1

Radionuclide therapy in neuroendocrine tumors 1

2

Wouter A. van der Zwan1, Lisa Bodei2, Jan Mueller-Brand3, Wouter W. de Herder1, 3

Larry K. Kvols4, Dik J. Kwekkeboom1. 4

5

1Department of Nuclear Medicine, Erasmus MC, University Medical Center, 6

Rotterdam, the Netherlands. 7

2Department of Nuclear Medicine, European Institute of Oncology, Milan, Italy. 8

3Department of Nuclear Medicine, University Hospital Basel, Basel, Switzerland. 9

4Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute, 10

Tampa, Florida, USA. 11

12

Corresponding Author: 13

W.A. van der Zwan 14

Department of Nuclear Medicine, Erasmus MC, University Medical Center, 15

s-Gravendijkwal 230, 3015CE Rotterdam, the Netherlands. 16

Tel: +31-10-704 01 32 17

Fax: +31-10-703 46 47 18

Email: w.vanderzwan@erasmusmc.nl 19

20

Short title: PRRT in neuroendocrine tumors 21

Key words: Neuroendocrine tumour, Carcinoids, Radionuclide therapy, PRRT 22

Word count of full article: 2585 23

24

Page 1 of 20 Accepted Preprint first posted on 12 August 2014 as Manuscript EJE-14-0488

Copyright © 2014 European Society of Endocrinology.

2

Abstract 1

Peptide Receptor Radionuclide Therapy (PRRT) is a promising new treatment 2

modality for inoperable or metastasized GastroEnteroPancreatic NeuroEndocrine 3

Tumors (GEPNET) patients. Most studies report objective response rates in 15-35% 4

of patients. Also, outcome in terms of PFS and OS compares very favourably with 5

that for somatostatin analogues, chemotherapy, or new, “targeted” therapies. They 6

also compare favourably to PFS data for liver-directed therapies. 7

Two decades after the introduction of PRRT there is a growing need for randomised 8

controlled trials comparing PRRT to “standard” treatment, that is treatment with 9

agents that have proven benefit when tested in randomised trials. 10

Combining PRRT with liver-directed therapies, or with targeted therapies could 11

improve treatment results. The question to be answered, however, is whether a 12

combination of therapies performed within a limited time-span from one another, 13

results in a better PFS than a strategy in which other therapies are reserved until 14

after (renewed) tumor progression. 15

Randomized clinical trials comparing PRRT with other treatment modalities should be 16

undertaken to determine the best treatment options and treatment sequelae for 17

patients with GEPNETs. 18

19

Page 2 of 20

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Introduction 1

The majority of GastroEnteroPancreatic NeuroEndocrine Tumors (GEPNETs) express 2

somatostatin receptors and can be treated with radiolabeled somatostatin analogues. 3

The majority of patients that have been treated with this socalled Peptide Receptor 4

Radionuclide Therapy (PRRT) had inoperable metastatic disease, and 70-90% of 5

them had liver metastases.1-5 6

7

PRRT: Efficacy 8

Because at that time somatostatin analogues labeled with beta-emitting radionuclides 9

were not available for clinical use, early studies in the 1990s used high activities of the 10

Auger electron emitting [111In-DTPA0]octreotide (111In-octreotide) for PRRT. These 11

treatments often resulted in symptom relief in patients with metastasized 12

NeuroEndocrine Tumors (NETs), but objective tumor responses were rare (table 1).6, 7 13

The next generation of analogues used in PRRT consisted of a modified 14

somatostatin analogue, [Tyr3]octreotide, and a different chelator, DOTA instead of 15

DTPA, which allows stable binding of the β-emitting radionuclide 90Yttrium (90Y). Its 16

maximal tissue penetration is 12 mm and its half life is 2.7 days. [90Y-17

DOTA0,Tyr3]octreotide (90Y-DOTATOC) was used in several phase-1 and phase-2 18

PRRT trials in various countries (Table 1). The registered objective responses range 19

from 4% to 33%. Differences in cycle doses and administered cumulative dose, as 20

well as differences in patient characteristics (included tumor types, patient 21

performance status) make it virtually impossible to compare these studies. Different 22

studies report median Progression Free Survival (PFS) varying from 17 to 29 23

months, and median Overall Survival (OS) from 22 to 37 months (Table 2).1-5 In a 24

