional
`parts of the evaluation protocol. Side effects of
`90Y-DOTATOC were documented according to the
`National Cancer Institutes (NIH) Cancer Clinical
`Trials Common Toxicity Criteria (CTC). For qual-
`ity-of-life assessment, an SF-36 survey (SF-36 Health
`
`Survey, version 2; IQOLA Project, Standard, Ger-
`many) for quality-of-life measurement was applied.
`After completion of treatment, follow-up examina-
`tions including ultrasonography took place every 3
`months.
`
`RESULTS
`Twenty patients, 14 men and 6 women aged 29
`to 76 years (median age, 53.8 years) referred to our
`center for treatment of neuroendocrine hepatic
`metastases were included in this study. Of these
`patients, 15 presented with NET of the pancreas, 2
`with midgut NET, 1 with a sporadic gastrinoma, 1
`with a paraganglioma, and 1 with a NET of un-
`known primary origin. Further patient characteris-
`tics are given in Table I.
`Multiple bilobar liver lesions were demonstrable
`in 111In–DTPAOC or 68Ga-DOTATOC PET/CT in
`19 patients. Additional extrahepatic metastatic
`spread, not documented in standard imaging tech-
`niques, was evident in 36.8% of the patients (Figs 1
`and 2). In the patient with a paraganglioma (no.
`3), in whom several resections for metastatic dis-
`ease in various localizations had been carried out in
`
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`

`Surgery
`Volume 140, Number 6
`
`Table I. (Continued)
`Total dose of
`Toxicity grade after
`90Y- DOTATOC
`90Y- DOTATOC
`MBq
`treatment
`
`11,100
`5550
`6475
`13,875
`14,800
`15,540
`6475
`10,730
`12,654
`11,840
`15,170
`7400
`7400
`11,100
`7400
`7400
`11,100
`7400
`11,100
`9250
`
`0
`1
`1
`0
`0
`0
`1
`3
`0
`0
`0
`0
`1
`0
`1
`0
`1
`0
`0
`1
`
`Frilling et al 971
`
`No. of
`177Lu- DOTATOC
`treatments
`
`Total dose of
`177Lu- DOTATOC
`MBq
`
`Response 3 mo after
`last DOTATOC
`treatment
`
`Follow-up
`(mo)*
`
`Present
`status†
`
`2
`2
`
`2
`2
`
`2
`
`2
`
`14,800
`12,950
`
`9,546
`12,950
`
`14,800
`
`11,100
`
`Stable disease
`Partial response
`Partial response
`Stable disease
`Progressive disease
`Partial response
`Stable disease
`Progressive disease
`Stable disease
`Partial response
`Progressive disease
`Stable disease
`Partial response
`Progressive disease
`Stable disease
`Stable disease
`Stable disease
`Stable disease
`Stable disease
`Stable disease
`
`6
`16
`18
`24
`36
`29
`8
`25
`27
`19
`18
`12
`15
`24
`21
`26
`14
`20
`24
`14
`
`Alive
`Alive
`Alive
`Alive
`Dead
`Alive
`Alive
`Dead
`Alive
`Alive
`Alive
`Alive
`Alive
`Dead
`Alive
`Alive
`Alive
`Alive
`Alive
`Alive
`
`the past, 68Ga-DOTATOC PET/CT disclosed recur-
`rent metastatic bulk in the mediastinum, within the
`liver, and alongside the vertebral column (Fig 3 A
`and B). A preceded metaiodobenzylguanidine
`(123I-MIBG) scintigraphy showed no uptake in any
`standard 111In–
`of
`these positions, whereas
`DTPAOC scanning revealed the mediastinal lesion
`only.
`Each patient underwent at least 2 treatment ses-
`sions. In 8 patients the therapy had to be repeated
`more than once (median, 3 times; range, 2-5
`times). Whereas the treatment concept encom-
`passed only 90Y-DOTATOC in 14 (70%) patients,
`sessions with177Lu-DOTATOC took
`additional
`place in 6 individuals. In 5 of them, the switch to
`[177Lu] was enforced because of tumor relapse,
`and in 1 patient because of the small size and
`multilocularity of the neoplastic lesions. After 90Y-
`DOTATOC treatment, toxicity grade 1 concerning
`hemoglobin and/or creatinine was evident in 7
`patients. In 1 additional patient (no. 8), who was
`under immunosuppressive therapy after liver trans-
`plantation (LTX), a decrease in hemoglobin level
`from 11.5 g/dL to 6.2 g/dL with requirement for
`administration of 4 units of blood was observed. No
`serious adverse events occurred, and the treatment
`did not have to be discontinued in any patient.
`Concerning the tumor growth, partial response
`was documented in 5 (25%) patients and stable dis-
`
`ease in 11 (55%) patients. Progressive disease was
`seen in 4 patients, 3 of whom died during the fol-
`low-up (Fig 4). Chromogranin A levels decreased
`post-therapeutically in the subgroup of patients
`who attained partial response; however, they re-
`mained unchanged in cases of stable disease (Table
`II). In both patients symptomatic before treatment,
`clinical improvement and decrease of specific hor-
`mones occurred. In the patient with a NET-ileum
`(no. 1), serotonin decreased from 450 to 186 ␮g/L
`(reference, 110-330 ␮g/L), and in the patient with
`a gastrinoma a decrease in the serum gastrin level
`from 288 to 177 ng/L (reference, ⬍ 115 ng/L) was
`documented. In the subgroup of patients with par-
`tial response or stable disease, 10 reported im-
`provement in their quality of life (Table III).
`During the follow-up since the last DOTATOC
`treatment session, 2 patients underwent further
`invasive interventions for their metastatic disease.
`In the patient with a paraganglioma (no. 3) a com-
`bined resection of a liver metastasis and of the
`paravertebral lesions was carried out (Fig 3 A and
`B). This strategy attributed to the unique behavior
`of the metastatic deposits with a very high uptake of
`the radionuclide within the mediastinal tumor and
`virtually no uptake below the diaphragma stellae.
`The second patient required a left hepatectomy
`because of upper abdominal discomfort caused by
`
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`

