Cycles Of Peptide Receptor Radionuclide Therapy Research Articles

Single institution experience with peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET).

623 Background: Neuroendocrine tumors (NETs) are rare but increasing in incidence. The only curative treatment is surgery, which in many cases is not an option due to metastatic disease at diagnosis. The NETTER-1 study showed high efficacy and low toxicity of peptide receptor radionuclide therapy (PRRT) for midgut NETs. Here, we present our initial experience with PRRT in the treatment of patients with NET. Methods: Fifty-two patients (27 males and 25 females; 37 - 81 yo, mean ± SD: 61.8 ± 10.6 years) with documented progressive NET (25 pancreas, 17 small intestine, 1 coecum, 4 unknown primary, 3 paragangliomas, and 2 pheochromocytomas) were referred to undergo PRRT at our institution from July 2018 to September 2019. Laboratory tests were obtained at baseline, 1 week before each cycle and every 3 months following treatment. Progression-free survival (PFS), objective response rate (ORR) and toxicity were assessed. An interim overall survival (OS) analysis was performed. Results, when possible, were compared with the NETTER-1 trial. Lines of therapy were documented. Results: 22/52 (42%) patients completed all 4 cycles of PRRT. 18/52 (34%) patients are currently being treated. 12/52 (23%) patients had to discontinue treatment. Hematotoxicity was the only side effect which can be related to PRRT. The 6-month and 9-month PFS rate was 82.4% and 66.8% respectively vs. 89% and 84% in the NETTER-1 trial. The ORR was 36% vs. 18% in the NETTER-1 trial. In the interim OS analysis, 6 deaths occurred. In contrast to the NETTER-1 study, PRRT in our patient cohort was performed later in the course of treatment (median lines of therapy before PRRT = 4 ±1.3 (range 1-6)). Conclusions: Our preliminary data show overall good results of PRRT in patients with NETs. However, compared to the NETTER-1 trial, PFS is shorter which is most likely due to the extensive pretreatment, but ORR was higher. [Table: see text]

Dosimetry after peptide receptor radionuclide therapy: impact of reduced number of post-treatment studies on absorbed dose calculation and on patient management

BackgroundAfter each cycle of [177Lu]-DOTA-TATE peptide receptor radionuclide therapy (PRRT) dosimetry is performed to enable precise calculation of the radiation-absorbed dose to tumors and normal organs. Absorbed doses are routinely calculated from three quantitative single-photon emission computed tomography (SPECT) studies corrected by computed tomography (CT) acquired at t1 = 24 h, t2 = 96 h, and t3 = 168 h after the first cycle of treatment. After following cycles, a single SPECT/CT study is performed. The aim of the present study is to assess the feasibility of a “two time point” quantitative SPECT/CT protocol after the first PRRT cycle and its impact on patient management.Quantitative SPECT/CT data of 25 consecutive patients with metastatic neuroendocrine tumors after PRRT were retrospectively analyzed. Radiation-absorbed doses calculated using the standard protocol with three SPECT/CT studies acquired at (t1, t2, t3) were compared to those obtained from three different “two time point” protocols with SPECT/CT studies performed at (t1, t2), (t1, t3), or (t2, t3).ResultsThe best agreement for the cumulative doses absorbed by the kidneys, bone marrow, liver, spleen, and tumors with the conventional protocol was obtained with the (t1, t3) protocol with mean relative differences of − 1.0% ± 2.4%, 0.4% ± 3.1%, − 0.9% ± 4.0%, − 0.8% ± 1.1%, and − 0.5% ± 2.0%, respectively, and correlation coefficients of r = 0.99 for all.In all patients, there was no difference in the management decision of whether or not to stop PRRT because of unsafe absorbed dose to risk organs using either the standard protocol or the (t1, t3) protocol.ConclusionThese preliminary results demonstrate that dosimetry calculations using two quantitative SPECT/CT studies acquired at 24 and 168 h after the first PRRT cycle are feasible and are in good agreement with the standard imaging protocol with no change in patient management decisions, while enabling improved patient comfort and reduced scanner and staff time.

Inflammation-Based Index and 68Ga-DOTATOC PET-Derived Uptake and Volumetric Parameters Predict Outcome in Neuroendocrine Tumor Patients Treated with 90Y-DOTATOC.