Page 3 of 20

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recent report on the treatment effects of 90Y-DOTATOC in a large group of patients, 1

the response to 90Y-DOTATOC was associated with longer survival.11 2

177Lutetium (177Lu) is a medium energy β-emitter, with a maximal tissue penetration 3

of 2 mm. 177Lu also emits low-energy γ-rays, allowing scintigraphy and subsequent 4

dosimetry using the same, therapeutic, compound. The somatostatin analogue 5

[DOTA0,Tyr3]octreotate differs from [DOTA0,Tyr3]octreotide only in that the C-terminal 6

threoninol is replaced with threonine, resulting in a higher affinity for the somatostatin 7

receptor subtype 2 than octreotide.12 The treatment effects of [177Lu-8

DOTA0,Tyr3]octreotate (177Lu-octreotate) therapy were described in a large group of 9

GastroEnteroPancreatic NET (GEPNET) patients.5 Complete Remission (CR) was 10

found in 5 (2%) patients, Partial Remission (PR) in 86 (28%) and Minor Response 11

(MR) in 51 (16%) patients (Table 2). Prognostic factors for predicting tumor remission 12

(CR, PR, or MR) as treatment outcome were high uptake on the Octreoscan, 13

Karnofsky Performance Score > 70, and low metastatic load to the liver. Median time 14

to progression was 40 months from start of treatment. Progression of disease was 15

more common in patients with an extensive disease or in a poor general clinical 16

condition (Karnofsky score <70%, significant weight loss, presence of bone 17

metastases). Several of these factors that had a significant impact on PFS were also 18

found in another study.13 Median OS was 46 months (Table 2). It may be postulated 19

that early treatment with PRRT can increase the PFS and OS. However, in a 20

retrospective serie of 68 patients suffering from advanced pNET, 35 patients 21

received PRRT as first-line treatment. The outcome regarding PFS and OS did not 22

differ from patients treated with PRRT in a later setting.14 23

In a large group of (nearly 300) patients treated with PRRT and who had a long 24

follow-up, it was shown that Quality of Life (QoL), but also symptomatology improved 25

Page 4 of 20

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in 40-70% of cases, depending on the preexistence of a certain symptom.15 This is 1

important because the months to years that are gained after PRRT can only be 2

called promising if the time that is gained is free of serious side-effects or 3

symptomatology that affect QoL. By contrast, it was shown that the years gained 4

after PRRT show an improved QoL, as judged by the patients themselves, according 5

to a validated questionnaire.15 6

7

PRRT: Side-effects 8

PRRT is generally well tolerated. Acute side-effects are usually mild and self-limiting. 9

Nausea or, more rarely, vomiting is related to the concomitant administration of 10

nephro-protective amino acids. Other, more subacute side-effects are related to the 11

radiopeptide itself, such as fatigue, hematologic or renal toxicity, mild hair loss 12

(observed with 177Lu-octreotate), impairment of male fertility or, more rarely, an 13

exacerbation of a clinical syndrome. The most common subacute side-effect of 14

PRRT, occurring within 4-6 weeks after therapy is hematologic toxicity. Hematologic 15

toxicity is caused by irradiation of the bone marrow. Usually hematologic toxicity is 16

mild and reversible. More serious, WHO grade 3 or 4 toxicity may occur in less than 17

15% of patients.1, 3, 11, 13, 16-19 18

Long-term serious side-effects of PRRT are renal failure or Myelodysplastic 19

Syndrome (MDS)/leukemia (Table 3). Proper kidney protection, with the co-infusion 20

of positively charged amino acids, is mandatory in PRRT. With advances in expertise 21

and knowledge about PRRT, cases of severe, end-stage, renal damage are currently 22

very rare. However, despite kidney protection, loss of kidney function can occur after 23