`972 Frilling et al
`
`Surgery
`December 2006
`
`significant tumor necrosis within the left liver lobe
`(Fig 5 A and B).
`
`DISCUSSION
`Advanced NETs lack a widely accepted rationale
`for treatment. The decision of which treatment
`option to choose is triggered by the subjective ex-
`perience of the therapist and the local availability
`of the methodology rather than by evidence-based
`information.
`After it has been shown that NETs can be visu-
`alized by targeting with specific radioisotopes, pep-
`tide receptor radionuclide therapy (PRRT) has
`been integrated into the treatment concept of me-
`tastasized NETs, mainly in those originating from
`the gastroenteropancreatic system.11 In the initial
`studies on the effectiveness of 111In-pentetreotide
`treatment, responses have been seen in 62% to
`69% of patients.16,17 More recently, Pasieka et al18
`documented symptomatic benefit in 55% of the
`patients subjected to this treatment. While therapy
`with this radiopharmaceutical led to improvement
`of clinical symptoms in a significant portion of
`patients, tumor regression was rather uncommon.
`For pretherapeutic tumor visualization tradition-
`ally 111In–DTPAOC scintigraphy was used.2 By
`binding of 111In to DOTATOC or DOTA-1-Nal3
`octreotide (DOTANOC), and most recently by la-
`beling of DOTATOC or DOTANOC with 68Ga,
`imaging results can be further improved in terms of
`detection of very small lesions or tumors with a low
`density of SSTs.3,4,8,12,19 During planning of endo-
`crine surgery, particular attention should be given
`to 68Ga–DOTATOC in connection with PET/CT
`because, apart from a very high tumor to physio-
`logic background ratio, this technology offers bidi-
`mensional anatomic landmarking possibilities, thus
`enabling a focused strategic approach. Although in
`our experience, CT proved to be more sensitive
`than 111In–DTPAOC and 68Ga–DOTATOC PET in
`evaluation of neuroendocrine hepatic lesions,
`111In–DTPAOC and particularly 68Ga–DOTATOC
`PET/CT provide excellent results in detecting ex-
`trahepatic tumor spread. As shown in this study,
`40% of the patients exhibited with numerous ex-
`trahepatic somatostatin receptor–positive lesions
`not disclosed by standard imaging (Fig 1). The
`value of this new localization technique could be
`impressively shown in the patient with a paragan-
`glioma (no. 3), in whom neither 123I-MIBG nor
`standard 111In–DTPAOC scintigraphy detected the
`lesions revealed by 68Ga–DOTATOC. In addition,
`these results underline the hypothesis that, in the
`course of the disease, NETs can dedifferentiate and
`subsequently lose their primary character. Apart
`
`Evergeen Ex. 1036
`5 of 10
`
`Fig 1. Anterior 68Ga-DOTATOC PET/CT image (85
`MBq) in a patient with multiple liver and abdominal
`lymph node metastases (circle) of a neuroendocrine pan-
`creatic tumor.
`
`Fig 2. Anterior 68Ga-DOTATOC PET/CT image (85
`MBq) disclosing metastases of a neuroendocrine tumor
`of the ileum within the liver, bone, and upper abdominal
`lymph nodes.
`
`