We performed post hoc analyses on the utility of pretherapeutic and early interim 68Ga-DOTATOC PET tumor uptake and volumetric parameters and a recently proposed biomarker, the inflammation-based index (IBI), for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumor (NET) patients treated with 90Y-DOTATOC in the setting of a prospective phase II trial. Methods: Forty-three NET patients received up to 4 cycles of 90Y-DOTATOC at 1.85 GBq/m2/cycle with a maximal kidney biologic effective dose of 37 Gy. All patients underwent 68Ga-DOTATOC PET/CT at baseline and 7 wk after the first PRRT cycle. 68Ga-DOTATOC-avid tumor lesions were semiautomatically delineated using a customized SUV threshold-based approach. PRRT response was assessed on CT using RECIST 1.1. Results: Median progression-free survival and overall survival (OS) were 13.9 and 22.3 mo, respectively. An SUVmean higher than 13.7 (75th percentile) was associated with better survival (hazard ratio [HR], 0.45; P = 0.024), whereas a 68Ga-DOTATOC-avid tumor volume higher than 578 cm3 (75th percentile) was associated with worse OS (HR, 2.18; P = 0.037). Elevated baseline IBI was associated with worse OS (HR, 3.90; P = 0.001). Multivariate analysis corroborated independent associations between OS and SUVmean (P = 0.016) and IBI (P = 0.015). No significant correlations with progression-free survival were found. A composite score based on SUVmean and IBI allowed us to further stratify patients into 3 categories with significantly different survival. On early interim PET, a decrease in SUVmean of more than 17% (75th percentile) was associated with worse survival (HR, 2.29; P = 0.024). Conclusion: Normal baseline IBI and high 68Ga-DOTATOC tumor uptake predict better outcome in NET patients treated with 90Y-DOTATOC. This method can be used for treatment personalization. Interim 68Ga-DOTATOC PET does not provide information for treatment personalization.

Clinical utility of 177 Lu-DOTATATE PRRT in somatostatin receptor-positive metastatic medullary carcinoma of thyroid patients with assessment of efficacy, survival analysis, prognostic variables, and toxicity.

The primary aim of this study was to evaluate the therapeutic efficacy and outcome of 177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in somatostatin receptor-positive metastatic medullary thyroid carcinoma (MTC), including progression-free survival (PFS) and overall survival (OS), and also to determine the various prognostic variables. The secondary aim was toxicity assessment of PRRT in this group of patients. A total of 43 somatostatin receptor-positive metastatic MTC patients, treated with 177 Lu-DOTATATE PRRT in a large tertiary care center, were included in this analysis. After receiving the therapy, post-treatment response evaluation was undertaken for symptomatic and biochemical responses (serum calcitonin) and imaging responses with 68 Ga-DOTATATE, 18 F-FDG PET-CT, CeCT (PERCIST and RECIST 1.1 criteria). Calcitonin doubling time (CtnDT) was calculated by the American Thyroid Association calculator. The adverse events were graded according to the NCI-CTCAE v5.0 criteria. The observed Kaplan-Meier curves for both PFS and OS since first PRRT were compared with CtnDT (more than 24 months vs less than 24 months) by log-rank (Mantel-Cox) test. The prognostic variables were investigated for their association with CtnDT and response to PRRT using Cox proportional-hazards model. The median OS was 26 months (95% CI 16.6-35.3 months) and the median PFS 24 months (95%.CI: 15.1-32.9 months). Following 177Lu-DOTATATE PRRT, the observed median PFS and OS was longer in patients who had CtnDT more than 24 months compared to those with CtnDT less than 24 months (median PFS not yet reached vs 10 months and median OS 60 months vs 20 months). Assessing from the time-point of first 177 Lu-DOTATATE PRRT cycle, the patients with CtnDT more than 24 months had a significantly longer PFS (P < .001) and OS (P < .001) compared to those with less than 24 months. Less than 5 lesions, FDG uptake in lesions (SUVmax of <5) and patients alive at the time of analysis were the significant variables for association with CtnDT (more than 24 months). Out of 43 patients, 26 were responders (61%) and 17 nonresponders (39%) based upon PERCIST criteria, and 27 were responders (62%) while 16 patients were nonresponders (38%) based upon RECIST 1.1 criteria. The univariate analysis showed significant association between responses to PRRT with following prognostic variables: (a) size of lesions (<2 cm) and (b) FDG uptake in lesions (SUVmax of <5). PRRT was well tolerated in all patients without any major grade 3 or 4 toxicity. The results demonstrated that, 177 Lu-DOTATATE is a potentially efficacious and safe therapeutic option in SSTR avid metastatic MTC patients.

Prognostic Significance of Somatostatin Receptor Heterogeneity in Progressive Neuroendocrine Tumor Treated with Lu-177 DOTATOC or Lu-177 DOTATATE.