PRRT, with a creatinine clearance loss of about 3.8% per year for 177Lu-octreotate 24

and 7.3% per year for 90Y-DOTATOC.20 Studies have demonstrated that a higher 25

Page 5 of 20

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and more persistent decline in creatinine clearance is more frequent if risk factors for 1

delayed renal toxicity are present, particularly long-standing and poorly controlled 2

diabetes and hypertension.21 3

With adequate renal amino acid protection, grade 3-4 renal toxicity occurs in less 4

than 3% of patients (Table 3). One recent study, however, states a grade 3-4 renal 5

toxicity in 9% of their patients.11 This relatively high incidence could be related to 6

relatively high activities administered per cycle and to the fact that patients with pre-7

existing reduced kidney function were not excluded from treatment. The possible lack 8

of use of amino acids in the first years of this study must also be taken into account.22 9

Serious side-effects of PRRT on the bone marrow, such as MDS or leukemia, have 10

been reported by various groups. An exact measure of these events is frequently 11

hampered by their occurrence in heavily pretreated patients and the short follow up 12

of the patients. These events are rare and the causal relationship with PRRT may be 13

controversial, because of previous treatments, such as chemotherapy or 14

radiotherapy. Their frequency seems higher after 177Lu-octreotate than after 90Y-15

DOTATOC, but also in analyses with long patient follow-up their frequency does not 16

exceed 2% of patients (D J Kwekkeboom, unpublished observation). 17

18

PRRT: Variants 19

Over the last years, there have been a number of attempts to improve PRRT using 20

different approaches. 21

From experiments in rats, it became clear that 90Y-labeled somatostatin analogues may 22

be more effective for larger tumors, and 177Lu-labeled somatostatin analogues may be 23

more effective for smaller tumors, whilst their combination may be the most effective.23 24

Several retrospective, non-randomised patient studies seem to indicate the same.24-26 A 25

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recent follow-up report on the efficacy of the combination of PRRT Seregni et al. 1

reported an objective response rate in 43% of the cases, whereas in their initial report 2

an objective response rate of 67% was found.25, 27 Prospective, randomised controlled 3

studies are needed to ultimately prove that PFS is better when using a combination of 4

radionuclides. 5

Several groups have investigated the feasibility of locoregional, i.e. intraarterial, 6

administration of radiolabeled somatostatin analogues.28-31 It results in a higher 7

uptake of radioactivity in livermetastases and tumor response rates seem higher than 8

with i.v. administration. Long-term responses and toxicity are not available yet. 9

The application of radiosensitizing chemotherapeutical agents in the treatment of 10

tumors with External Beam Irradiation may lead to increased anti-tumoral efficacy 11

and another way to improve PRRT. After proving the safety of the combined therapy 12

of 5-fluorouracil (5-FU) and PRRT, a randomized trial was started comparing 13

treatment with 177Lu-octreotate with and without capecitabine (the oral prodrug of 5-14

FU) (Xeloda; Roche, Basel, Switzerland) in patients with GEPNETs.32 Results of 15

another non-randomized phase II study treating patients with a combination of 16

capecitabine and 177Lu-octreotate demonstrated tumor control and stabilization in 17

94% of the 33 included patients. However, due to grade 3 capecitabine-induced 18

angina 3 patients discontinued the drug, but were able to complete the intended 4 19

cycles of PRRT.33 Feasible results were also published for the combination of 20

capecitabine and 90Y radioimmunotherapy and 111In-octreotide radiopeptide 21

therapy.34, 35 The use of radiosensitizing agents is therefore not limited to the 22

combination of one specific type of radionuclide. 23

New applications of PRRT may include the neoadjuvant use of PRRT for pancreatic 24

NETs. A few case reports have described the neoadjuvant use of PRRT in patients 25

Page 7 of 20

8

with pancreatic NETs who could be operated on successfully after PRRT.36, 37 Since 1

surgery is the only curative option for patients with GEPNETs, this neoadjuvant 2

treatment is very promising. 3

PRRT may also be used in an adjuvant setting after surgery of GEPNETs, preventing 4

tumor development after spread due to manipulation of the tumor during surgery or 5

preventing further growth of already present micrometastases. In an animal study, 6

therapy with 177Lu-octreotate prevented or significantly reduced the growth of tumor 7

deposits in the liver after injection of tumor cells via the portal vein mimicking per-8

operative tumor spill.38 To detect a difference in survival and/or tumor recurrence rate 9

in patients treated with and without adjuvant PRRT, a large, multicenter trial with 10

years of follow-up would be needed. 11

12

PRRT as salvage therapy 13

Although tumor response rates after initial treatment with PRRT are encouraging, 14

complete remission is rare and eventually the residual tumor(s) will progress again. 15

