Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-013-2677-3

ORIGINAL ARTICLE

Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours Samer Ezziddin & Feras Khalaf & Maria Vanezi & Torjan Haslerud & Karin Mayer & Abdullah Al Zreiqat & Winfried Willinek & Hans-Jürgen Biersack & Amir Sabet Received: 13 August 2013 / Accepted: 20 December 2013 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with 177Luoctreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2). Methods We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with 177 Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory

work-up including blood count, and liver and renal function, supplemented with serial 99mTc-DTPA clearance measurements. Results The median follow-up period was 58 months (range 4 – 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 – 42) and 53 months (95 % CI 46 – 60), respectively. A G1 proliferation status was associated with longer PFS (p=0.04) and OS (p= 0.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤70 %, p=0.007), a high hepatic tumour burden (≥25 % liver volume, p=0.017), and an elevated plasma level of neuron-specific enolase (NSE >15 ng/ml, p=0.035). Conclusion The outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient’s performance status, tumour burden and baseline plasma NSE level.

S. Ezziddin (*) : F. Khalaf : M. Vanezi : T. Haslerud : A. Al Zreiqat : H.
Keywords PRRT . 177Lu-octreotate . Pancreatic NET . Neuroendocrine tumours . Radionuclide therapy

K. Mayer Department of Internal Medicine and Oncology, University Hospital, Bonn, Germany W. Willinek Department of Radiology, University Hospital, Bonn, Germany

Introduction Increasing evidence supports the efficacy of peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues for metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NET) [1–3]. However, due to the

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heterogeneity of tumours of neuroendocrine origin in published studies, it is challenging to extract solid conclusions regarding the clinical benefit of PRRT in patients with pancreatic neuroendocrine tumours (pNET). The largest study on the efficacy of PRRT with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) in neuroendocrine tumours reported an overall response rate of about 60 % in pNET, but results for survival outcome, i.e. overall survival (OS) and progression-free survival (PFS), were not available for this specific tumour group [2]. A recent prospective study assessing the outcome of pNET after PRRT with 177Lu-octreotate at two different therapeutic dosages (reduced and regular) reported a disease control rate (DCR) of 81 % in the entire cohort, but in the small population (26 patients) treated with the regular dose, median PFS and OS were not reached during follow-up [4]. We aimed to assess the outcome and toxicity of PRRT with 177Lu-octreotate in a wellcharacterized patient population with advanced grade 1/2 (G1/ 2) pNET including exploration of potential predictors of impaired survival.

Materials and methods Patients All 68 consecutive patients with histologically confirmed, unresectable, metastatic pNET treated with 177Lu-octreotate at our institution (35 men, 33 women; age range 37 – 82 years, mean age 62 years) were included in this retrospective analysis. Patients were classified according to the current TNM staging and grading system for neuroendocrine tumours [5]. All tumours were well-differentiated endocrine carcinomas according to the histopathology with the presence of distant metastases (TNM stage IV). Other inclusion criteria were sufficient tumour uptake, i.e. uptake greater than liver uptake on baseline receptor imaging, a glomerular filtration rate (GFR) >30 ml/min/1.73 m 2 , a white blood cell count ≥2,000/mm3, haemoglobin ≥8 g/dl and platelets ≥75,000/ mm3. Metastatic sites included the liver in 65 patients (97.1 %), lymph nodes in 41 (60.3 %), bone in 25 (35.3 %) and other organs in 19 (27.9 %). Treatment decisions were made on a multidisciplinary basis. Morphological tumour progression was documented in 46 patients (67.6 %) during the 12 months before initiation of PRRT. Nine patients (13.2 %) showed uncontrolled functional symptoms despite other treatments and 13 patients (19.1 %) presented with late stage disease and high tumour burden at the time of diagnosis not suitable for less aggressive treatment strategies. PRRT was the first-line systemic therapy in 35 patients (51.5 %). Previous treatments were surgery (30 patients, 44.1 %), biotherapy (20 patients, 29.4 %), chemotherapy (17 patients, 25 %) and locoregional treatment (7 patients, 10.3 %). For the purposes of the study, hepatic tumour burden at baseline was