One of the primary prerequisites for peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors (NET) is the presence of somatostatin receptors (SSTR) on NET cells. NET are highly heterogeneous and an individual patient as well as separate metastases can harbor cells with different clones, which influence the SSTR expression on NET cells. With this background we looked into our institutional database to assess the prognostic significance of quality of SSTR expression on SSTR PET/CT imaging in patients treated with at least two cycles of Lu-177 DOTATOC or Lu-177 DOTATATE. Clinical reports and images from 65 (25 females, 40 males; 65 ± 11 years old) patients with progressive grade 1 or grade 2 NET with 2-5 therapy cycles of PRRT with an average administered dose of 6.6 ± 0.97GBq Lu-177 DOTATOC or Lu-177 DOTATATE were analyzed. All patients were examined with baseline Ga-68 DOTATATE or Ga-68 DOTATOC PET/CT (PET). Quality of SSTR expression as a measure of heterogeneity on indexed lesions was assessed visually. Patients were followed for a median duration of 25months after the first PRRT (range 5-77months). A total of 70% of the patients received three or more therapy cycles. Twenty-six patients (40%) were treated with PRRT as first or second line while 39 (60%) as third line or more. SSTR expression was heterogeneous in 28 (44.4%) and homogeneous in 35 (55.6%) patients. Disease stabilization could be achieved in 23 patients (35.4%), whereas 17 (26.1%) showed partial remission and 25 patients (38.5%) had disease progression. Median OS was not reached. The 24-month survival rate of the whole study cohort was 83%. In univariate analyses, factors influencing OS were carcinoid heart disease, carcinoid syndrome and quality of SSTR expression (p < 0.05). Patients with heterogeneous SSTR expression on target lesions had a significantly lower OS (p = 0.01). Median time to progression in total patient population was found to be 40months. Patients with heterogeneous SSTR expression on target lesions had significantly lower TTP (26months vs 54months log Rank p = 0.013). By multivariate analyses, quality of SSTR was found to be the only prognostic factor for OS (p = 0.04; HR = 3.68) and also for TTP (p = 0.03; HR = 3.09). Visual assessment of SSTR heterogeneity has both predictive and prognostic value in progressive grade 1 or grade 2 NET patients undergoing PRRT.

Salvage PRRT with 177Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival

BackgroundNETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression.MethodsThirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99mTc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method.ResultsThe median PFS after initial PRRT was 33 months (95% CI: 30–36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5–47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0–16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92–119) and 51 months (95% CI: 41–61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively.ConclusionsSalvage therapy with 177Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET.

Quality of life in patients with midgut NET following peptide receptor radionuclide therapy.

There is convincing evidence that peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE compared to octreotide therapy has a positive effect on overall survival and progression-free survival in midgut neuroendocrine tumors (NET). The current study analyzed health-related quality of life (QoL) in patients undergoing PRRT with a special focus on differences in functional performance. In our study, 70 patients (39 men or 31 female) suffering from midgut NET were included, with a mean age of 64.2years. Functional performance was assessed by the index of the Eastern Cooperative of Oncology Group (ECOG). Thirty-three patients (47%) showed ECOG 0, 31 patients (44%) ECOG 1, and six patients (9%) ECOG 2. Health-related QoL was assessed by the EORTC QLQ-C30 questionnaire filled in at baseline and 3months after each PRRT cycle. The median cumulative administered activity was 27.4GBq. Global health status significantly improved compared to baseline status after 1st (p = 0.05), 2nd (p = 0.004), and 3rd (p = 0.04) treatment cycle. Analyzing specific aspects of QoL, emotional functioning significantly improved after 1st and 2nd treatment cycle (both p < 0.001) as well as after 3rd cycle (p = 0.001). With regard to cognitive functioning, there was a significant improvement after 1st and 2nd treatment cycle (p = 0.003 and p = 0.05 respectively). With regard to alleviation of somatic symptoms, a significant reduction in pain and diarrhea was observed after the 2nd cycle (p = 0.038) and 3rd cycle (p = 0.036). Furthermore, changes in QoL in relation to functional performance status as assessed by ECOG were analyzed. There were no significant differences with regard to QoL alterations between patients with high (ECOG 0 or 1) and moderate performance status. Our study confirmed an equally positive effect of PRRT on quality of life in midgut NET patients with high or moderate functional status in terms of increasing global health, functional status, and alleviating symptoms.