Retreatment with extra cycles of PRRT as salvage therapy may be considered when 16

better alternatives are not available. It has been reported that “salvage” therapy with 17

2 additional cycles of 177Lu-octreotate does not lead to serious haematological or 18

nephrotoxic side effects. However, the tumor response rate was lower compared to 19

initial treatment.39 It seems that long-lasting PFS after the initial treatment with PRRT 20

also predicts a prolonged PFS after salvage therapy.40 21

22

23

24

25

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Discussion 1

PRRT is a promising new treatment modality for inoperable or metastasized 2

GEPNET patients (figure 1). Complete and partial responses obtained after treatment 3

with 90Y-DOTATOC are in the same range as after treatment with 177Lu-octreotate. 4

Most studies report objective response rates in 20-35% of patients. Also, outcome in 5

terms of PFS and OS (from 16-33 months, and from 22-46 months, respectively) 6

compares very favourably with that for somatostatin analogues, chemotherapy, or 7

new, “targeted” therapies. They also compare favourably to PFS data for liver-8

directed therapies, i.e. embolization, chemoembolization, or treatment with 90Y-9

labelled microspheres. Several facts that may invalidate such comparisons should be 10

considered, however: 1. The patient populations that undergo liver-directed therapies 11

or PRRT may be different (for instance patients who had Whipple-procedures are 12

excluded from the first, whereas patients who have somatostatin-receptor-negative 13

tumors are excluded from the second); 2. The results for PRRT pertain to patients 14

with limited as well as extensive liver involvement. From multivariate analysis it is 15

known that patients extensive liver involvement perform worse.5, 13 It may however be 16

assumed that in patients with predominant liver disease PRRT performs better in 17

terms of PFS than liver-directed therapies. 18

There is a need for randomised controlled trials comparing PRRT to “standard” 19

treatment, that is treatment with agents that have proven benefit when tested in 20

randomised trials (Sandostatin LAR in metastatic midgut carcinoids and everolimus 21

and sunitinib in inoperable and/or metastatic pancreatic NETs). The same holds for 22

liver-directed therapies. A randomised study comparing PRRT with 177Lu-octreotate 23

to high-dose Sandostatin LAR treatment in patients with progressive metastatic 24

midgut carcinoids was recently started in Europe and the USA. A study comparing 25

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PRRT to sunitinib or everolimus in patients with pancreatic NETs is expected to 1

follow soon. 2

Recently, the results of new targeted therapies for the treatment of GEPNETs have 3

been presented. Treatment with sunitinib (Sutent; Pfizer Inc, New York, NY), a 4

tyrosine kinase inhibitor, resulted in a longer median PFS than placebo (11 versus 5 5

months) in patients with pancreatic NETs.41 Also, treatment with everolimus (Afinitor; 6

Novartis Pharmaceuticals, Basel, Switzerland), an inhibitor of mammalian target of 7

rapamycin (mTOR), resulted in a longer median PFS than placebo (11 versus 5 8

months) in patients with pancreatic NETs.42 The combination of PRRT with sunitinib 9

or everolimus, or the sequential use of PRRT with one of these compounds may be 10

of interest in the treatment of patients with pancreatic NETs. 11

The next question to be addressed is then, whether combining PRRT with liver-12

directed therapies, or, for that matter, with targeted therapies, such as treatment with 13

everolimus or sunitinib, could improve treatment results in terms of percentage 14

objective responses, or, preferentially, PFS and OS. The results of such an approach 15

in a sequential setting, i.e. 90Y-microsphere treatment after failure to or reprogression 16

after PRRT, were recently published and hold great promise.43 The question to be 17

answered, however, is whether a combination of PRRT and liver-directed therapy 18

performed within a limited time-span from one another (for instance 3-4 months), 19

results in a better PFS than a strategy in which liver-directed therapy is reserved until 20

after (renewed) tumor progression. This same question can be asked for the 21

combination of PRRT with chemotherapy with for instance temozolomide and 22

capecitabine or with everolimus or sunitinib. Such combinations, in our view, are 23

promising only of they result in a longer PFS/OS than when using a sequential 24

approach, in which the second treatment is only started if the disease progresses 25