retrospectively assessed from pretreatment CT/MRI imaging and expressed in terms of percentage of the whole liver. The cut-off value of 25 % liver involvement was identified as the best predictive separator, and was used for all survival analyses. The study was performed in accordance with the Declaration of Helsinki and with national regulations. The local committee on ethics approved this retrospective study and all subjects signed written informed consent for the scientific analysis of their data. PRRT PRRT was performed with a mean of 8.0 GBq (216 mCi) 177 Lu-octreotate per treatment cycle, aiming at four courses with standard intervals of 3 months (10 – 14 weeks). The 177 Lu (IDB Holland, Baarle-Nassau, The Netherlands) had a specific activity in the approximate range 100 – 160 GBq/ μmol at the time of administration. Peptide labelling [6, 7] was performed such that an apparent specific activity of about 54 GBq/μmol (ratio of activity to the total amount of peptide) was obtained. Nephroprotection was implemented with standard amino acid coinfusion according to the Rotterdam protocol [8, 9] (lysine 2.5 % and arginine 2.5 % in 1 L 0.9 % NaCl; infusion 250 ml/h). Tumour uptake was classified according to the 177Lu-octreotate therapy scan of the first PRRT cycle (grade 3, more than kidney/spleen uptake; grade 2, more than liver uptake; grade 1 approximately the same as liver uptake). This was done to standardize the uptake score for the entire cohort, since some patients underwent somatostatin receptor scintigraphy (e.g. Octreoscan) at baseline, whereas others received PET imaging with a 68Ga labelled somatostatin analogue. Response and toxicity assessment Haematological parameters were determined prior to each treatment course, during the 2 – 4-week intervals between the courses, 8 – 12 weeks after the last course of PRRT, and at 3-monthly intervals during follow-up. Toxicity was recorded using the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Restaging was performed 3 months after termination of PRRT. Imaging consisted of CT and/or MRI according to the baseline imaging modality. Follow-up imaging was performed at 6-month intervals after the first restaging. Overall tumour response was defined according to the modified Southwest Oncology Group (SWOG) criteria [10]; the additional response category, minor response (MR) was defined as a 25 – 49 % remission of the sum of the products of perpendicular diameters of all measurable tumour lesions. In order to facilitate comparison of the response rates with those in other studies, we additionally reevaluated the restaging imaging applying Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The

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results of standard functional imaging (pretreatment and posttreatment somatostatin receptor imaging) were not incorporated into the response designation in this study.

Table 1 Patient characteristics and disease control rate (DCR), defined as the sum of PR, MR and SD

Survival assessment and statistical analysis

Total 68 Age (years) ≤65 35 >65 33 Karnofsky performance status ≤70 16 >70 52 Ki-67 index (%) ≤2 19 3 – 20 49 Hepatic tumour burdena <25 26 ≥25 42 Tracer uptake ≤grade 2 8 >grade 2 60

Survival was analysed using the Kaplan-Meier curve method. PFS was censored at the start of a subsequent antiproliferative treatment. Univariate analysis using the log-rank test was performed for each baseline factor. Multivariate analysis (Cox proportional hazards model) was performed with those variables showing at least a trend (p<0.1) for an effect in the univariate analysis (log-rank test). All tests were performed applying a significance level of p<0.05. The statistical software package SPSS (version 20; SPSS Inc., Chicago, IL) was used to analyse the data.

Results A total of 232 PRRT courses were performed in 68 patients. Lu-octreotate administrations were well tolerated without any serious acute adverse events. In three patients, treatment was stopped after one (one patient) or two (two patients) cycles because of documented disease progression. Relevant haematotoxicity (grade 3/4) was observed 3 – 10 weeks after at least one of the administrations in four patients (5.9 %). Significant leucopenia occurred after four administrations (1.7 %), thrombocytopenia after five (2.2 %) and anaemia after two (0.9 %). Blood count values returned to the normal range in all patients, the mean time to complete bone marrow recovery was 11 months after termination of PRRT (range 3 – 18 months). No significant nephrotoxicity (grade 3 or more) was observed during follow-up with a minor mean relative change of GFR (-2 % per year). No other relevant toxicities or treatment-related deaths were observed. The mean cycle activity of 177Lu-octreotate was 8.0± 0.56 GBq. The observed treatment response according to modified SWOG criteria consisted of partial response (PR) in 41 patients (60.3 %), MR in 8 (11.8 %), stable disease (SD) in 9 (13.2 %), and progressive disease (PD) in 10 (14.7 %). The baseline characteristics of the study population and the associated DCR, defined as the sum of PR, MR and SD, are given in Table 1. According to RECIST 1.1 the following responses were recorded: PR in 39 patients (57.4 %), SD in 19 (27.9 %), and PD in 10 (14.7 %). The DCR was unchanged from that derived from SWOG criteria. Figure 1 illustrates tumor response in a patient with a G1 pNET and liver metastases. The median follow-up period was 58 months (range, 4 – 112 months). Median PFS was 34 months (95 % CI 26 – 42) from the start of treatment (Fig. 2a). Patients with G1 tumours had a median PFS of 45 months (95 % CI 35 – 55) 177