Surgery and peptide receptor radionuclide therapy: An effective multimodal approach for metastatic neuroendocrine tumors.

4113 Background: Neuroendocrine neoplasia (NEN) of the pancreas (PanNEN) or small bowel (SBNEN) frequently present with metastases at initial diagnosis, undermining the efficacy of surgical treatment. Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, 90Y-DOTATOC and 177Lu-DOTATATE, has been shown to achieve prolonged progression-free survival (PFS) and overall survival (OS) in a substantial number of non-surgical patients with advanced NEN. Our aim was to prospectively determine the efficacy of a combination of radical loco-regional surgery and 177Lu PRRT in patients with metastasised NEN. Methods: A set of inclusion criteria was defined (e.g. PanNEN or SBNEN, G1/G2 NEN, initial tumour diagnosis, treatment naïve patient, stage IV NEN, positivity on 68Ga DOTATATE or DOTATOC PET/CT, eligibility for surgery and PRRT). Patients underwent PRRT within 3 months following surgery. Follow-up included biochemistry and imaging. Outcome measures included 1-, 3-, and 5-year OS and PFS from initial diagnosis. Results: Forty-one patients met eligibility criteria and were included. There were 26 males (63.4%) and median age at surgery was 58.8 years (range 32.1-78.3). All patients with SBNEN underwent right hemicolectomy, terminal ileal resection and mesenteric lympadenectomy. In PanNEN patients either Whipple procedure or distal pancreatectomy and peripancreatic lymphadenectomy were performed. The median number of PRRT cycles was 4 (range 2-6). Post-treatment mortality was 0%. Surgical morbidity was 12% (all grade 1 according Clavien-Dindo) and transient grade 1 toxicity occurred post PRRT in 40%. There was no grade 3 toxicity. Median follow-up was 5.48 years (range 0.53 – 11.98). Median PFS and OS were 3.33 years and 9.07 years, respectively. Progression-free survival (with 95% CI) was at 1-, 3-, and 5-years 80% (68.7-92.6), 60.9% (45.9-75.9) and 43.3% (27.4-59.3), respectively. Overall survival (with 95% CI) at 1-, 3-, and 5-years was 97.6% (93-100), 97.6% (93-100), and 95% (87-100), respectively. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NEN.

Non-Invasive Imaging Methodologies for Assessment of Radiation Damage to Bone Marrow and Kidneys from Peptide Receptor Radionuclide Therapy

Background/Aims: Peptide receptor radionuclide therapy (PRRT) is becoming clinical routine for management of neuroendocrine tumours. The number of PRRT cycles is correlated with treatment effect but theoretically limited by off-target radiation damage to kidneys and bone marrow. New imaging biomarkers for assessment of PRRT tissue damage would enable evaluation of novel renal and bone marrow protective agents, as well as personalised PRRT treatment regiments. Methods: Mice treated with [¹⁷⁷Lu]Lu-DOTA-TATE PRRT or vehicle were examined at baseline and following treatment with [¹⁸F]fluorothymidine (FLT) positron emission tomography (PET) and technetium-99m-mercapto-acetyl-tri-glycine ([^99mTc]Tc-Mag3) single-photon emission tomography (SPECT) to assess dynamic changes in bone marrow proliferation and renal function, respectively. Results: Bone marrow proliferation as assessed by [¹⁸F]FLT was decreased 2 days after PRRT treatment, but not vehicle, compared to baseline (target-to-background ratio [TBR_max] baseline:1.69 ± 0.29 vs. TBR_max PRRT: 0.91 ± 0.02, p < 0.01). Renal function as assessed by [^99mTc]Tc-Mag3 SPECT was similarly decreased 2 days following PRRT compared to vehicle (fractional uptake rate [FUR] vehicle: 0.030 ± 0.014 s^–1 vs. FUR PRRT: 0.0051 ± 0.0028 s^–1, p < 0.01). Conclusion: [¹⁸F]FLT PET and [^99mTc]Tc-Mag3 SPECT are promising techniques for assessing bone marrow and renal injury from [¹⁷⁷Lu]Lu-DOTA-TATE PRRT and may potentially improve patient management by allowing evaluation of protective interventions as well as enabling personalised PRRT treatments.

Highly favourable outcomes with peptide receptor radionuclide therapy (PRRT) for metastatic rectal neuroendocrine neoplasia (NEN).