`

`Surgery
`Volume 140, Number 6
`
`Frilling et al 973
`
`Fig 3. A, Anterior and lateral 68Ga-DOTANOC PET/CT images 90 minutes after injection of 120 MBq 68Ga-DOTATOC.
`Metastases of a paraganglioma are evident in the mediastinum, liver and within the abdominal lymph nodes (arrows).
`B, After treatment with 6475 MBq 90Y-DOTATOC, partial response is seen with the mediastinum. No uptake is evident
`in the other lesions.
`
`from the issues concerning targeted radionuclide
`therapy, we found the superior image quality of
`68Ga–DOTATOC PET/CT concerning extrahe-
`patic tumor manifestation to be particularly valu-
`able in evaluation of patients with NET who were
`potential candidates for LTX.20
`In the cohort of the 20 patients presented here,
`PRRT was of objective beneficial effect in 5 (25%)
`of them in terms of morphologic tumor load re-
`
`duction and marked decrease of chromogranin A.
`These encouraging results confirm the experience
`published so far; however, they might also be bi-
`ased by our selection of patients.6,10,15,21,22 First, in
`75% of patients, the primary NET was localized
`within the pancreas. As shown by Kwekkeboom
`et al,22 this might be the tumor entity in which
`particularly good response may be expected. The
`vast majority of the patients were asymptomatic and
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`

`974 Frilling et al
`
`Surgery
`December 2006
`
`Fig 4. Anterior and posterior images in a patient with multiple liver metastases of a pancreatic NET. After 90Y-
`DOTATOC treatment (7400 MBq), no response was seen.
`
`Table II. Chromogranin A levels before and after
`DOTATOC treatment (reference level, ⬍ 40 U/L).
`Chromogranin A
`3 mo after the last
`DOTATOC
`treatment (U/L)
`
`Chromogranin A before the
`first 90Y-DOTATOC
`treatment (U/L)
`
`Patient
`no.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`183
`355
`218
`167
`218
`289
`215
`341
`176
`317
`222
`154
`290
`312
`180
`212
`344
`165
`177
`201
`
`177
`65
`59
`155
`523
`124
`187
`388
`181
`205
`380
`161
`71
`422
`156
`200
`321
`158
`165
`195
`
`90Y-DOTATOC, Yttrium-90 1, 4, 7, 10-tetra-azacyclododedcan-4, 7, 10-
`tricarboxy-methyl-1-yl-acetyl-D-Phe1 Try3 – octreotide.
`
`in very good clinical condition, presenting tumors
`with a significant uptake on SSR. Because of the
`rather short follow-up (19.9 months; range, 6-36
`months), it can be expected that some of the pa-
`tients classified as having benefit at present may
`develop tumor recurrence in the near future. As a
`cutoff value for long-term therapeutic effect, a fol-
`low-up of 24 months should be considered. All
`
`Table 3. Health-related quality-of-life assessment
`of patients before and after DOTATOC treatment
`Score before the first
`90Y-DOTATOC
`treatment*
`
`Score 3 mo after the last
`DOTATOC treatment*
`
`Patient
`no.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`30/100
`50/100
`65/100
`50/100
`30/100
`65/100
`75/100
`50/100
`45/100
`65/100
`45/100
`NA
`60/100
`40/100
`45/100
`65/100
`55/100
`60/100
`50/100
`NA
`
`40/100
`85/100
`95/100
`50/100
`35/100
`80/100
`80/100
`30/100
`55/100
`85/100
`45/100
`NA
`70/100
`25/100
`45/100
`75/100
`55/100
`75/100
`45/100
`NA
`
`NA, Not available; 90Y-DOTATOC, yttrium-90 1, 4, 7, 10-tetra-azacyclo-
`dodedcan-4, 7, 10-tricarboxy-methyl-1-yl-acetyl-D-Phe1 Try3 – octreotide.
`*Score of zero ⫽ worst general health condition; score of 100 ⫽ best
`general health condition.
`
`patients had disseminated bilobar liver metastases;
`nevertheless, the total hepatic tumor burden was
`not extremely high because it is our center’s policy
`that patients with NET and rapidly growing multi-
`focal bulky hepatic metastases are potential candi-
`dates for LTX rather than for any other treatment.
`In our opinion, patients with a significant portal
`
`Evergeen Ex. 1036
`7 of 10
`
`