Variable

No. of patients

Progression at baselineb No 22 Yes 46 Presence of bone metastases No 44 Yes 22 Functionality Nonfunctional 50 Functional 18 Chromogranin A (ng/ml) ≤600 33 >600 35 Neuron-specific enolase (ng/ml) ≤15 28 >15 40 a

DCR, n (%)

p value

58 (85.3) 29 (82.9) 29 (87.9)

0.735

13 (81.3) 45 (86.5)

0.680

18 (94.7) 40 (81.6)

0.262

24 (92.3) 34 (81.0)

0.297

7 (87.5) 51 (85.0)

1.0

19 (86.4) 39 (84.8)

1.0

39 (88.4) 19 (79.2)

0.307

44 (88.0) 14 (77.8)

0.457

31 (93.9) 27 (77.1)

0.085

27 (96.4) 31 (77.5)

0.039

Percent of total liver volume

b

Documented pretreatment morphological tumour progression during the 12 months before initiation of PRRT

as opposed to 28 months (95 % CI 20 – 36) in those with G2 tumours (p=0.04). In addition to the current WHO grading with a Ki-67 cut-off value of 2 % (G1 vs. G2), we also performed an analysis applying a cut-off value of 5 % based on a previous suggestion [11]. A proliferation index of >5 % was also associated with a shorter PFS in our cohort (24 vs. 40 months, p=0.03). Figure 3 illustrates the PFS-related patient stratification for both cut-off values. 22The median OS of the entire cohort was 53 months (95 % CI 46 – 60; Fig. 2b). Patients with lower Ki-67 indices also had a significantly longer OS, as shown in Fig. 4. The analysis of various baseline factors for their potential contribution to OS is shown in Table 2. Of all the variables

Eur J Nucl Med Mol Imaging Fig. 1 68Ga-DOTATOC PET/CT images before (a) and 3 months after (b) PRRT showing partial remission illustrated in a patient with metastatic G1 pNET. From left to right Maximum intensity projection PET images (coronal view), fused PET/CT images and unfused CT images( arrows selected lesion)

contributing to OS in the univariate analysis, performance status (KPS ≤70, hazard ratio, HR, 3.1, 95 % CI 1.4 – 7.1; p=0.007), WHO grading (G2, HR 2.8, 95 % CI 1.1 – 7.8; p=0.044), hepatic tumour burden >25 % (HR 2.9, 95 % CI 1.2 – 7.0; p=0.017), and neuron-specific enolase (NSE) >15 ng/ml (HR 2.2, 95 % CI 1.0 – 4.4; p=0.035) remained significant in the multivariate analysis (Fig. 5). Patients treated with PRRT in the first-line setting had a comparable outcome (p=0.591 and 0.254 for PFS and OS, respectively) to patients treated in a later setting (second-line or later). The same applied to patients with documented pretreatment morphological tumour progression when compared with the remaining cohort.