Rectal neuroendocrine neoplasia (NEN) is more common than other NEN origins, but is less commonly metastatic. However, when present, distant disease carries a particularly poor prognosis. Evidence guiding optimal treatment of such patients is lacking. We assessed PRRT outcomes in patients with somatostatin receptor (SSTR) positive metastatic rectal NEN from two referral centres. Patients treated with PRRT were retrospectively reviewed. Morphologic (RECIST 1.1), SSTR imaging responses and toxicity were assessed 3months post-PRRT. Kaplan-Meier estimate was used to determine progression-free survival (PFS) and overall survival (OS) from start of PRRT. Twenty-seven consecutive patients (M = 20, age 31-81 years) were reviewed. The majority (70%) had ENETs grade 2 disease (19 patients), three had Grade 3, one Grade 1, and four not documented. Overall, 63% (10/16 patients with available FDG PET/CT) had FDG avid disease. Twenty-six patients were treated for disease progression. Most had 177Lu-DOTA-octreotate with median cumulative activity of 30GBq, median fourcycles. 14 patients had radiosensitising chemotherapy (5FU or capecitabine). At 3months post-PRRT, CT disease control rate (DCR) was 96%: partial response was observed in 70% (19/27) and stable disease in 26%. All but one had partial SSTR imaging response. The median PFS was 29months. Ten patients died, with median overall survival 81months with a median follow-up of 67months. Seventeen patients had further treatments after initial PRRT (10 had further cycles of PRRT). Three patients had grade 3 lymphopenia, without significant renal toxicity, MDS or leukaemia. Our results indicate high efficacy and morphologic responses with minimal toxicity and very encouraging survival from PRRT in patients with metastatic rectal NEN despite the adverse prognostic features of this cohort. Further prospective PRRT trials are warranted in this subgroup.

1324P - The role of modulation of somatostatin analogues (SSAs) in association to peptide receptor radionuclide therapy (PRRT) after SSAs progression disease (PD) in advanced well-differentiated (WD) entero-pancreatic neuroendocrine tumours (EP-NETs)

Background: The NETTER-1 trial has recently shown the efficacy of 177Lu-DOTATATE in association with Octreotide (OCT) in somatostatin receptor positive midgut NETs, progressing to OCT. The aim of this analysis was to evaluate the role of SSA in association to PRRT beyond PD or after switch to other SSA at PD. Methods: Out of 107 WD EP-NETs, treated with PRRT (90Y-DOTATOC/DOTATATE and/or 177Lu-DOTATOC/DOTATATE) at the Istituto Nazionale Tumori of Milan, from 2008 to 2017, 69 patients (pts) treated with the combination of PRRT and SSA (OCT or Lanreotide, LAN) after SSA treatment failure, were evaluated for present analysis. We identified 2 groups: S1, pts who kept the same SSA treatment beyond first PD; S2, pts who switched the SSA with another SSA after first PD. Median Progression Free Survival (mPFS) (from the start of first SSA) and Overall Survival (OS) have been evaluated using the Kaplan-Maier method. Results: In S1 (n = 47) and S2 (n = 22) groups median age and sex were 58 ys (range 29-78) and 59.5% males vs 52.5 ys (range 35-78) and 45.4% males, respectively. We had a P-NETs percentage of 34% vs 40.9% in the S1 vs S2 groups, respectively. The most of pts (82.9% in S1 and 86.3% in S2) received PRRT with alternate radionuclides (90Y/177Lu). Overall the median number of PRRT cycles was 4.2 in S1 and 4.8 in S2 (p = 0.09). In the S1 (SSA beyond PD) group PRRT was associated with OCT in 74.5% and LAN in 25.5% of pts. In the S2 group (SSA switched with other SSA) PRRT was associated with OCT in 27.3% and LAN in 72.7% of pts. In the overall population the mPFS and OS were 70 (CI95% 52.8-87.1) and 82 (CI95% 66.7-97.2) months (mo), respectively. The difference on mPFS was 53 and 127 mo in S1 and S2, respectively (p = 0.001; HR: 0.31; CI95% 0.15-0.63). In S1 group the OS was 69 mo vs 150 mo in S2 (p = 0.004; HR: 0.32; CI95% 0.14-0.71). Conclusions: Despite the retrospective nature of the analysis and the low number of pts, we found a significant difference on mPFS and OS between S1 and S2 groups. In pts with advanced WD EP-NETs treated with PRRT plus SSA after SSA failure, the “switch” strategy of SSA after PD, might improve PFS and/or OS. Legal entity responsible for the study: Sara Pusceddu. Funding: Has not received any funding. Disclosure: N. Prinzi: Italfarmaco, Novartis: Consultancies. G. Lo Russo: AstraZeneca, BMS, MSD: Consultancies. S. Pusceddu: Novartis, Ipsen, Italfarmaco, Pfizer and advanced accelerator applications (AAA). All other authors have declared no conflicts of interest.