`

`Surgery
`Volume 140, Number 6
`
`Frilling et al 975
`
`rate of side effects of PRRT seen in our patients
`so far. Only in 1 patient (no. 8) was rehospital-
`ization and intervention necessary after treat-
`ment with 90Y-DOTATOC. It should be stressed,
`however, that in this patient PRRT was carried
`out as an “ultima ratio” treatment because no
`other therapeutic options were available, and the
`still acceptable general condition of the patient
`and her subjective attitude toward her disease
`prohibited cessation of our treatment attempts.
`As reported in the past, nephrotoxicity from 90Y-
`DOTATOC can be an issue despite administra-
`tion of kidney-protective solutions and must be
`recognized when indication for PRRT is consid-
`ered.14,23
`More recently, an increase of the therapeutic
`effect in an animal model was reported by the
`group from Rotterdam by a combination treatment
`encompassing 90Y- and 177Lu-labeled somatostatin
`analogues and by labeling of DOTATOC with the
`high linear energy transfer alpha-emitter 213Bi.24,25
`Further improvement might be expected from up-
`regulation of SST activity or implementation of
`radiosensitizers.
`
`Some of the patients presented in this study under-
`went diagnostic or therapeutic procedures in the Depart-
`ments of Nuclear Medicine at Bonn (Head: H.-J.
`Biersack), Bad Berka (Head: R. P. Baum), Hannover
`(Head: W. H. Knapp), all in Germany, and in the De-
`partment of Internal Medicine Seoul (Head: M. C.
`Young), Korea. We would like to thank these colleagues
`for their contribution and are indebted to all technical
`personnel for their support.
`
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`Fig 5. A, Abdominal CT disclosing multiple metastases
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`
`DISCUSSION
`Dr Janice L. Pasieka (Calgary, Alberta, Canada).
`Dr Frilling, a beautiful study, and thank you for
`trying to sort out the lutetium versus the yttrium, as
`we are in the process of moving to lutetium oct-
`reotide in our treatment.
`I was wondering if you had any data on the
`quality of life and relief of symptoms following
`therapy. We have found that with our MIGB ther-
`apy we are seeing a significant reduction in bony
`pain. This has been a really remarkable palliative
`therapy in patients with bony metastasis, and I won-
`der if you are seeing the same with the lutetium or
`the yttrium octreotide.
`My second question was, I was very surprised to
`see only 2 patients with midgut carcinoids. Is this
`just a referral selection bias? Clearly those would be
`the patients most likely to take up octreotide.
`Dr Andrea Frilling. To answer your first ques-
`tion, I know the data you presented 2 years ago at
`the meeting of the Association and I am aware of
`your paper published in Surgery. The patients we
`saw were in rather good general condition, and
`none of the patients was symptomatic due to bone
`metastases. So I cannot answer you if this treatment
`might be also beneficial in patients being symptom-
`atic due to bone lesions. I think that the fact that
`most of our patients presented with stable general
`condition might also bias the results of our study.
`Dr Janice L. Pasieka. The second question, only
`2 patients with midgut carcinoids?
`Dr Andrea Frilling. Yes, this was due to the re-
`ferral and not to our center-specific selection of
`patients with neuroendocrine tumors.
`Dr Britt Skogseid (Uppsala, Sweden). Very inter-
`esting data. I would like to just comment that we use
`this mostly for midgut carcinoids since we use chemo-
`therapy mostly for endocrine pancreatic tumors. And
`it is a very efficient expensive palliative treatment. We
`really see quite a lot of relief, as Dr Pasieka pointed
`out as well. However, we do have much more side
`effects in our tumors tha