Discussion In this retrospective study we analysed the survival outcome data derived from a large cohort of patients with pNET undergoing PRRT with 177Lu-octreotate. The results of this

Fig. 2 PFS (a) and OS (b) of the entire patient cohort. The median PFS and OS were 34 months (95 % CI 26 – 42) and 53 months (95 % CI 46 – 60), respectively

analysis in a well-characterized cohort of 68 patients demonstrate the efficacy of PRRT in patients with pNET with a DCR of 85.3 % and an impressive median time-to-progression of 34 months. Lack of prospective clinical trials and studies in homogeneous series of patients has previously limited the widespread acceptance of PRRT as a first-line therapy in patients with metastatic well-differentiated pNET [12]. In the largest study of PRRT with 177Lu-octreotate, 310 patients with various primary GEP-NET tumours including 92 patients with advanced pNET were treated with standard cumulative activities of 27.8 – 29.6 GBq (Table 3). The median OS was 46 months and the median PFS was 33 months in the entire cohort. However, survival information regarding the subgroup of patients with pNET was not available [2]. In the only prospective study of PRRT in pNET, only 26 of 52 patients received a standard cumulative dose while the other patients with risk factors received a markedly reduced dose of 17.8 GBq (range 11.1 – 19.9 GBq) to avoid severe renal or haematological toxicity (Table 3). The reported DCR (i.e. CR,

Eur J Nucl Med Mol Imaging Fig. 3 PFS stratified by (a) tumour grade using the current WHO definition with a Ki-67 cutoff of 2 % and (b) the suggested new Ki-67 cut-off of 5 %. The median PFS (a) was 45 months (95 % CI 35 – 55) in patients with G1 tumours and 28 months (95 % CI 20 – 36) in patients with G2 tumours (p=0.04). Applying the suggested cut-off of 5 % (b), the median PFS was 37 months (95 % CI 27 – 47) and 23 months (95 % CI 18 – 28) in patients with G1 and G2 tumours, respectively (p=0.019)

PR and SD) in the study was 81 % and PFS was 29 months [4]. pNETs are more sensitive to cytotoxic chemotherapy than other GEP-NET [13, 14]. Nitrosourea streptozocin, alone or in combination with 5-fluorouracil/doxorubicin, was one of the first agents investigated in pNET and resulted in limited benefit [15–17]. Subsequent studies indicated higher response rates after treatment with temozolomide-based regimens [18–20]. In a retrospective study in 30 patients with advanced G1/2 pNET, the oral combination of capecitabine and temozolomide (as first-line chemotherapy) resulted in very high response rates (objective response rate 70 %) with a median PFS of 18 months (95 % CI 9 – 31) [21]. Our results indicate a considerably longer PFS after PRRT with a median of 34 months (95 % CI 26 – 42) derived from a cohort including patients treated in a second-line or later setting (Table 4). The characteristics of the population in the study by Strosberg et al. of capecitabine/temozolomide [21] were very comparable to Fig. 4 OS stratified by (a) tumour grade using the current WHO definition with a Ki-67 cut-off of 2 % and (b) the suggested new Ki-67 cut-off of 5 %. a The median OS was not reached during follow-up in patients with G1 tumours and was 49 months (95 % CI 45 – 53) in patients with G2 tumours (p=0.014). b Applying the suggested cut-off of 5 %, the median OS was 63 months (95 % CI not available) and 48 months (95 % CI 29 – 66) in patients with G1 and G2 tumours, respectively (p=0.038)

our study cohort in most respects (mean age, proportions of each sex, nonfunctional pNET, baseline progression) or even in favour of the chemotherapy study (100 % firstline patients vs. 51.5 % in our study, 64 % of patients with low-grade tumours of those with known grades vs. 28 % G1 tumours in our study). Although metastatic tumour burden and patient performance status were not described in the report of the other study, there is no reason to assume a population-induced skewed (impaired) outcome in the chemotherapy study according to the known characteristics. Recent prospective trials have evaluated a variety of novel targeted agents [22–29] and have demonstrated an improved PFS of up to 12 months in patients with advanced pNET treated with sunitinib or everolimus (Table 4). In a phase III placebocontrolled trial on patients with progressive well-differentiated (G1/2) pNET, everolimus (10 mg/day) prolonged the median PFS to 11 months (95 % CI, 10.8 – 14.8) [30]. In a similar trial,

Eur J Nucl Med Mol Imaging Table 2 Survival outcomes according to various baseline factors

Variable

Total

OS (95 % CI) in months

b

Percent of total liver volume

Documented pretreatment morphological tumour progression during the 12 months before initiation of PRRT

Multivariate analysis

p value

HR (95 % CI)

p value

<0.001

3.1 (1.4 – 7.1)

0.007

0.014

2.8 (1.1 – 7.8)

0.044

0.041

2.9 (1.2 – 7.0)

0.017

0.019

0.5 (0.2 – 1.2)