Additional hepatic 166Ho-radioembolization in patients with neuroendocrine tumours treated with 177Lu-DOTATATE; a single center, interventional, non-randomized, non-comparative, open label, phase II study (HEPAR PLUS trial)

BackgroundNeuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE.MethodsThe HEPAR PLUS trial (“HolmiumEmbolizationParticles forArterialRadiotherapyPlus177Lu-DOTATATE inSalvage NET patients”) is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30–48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry.DiscussionThis is the first prospective study to combine PRRT with 177Lu-DOTATATE and additional 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE may lead to an improved response rate without significant additional side-effects.Trial registrationClinicaltrials.gov NCT02067988, 13 February 2014. Protocol version: 6, 30 november 2016.

Peptide Receptor Radionuclide Therapy and the Treatment of Gastroentero-pancreatic Neuroendocrine Tumors: Current Findings and Future Perspectives.

Patients with inoperable and metastasized neuroendocrine tumors (NETs), particularly those with grades 1 and 2, usually receive treatment with somatostatin analogues (SSAs). Peptide receptor radionuclide therapy (PRRT) has gained momentum over the past two decades in patients who progress on SSAs. 177Lu-DOTATATE is currently the most widely used radiopeptide for PRRT. We reviewed the recent evidence on PRRT and the treatment of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs). 177Lu-DOTATATE can be used as neoadjuvant treatment in patients with inoperable GEP-NETs, who might be candidate for surgery after treatment and as adjuvant therapy after surgical intervention. Combination treatments of PRRT with chemotherapy or targeted agents as well as combinations of radionuclides in patients with NETs have been explored over the last few years. The majority of patients with NETs experience partial response or have disease stabilization, a small percentage has complete response, while some 30% of patients, however, will have disease progression. The safety and efficacy of retreatment with extra cycles of PRRT as salvage therapy have been evaluated in small retrospective series. Overall, there is evidence that disease control and quality of life improve significantly after 117Lu PRRT therapy. Clinical trials on this therapy are scarce, and there is a need for further studies to establish proper management guidelines.

Retreatment with peptide receptor radionuclide therapy in patients with progressing neuroendocrine tumours: efficacy and prognostic factors for response.

To evaluate the efficacy and toxicity of a repeat peptide receptor radionuclide therapy (PRRT) course in neuroendocrine tumour patients who have progressed following previous PRRT and to identify factors contributing to retreatment outcomes. This was a retrospective analysis of 47 consecutive patients who had been treated with PRRT (PRRT1) and following disease progression were retreated with a second course of PRRT (PRRT2). We reviewed patient, tumour and treatment characteristics, time to progression after PRRT1 and PRRT2, overall survival and toxicity. We evaluated Kaplan-Meier survival plots, multiple regression analysis on factors predictive of time to progression and toxicity. PRRT1:45/47 patients were initially were treated with 90Y-DOTATATE, with two patients treated with 177Lu-DOTATATE. The median progression free survival (PFS) following PRRT1 was 30 months [95% confidence interval (CI) (26.9-36.6 months)]. Two patients developed Grade1 renal toxicity. 3/47 patients had bone marrow toxicity, with 1 of these patients having Grade3 toxicity. PRRT2: At the second course of treatment, 29 patients were treated with 90Y-DOTATATE and 18 patients with 177Lu-DOTATATE. Of the 44 patients with evaluable survival data, 41 patients developed disease progression. The median PFS after PRRT2 was 17.5 months [95% CI(11-23.8 months)]. There was no statistically significant difference in median PFS dependent on the choice of radiopharmaceutical: median PFS for 177Lu-DOTATATE = 17.2 months, median PFS for 90Y-DOTATATE = 17.3 months. Male sex and high burden of liver metastases were associated with shorter PFS following a PRRT retreatment course. 17/41 (41%) patients had bone marrow toxicity (2/17 had Grade 3 toxicity; no Grade 4 toxicity was seen). One patient developed myelodysplastic syndrome. 6/41 (14.6%) developed Grade 1 renal toxicity and 1/41 (2.4%) had Grade 4 renal toxicity. The median overall survival from commencement of first PRRT cycle was 71 months. PRRT retreatment is safe and offers patients, who had progressed following initial PRRT course, a reasonably good PFS. Extra consideration is needed in patients with multiple comorbidities, as they may be at greater risk of renal and haematological toxicity. Male sex and high burden of liver metastases seem to be associated with shorter PFS following PRRT retreatment. The majority of studies on PRRT have shown that it is effective as an initial treatment. This study with long-term follow-up demonstrates that PRRT is safe and effective retreatment option in patients that have progressed following initial PRRT course.