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after the first. A higher percentage of objective responses with a combinatorial 1

approach may not be mistaken for a better treatment outcome, because with any of 2

the 2 single treatments a certain percentage of patients can be expected to have an 3

objective response anyhow, and the added responses will always exceed the 4

response of any single treatment. Also, it was shown in a large multivariate analysis, 5

that tumor response other than PD did not result in significant differences in PFS or 6

OS (that is: patients with PR had no longer PFS than those with SD).5 It should also 7

be kept in mind that in the vast majority of patients the goal of treatment is not cure, 8

but prevention of disease progression. With a limited number of treatment options, 9

combining treatment modalities at the beginning may leave the attending physician 10

empty-handed later on. 11

12

Conclusions 13

PRRT is a new and valuable treatment modality for patients with inoperable or 14

metastasized GEPNETs. PRRT is generally well tolerated and acute side-effects are 15

usually mild and self-limiting. Most studies report rates of 15-35% in terms of 16

objective response rates. In terms of PFS and OS PRRT compares favourably to 17

registered pharmaceutical and liver-directed therapies. Combining PRRT with 18

radiosensitizing chemotherapeutical agents or combining Y90 and 177Lu as tandem-19

treatment may improve the anti-tumoral efficacy. Another way to improve uptake of 20

the radiopharmaceutical is by intraarterial administration in case of high tumor load in 21

the liver. Randomized clinical trials comparing PRRT with other treatment modalities 22

should be undertaken to determine the best treatment options and treatment 23

sequelae for patients with GEPNETs. 24

25

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Author contribution Statement: 1

All authors have read this final version of the manuscript and have agreed with its 2

present form. All authors contributed equally. The enclosed manuscript has not been 3

submitted to any other journal. 4

5

Funding: 6

This research did not receive any specific grant from any funding agency in the 7

public, commercial or not-for-profit sector. 8

9

Acknowledgements: 10

None 11

Declaration of Interest: 12

I can declare that there is no conflict of interest that could be perceived as prejudicing 13

the impartiality of the research reported. 14

15

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21

22

Figure 1 : Example of partial response after 4 cycles of [177Lu-DOTA0, Tyr3] 23

octreotate (cumulative dose of 29, 6 GBq) in a patient with a metastasised pancreatic 24

neuroendocrine tumour. A) Upper row : baseline CT scan demonstrated a mass 25

within the pancreatic body with diffuse liver metastases. CT scans after treatment 26

again demonstrated multiple lover metastases and the pancreatic mass. However the 27

lesions clearly diminished in size and some disappeared. Lower row : Planar 28

scintigraphy performed 24 h pi (post injection) demonstrated intense uptake by the 29

receptor positive liver metastases and the pancreatic mass. During consecutive 30

treatment cycles, less tumour mass was observed indicating tumour response. B) 31

Plot depicts serum Chromogranine A (CgA) concentrations at baseline, 6 weeks after 32

each administration of PRRT (Post-PRRT) and during follow up. Due to a radiation 33

induced inflammatory reaction of tumour tissue an increase in CgA levels was 34

observed in response to PRRT. 35

Page 16 of 20

Table 1. Tumor responses in patients with GEPNETs, treated with different radiolabeled somatostatin analogues.