0.135

0.061

1.1 (0.5 – 2.3)

0.856

0.045

0.7 (0.2 – 2.0)

0.506

2.2 (1.0 – 4.9)

0.039

53 (46 – 60)

Age (years) ≤65 53 (45 – 61) >65 49 (39 – 52) Karnofsky performance score ≤70 37 (9 – 65) >70 63 (not available) Ki-67 index (%) ≤2 Not reached >2 49 (45 – 53) Hepatic tumour burdena <25 Not reached ≥25 48 (43 – 53) Tracer uptake ≤grade 2 45 (15 – 75) >grade 2 56 (41 – 71) Progression at baselineb Yes 54 (46 – 61) No 48 (43 – 52)

a

Univariate analysis

Presence of bone metastases Yes 49 (47 – 51) No Not reached Functionality Nonfunctional 63 (48 – 78) Functional 45 (37 – 53) CgA (ng/ml) ≤600 Not reached >600 54 (43 – 65) NSE (ng/ml) ≤15 Not reached >15 49 (42 – 56)

0.948

0.768

0.173

0.095

Fig. 5 OS stratified by pretreatment (a) NSE plasma level (cut-off 15 ng/ml), (b) Karnofsky performance score (cut-off 70), and (c) hepatic tumour burden (percent of liver volume, cut-off 25 %)

Eur J Nucl Med Mol Imaging Table 3 Previously reported tumour responses and survival in patients with pNET treated with PRRT Reference

Year

Type of study

Radioligand

No. of patients

ORR (%)

DCR (%)

PFS (months)

OS (months)

Kwekkeboom et al. [2] Bodei et al. [40] Imhof et al. [3] Sansovini et al. [4]

2008 2011 2011 2013

Retrospective Prospective Retrospective Prospective

177

Present study

2014

Retrospective

177

91 14 342 26a 26b 68

43 57 47 39 18 60

86 78 NA 85 77 85

NA NA NA 29+ 20 34

NA NA 55 NR NR 53

Lu-DOTATATE Lu-DOTATATE 90 Y-DOTATOC 177 Lu-DOTATATE 177

Lu-DOTATATE

ORR objective response rate, DCR disease control rate, PFS progression-free survival, OS overall survival, NA not available, NR not reached a

5.5 GBq/cycle (“full dose”)

b

3.7 GBq/cycle (“reduced dose”)

sunitinib (37.5 mg/day) also demonstrated antitumour efficacy in patients with pNET, with analogous results for PFS (a median of 11 months vs. 5.5 months in the placebo arm; HR 0.4) [31]. Our observed outcome following PRRT (median PFS 34 months) compares favourably with these agents, although we are aware that comparing our retrospective data with results from prospective trials is of limited validity. However, we aimed to distinguish and characterize our cohort in the best possible way to facilitate meaningful comparisons. In our cohort, the subgroup of patients receiving PRRT after documented morphological tumour progression during the preceding 12 months showed a median PFS of 28 months (95 % CI 21 – 35) and a median OS of 54 months (95 % CI 46 – 61).

Ki-67 index-based grading provides prognostic information in GEP-NET [32–36]. In our cohort, tumour grading was an independent predictor of OS, and – as demonstrated by our results – was of prognostic relevance in patients with welldifferentiated pNET after PRRT (HR 2.8, 95%CI 1.1 – 7.8; p= 0.044). Also the duration of disease stabilization was predicted by the grading, as patients with G1 tumours (Ki-67 ≤2 %) had a longer PFS than those with G2 tumours (Ki-67 3 – 20 %). A higher cut-off for the proliferation rate (i.e. 5 %) has been suggested to be more suitable for differentiating G1 and G2 pNET [4, 11]. In our study, the predictive value of grading for both PFS and OS was irrespective of the applied cut-off (2 % vs. 5 %). It is noteworthy, however, that even in

Table 4 Outcomes in different chemotherapy studies in patients with metastatic pNET Reference

Year

Type

Chemotherapy

No. of patients

ORR (%)

PFS (months)

OS (months)

Moertel et al. [15]

1980

Randomized controlled trial

Moertel et al. [16]