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms.

IntroductionPeptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study.MethodsIn our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria.ResultsOverall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare.ConclusionPRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

Safety and Effectiveness of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy After Regional Hepatic Embolization in Patients With Somatostatin-Expressing Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) with Lu-DOTATATE is shown to be an effective therapeutic option for somatostatin-expressing neuroendocrine neoplasms. Some concerns are raised over safety of this modality in patients with a history of regional chemoembolization and radionuclide hepatic embolization (CRHE) and is cause of reluctance among some physicians for suggesting Lu-DOTATATE in this patient population. We retrospectively reviewed 143 patients with somatostatin-expressing neuroendocrine tumors who underwent Lu-DOTATATE PRRT. Statistical analysis was performed on effect of Lu-DOTATATE in patients with and without prior CRHE using resampling procedures and correlation coefficient (r). Proportion of toxicity in patients with and without CRHE was comparable (P = 0.246). No statistically significant correlation (r) found between any toxicity and prior CRHE (r = -0.3 to -0.03) or time elapsed between embolization and the first cycle of PRRT (r = -0.59 to 0.17). Following PRRT, 76.5% of patients with CRHE experienced benefit (partial response + stable disease), whereas 23.4% experienced progressive disease. Patients with CRHE showed more stable disease (P = 0.048) and less progressive disease (P = 0.046) following PRRT compared with no CRHE. The CRHE and no-CRHE status shared same probability for developing partial response/complete response following PRRT (P = 0.50). Treatment with Lu-DOTATATE did not show clinically or statistically significant toxicity in CRHE patients regardless of frequency of embolization or time interval between embolization and first PRRT. Results suggested a statistically significant higher response rate in patients with a history of CRHE. A prior history of CRHE is not a contraindication to subsequent PRRT.

Improving quality of life in patients with pancreatic neuroendocrine tumor following peptide receptor radionuclide therapy assessed by EORTC QLQ-C30.

Neuroendocrine tumors (NETs) have proven to be appropriate neoplasms for peptide receptor radionuclide therapy (PRRT), as the majority of these slow-growing malignancies overexpress somatostatin receptors. The aim of this study was to evaluate changes in quality of life (QoL) of patients with P-NET following PRRT. Sixty-eight patients with P-NET (31 female, mean age 61.4 y) underwent PRRT: 12 with NET of grade 1, 40 of grade 2, 8 of grade 3 (grade non-available n=8). Prior to treatment, 39 patients showed ECOG 0, 26 patients ECOG 1, and three patients ECOG 2. Clinical assessment included evaluation of QoL and symptom changes using a standardized questionnaire (EORTC QLQ-C30) and was performed at baseline and every three months following each therapy cycle up to 12months. Primary analysis compared QoL at baseline and after the fourth treatment cycle (N=53). Up to four treatment cycles PRRT were performed for each patient. The median cumulative administered activity was 28.2GBq. Primary analysis revealed that compared to baseline QoL was significantly improved revealing increased global health status (p=0.008) and social functioning (p=0.049) at the end of the study. Furthermore, fatigue and appetite loss showed a significant improvement after the last PRRT cycle (fatigue: p=0.029, appetite loss p=0.015). Sub-analyses showed that QoL was improved revealing increased global health status (3months after first, second, and third treatment cycle p=0.048, p=0.002, and p<0.001, respectively), emotional functioning (3months after first-third cycle p=0.003, p=0.049, and p=0.001, respectively) and social functioning (3months after the first and second p<0.001, and after the third cycle p=0.015, respectively). Furthermore, some symptoms were significantly alleviated compared with baseline: fatigue (after first-third cycle p=0.026, p=0.050, and p=0.008, respectively), nausea and vomiting (after first and second cycle p=0.006 and p=0.001, respectively), dyspnea (after third cycle p=0.025), appetite loss (after first-third cycle p=0.010, p=0.001, and p=0.009, respectively), constipation (after first-third cycle p=0.050, p=0.003, and p=0.060, respectively). PRRT is an effective treatment of P-NET improving QoL of patients in terms of increasing global health and mitigation of physical complaints.