Tumor Response

Center (reference) Ligand N CR PR MR SD PD CR + PR

Rotterdam (Valkema et al. 2002) [111In-DTPA

0]octreotide 26 0 0 5 (19%) 11 (42%) 10 (38%) 0%

New Orleans (Anthony et al. 2002) [111In-DTPA

0]octreotide 26 0 2 (8%) NA 21 (81%) 3 (12%) 8%

Milan (Bodei et al. 2003) [90Y-DOTA

0,Tyr

3]octreotide 21 0 6 (29%) NA 11 (52%) 4 (19%) 29%

Basel (Waldherr et al. 2001/2002) [90Y-DOTA

0,Tyr

3]octreotide 74 3 (4%) 15 (20%) NA 48 (65%) 8 (11%) 24%

Basel (Waldherr et al. 2002) [90Y-DOTA

0,Tyr

3]octreotide 33 2 (6%) 9 (27%) NA 19 (57%) 3 (9%) 33%

Multicenter (Valkema et al. 2006) [90Y-DOTA

0,Tyr

3]octreotide 58 0 5 (9%) 7 (12%) 33 (61%) 10 (19%) 9%

Multicenter (Bushnell 2010) [90Y-DOTA

0,Tyr

3]octreotide 90 0 4 (4%) NA 63 (70%) 11 (12%) 4%

Copenhagen (Pfeifer 2011) [90Y-DOTA

0,Tyr

3]octreotide 53 2 (4%) 10 (19%) NA 34 (64%) 7 (13%) 23%

Warsaw (Cwikla 2010) [90Y-DOTA

0,Tyr

3]octreotate 58 0 13 (23%) NA 44 (73%) 3 (5%) 23%

Rotterdam (Kwekkeboom et al. 2008) [177Lu-DOTA

0,Tyr

3]octreotate 310 5 (2%) 86 (28%) 51 (16%) 107 (35%) 61 (20%) 29%

Gothenburg (Sward et al. 2010) [177Lu-DOTA

0,Tyr

3]octreotate 26 0 6 (38%) NA 8 (50%) 2 (13%) 38%

Lund (Garkavij et al. 2010) [177Lu-DOTA

0,Tyr

3]octreotate 12 0 2 (17%) 3 (25%) 5 (40%) 2 (17%) 17%

Milan (Bodei et al. 2011) [177Lu-DOTA

0,Tyr

3]octreotate 42 1 (2%) 12 (29%) 9 (21%) 11 (26%) 9 (21%) 31%

CR – complete response

PR – partial response

MR – minor response

SD – stable disease

PD – progressive disease

Page 17 of 20

Table 2. Survival data in patients with GEPNETs, treated with different radiolabeled somatostatin analogues.

Center (reference) Ligand N Livermetastases PFS OS

% of patients months months

Multicenter (Valkema et al. 2006) [90

Y-DOTA0,Tyr

3]octreotide 58 - 29 37

Multicenter (Bushnell 2010) [90

Y-DOTA0,Tyr

3]octreotide 90 72% 16 27

Copenhagen (Pfeifer 2011) [90

Y-DOTA0,Tyr

3]octreotide 53 87% 29 -

Warsaw (Cwikla 2010) [90

Y-DOTA0,Tyr

3]octreotide 58 85% 17 22

Rotterdam (Kwekkeboom et al. 2008) [177

Lu-DOTA0,Tyr

3]octreotate 310 89% 33 46

PFS – Progresion Free Survival

OS – Overall Survival

Page 18 of 20

Table 3. Long-term toxicity in patients with NETs, treated with different radiolabeled somatostatin analogues.

Toxicity

Center (reference) Ligand N FU Creatinine MDS Leukemia

Milan (Bodei et al. 2003) [90Y-DOTA

0,Tyr

3]octreotide 40 19 10% Grade 1 0 0

Basel (Waldherr et al. 2001) [90Y-DOTA

0,Tyr

3]octreotide 41 15 0 0 0

Basel (Waldherr et al. 2002) [90Y-DOTA

0,Tyr

3]octreotide 39 6 3% Grade 2 0 0

Multicenter (Valkema et al. 2006) [90Y-DOTA

0,Tyr

3]octreotide 58 18 3% Grade 4 1 0

Basel (Iten et al. 2007) [90Y-DOTA

0,Tyr

3]octreotide 31 12 12.9% Grade 3/4* 0 0

Copenhagen (Pfeifer 2011) [90Y-DOTA

0,Tyr

3]octreotide 53 17 0 1 0

Basel (Imhof 2011) [90Y-DOTA

0,Tyr

3]octreotide 1109 23 9.2% Grade 3/4* 1 1

Rotterdam (Kwekkeboom et al. 2008) [177Lu-DOTA

0,Tyr

3]octreotate 504 19 0.4% Grade 4 3 0

Milan (Bodei et al. 2011) [177Lu-DOTA

0,Tyr

3]octreotate 51 29 24% Grade1 0 0

FU: Follow-up; MDS: Myelodysplastic Syndrome.

Grades pertain to World Health Organisation (WHO) classification.

* toxicity based on glomerular filtration rate

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