1992

Randomized controlled trial

Kouvaraki et al. [17] Ramanathan et al. [41] Kulke et al. [18] Ekeblad et al. [20] Strosberg et al. [21] Kulke et al. [28] Yao et al. [23] Yao et al. [42]

2004 2001 2006 2007 2011 2008 2008 2010

Retrospective Phase II Phase II Phase II Retrospective Phase II Phase II Phase II

STZ STZ + 5-FU STZ + DOX STZ + 5-FU Chlorozotocin STZ + DOX + 5-FU DTIC TMZ + thalidomide TMZ TMZ + capecitabine Sunitinib Everolimus + SSA Everolimus Everolimus + SSA

42 42 36 33 33 84 43 11 12 30 66 30 115 45

36 63 69 45 30 39 33 45 8 70 17 27 9.6 4.4

NA 17 18 6 3 9.3 NA NR (17+) NA 18 7.7 11.6 9.7 16.7

16.5 26 26 18 18 40 19 31 7 NR (36+) NR (28+) NR (36+) 25 26+

Yao et al. [30] Raymond et al. [31] Chan et al. [43] Chan et al. [44]

2011 2011 2012 2013

Phase III Phase III Phase II Phase II

Everolimus Sunitinib TMZ + bevacizumab Everolimus + TMZ

207 171 15 40

5 9 33 40

11 11.4 14 15.4

NR (28+) NR (20+) NA NR (40+)

ORR objective response rate, PFS progression-free survival, OS overall survival, STZ streptozotocin, DOX doxorubicin, 5-FU 5-fluorouracil, TMZ temozolomide, SSA somatostatin analogue (octreotide acetate for injection), NA not available, NR not reached

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those patients with higher proliferation rates (Ki-67 >5 %) the outcome, i.e. median PFS and OS of 23 and 48 months, respectively, was not disappointing and compares favourably with that of other treatment modalities [30]. Similar to the findings of previous studies dealing with neuroendocrine tumours in other contexts [37–39], we identified the presence of an elevated NSE plasma level as an independent negative predictor of outcome: patients with a baseline NSE >15 ng/mL had a shorter OS (p=0.039). This predictive effect was independent of G1/2 grading in the multivariate analysis. Other contributing factors to shorter OS were, not surprisingly, high hepatic tumour burden and reduced performance status (Fig. 5) [2, 33]. Patients with a Karnofsky performance score ≤70 % had a significantly shorter OS, but the recorded median OS of 37 months after PRRT is still considerable and would not serve as an argument against performing the treatment. Previous studies have suggested tumour tracer uptake as a prognostically relevant factor contributing to treatment response [2] and survival [3]. In our cohort, qualitative tumour uptake of 177Lu-octreotate proved significant only in the univariate exploration (log-rank) and failed to show a dominant impact on survival in the multivariate analysis. However, the small number of patients in our cohort with only moderate uptake in the 177Lu-octreotate scan (n=8) may leave our distinction less optimal than those based mainly on 111In-DTPA octreotide imaging [2, 3]. However, in many clinical settings worldwide, pretreatment receptor imaging is not uniformly performed (e.g. with Octreoscan) leading to a similar situation with compromised standardized scoring of target tracer uptake. The limited population size and the retrospective nature of this study will inevitably affect the strength of our conclusions. The results of comparisons using historical data are limited by potential differences in the patient populations, and should be interpreted with particular caution. However, the low incidence of serious adverse events and the longer PFS and OS in our cohort compared to the findings of studies using other treatment modalities were most probably a reflection of a real difference in patient outcomes. Conclusion PRRT with 177Lu-octreotate seems to be highly effective in patients with advanced well-differentiated pNET, producing outstanding response rates and survival outcomes irrespective of the documented tumour progression status at baseline. Although, conclusions derived from a retrospective analysis should be handled with caution, we feel that the large discrepancy between the observed outcome (objective response rate and PFS) and that of other existing systemic treatment modalities does indicate a potent efficacy of this targeted radionuclide therapy and justifies its broader use despite the absence of data

from larger prospective studies. Also, the implementation of PRRT as a first-line treatment in inoperable progressive pNET might be considered given the results of this study. Randomized clinical trials comparing 177Lu-octreotate and everolimus would be helpful – although difficult to achieve in view of the assumed discrepancy in efficacy – to establish a new standard of care for this rare malignancy.

Conflicts of Interest None.

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