Persistent Hematologic Dysfunction after Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE: Incidence, Course, and Predicting Factors in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) may induce long-term toxicity to the bone marrow (BM). The aim of this study was to analyze persistent hematologic dysfunction (PHD) after PRRT with 177Lu-DOTATATE in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs). Methods: The incidence and course of PHD were analyzed in 274 GEP NET patients from a group of 367 patients with somatostatin receptor-positive tumors. PHD was defined as diagnosis of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN), MDS/MPN, or otherwise unexplained cytopenia (for >6 mo). Using data from The Netherlands Cancer Registry, the expected number of hematopoietic neoplasms (MDS, AML, MPN, and MDS/MPN) was calculated and adjusted for sex, age, and follow-up period. The following risk factors were assessed: sex, age over 70 y, bone metastasis, prior chemotherapy, prior external-beam radiotherapy, uptake on the [111In-DTPA0]octreotide scan, tumor load, grade 3-4 hematologic toxicity during treatment, estimated absorbed BM dose, elevated plasma chromogranin A level, baseline blood counts, and renal function. Results: Eleven (4%) of the 274 patients had PHD after treatment with 177Lu-DOTATATE: 8 patients (2.9%) developed a hematopoietic neoplasm (4 MDS, 1 AML, 1 MPN, and 2 MDS/MPN) and 3 patients (1.1%) developed BM failure characterized by cytopenia and BM aplasia. The median latency period at diagnosis (or first suspicion of a PHD) was 41 mo (range, 15-84 mo). The expected number of hematopoietic neoplasms based on The Netherlands Cancer Registry data was 3.0, resulting in a relative risk of 2.7 (95% confidence interval, 0.7-10.0). No risk factors for PHD could be identified for the GEP NET patients, not even bone metastasis or estimated BM dose. Seven patients with PHD developed anemia in combination with a rise in mean corpuscular volume. Conclusion: The prevalence of PHD after PRRT with 177Lu-DOTATATE was 4% in our patient population. The median time at which PHD developed was 41 mo after the first PRRT cycle. The relative risk for developing a hematopoietic neoplasm was 2.7. No risk factors were found for the development of PHD in GEP NET patients.

177Lu-DOTATATE peptide receptor radionuclide therapy in metastatic or advanced and inoperable primary neuroendocrine tumors of rare sites

The present study aimed at exploring the patient and imaging characteristics of primary neuroendocrine tumors (NETs) of rare sites who presented with metastatic and/or advanced inoperable stages and therefore was considered for peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. A retrospective analysis was undertaken of these patients focusing on the aforementioned aspects. All patients underwent dual-tracer molecular functional imaging with somatostatin receptor (SSTR)-based imaging (with either 99mTc-HYNIC-TOC or 68Ga-DOTATATE) and 18fluorine fludeoxyglucose positron emission tomography-computed tomography as the pretherapy assessment. Based on the qualitative uptake of tracer in SSTR imaging, the lesions were divided into four categories Grade 0–III. The response was assessed post-PRRT by three parameters: (i) symptomatic response, (ii) biochemical response (serum tumor marker), and (iii) objective imaging response. The response profiles under each of these scales were assessed utilizing predefined criteria (detailed in methods). The overall response classification into partial response, stable disease, and progressive disease was done based on documentation of similar scale/category of at least two parameters among the triple parametric assessment. A total of nine patients (7 males, 2 females; age range: 33–59 years) with rare site primary NET were found: The primary sites included ureter (n = 1), sacrococcygeal (n = 1), esophagus (n = 1), thymus (n = 3), and mediastinum (n = 3). Treatment response assessment was undertaken in eight patients who received more than 2 cycles of PRRT with 177Lu-DOTATATE. In this response assessment group (n = 8), the patients received 2–5 cycles and follow-up duration ranged from 5 to 48 months. Symptomatic responses and better quality of life were observed in 4/8 (50%) patients, stable symptomatic disease in 3/8 (37.5%), and progression in 1/8 patients (12.5%). Biochemically, partial response was seen in 3/8 (37.5%), stable values was seen in 3/8 (37.5%), and progression of tumor marker was seen in 2/8 (25%) patients. Morphologically, partial response was seen in 2/8 (25%), stable disease in 5/8 (62.5%), and progressive disease in 1/8 (12.5%) patients. On overall assessment, 2/8 patients (25%) demonstrated partial response, 4/8 stable disease (50%), and 2/8 progressive disease (25%) at the time of assessment. As per the RECIST 1.1, seven patients had stable disease and one patient had progressive disease. No specific correlation could be obtained between dual-tracer molecular imaging features and the response likely due to small population of the study group. Overall, there was evidence of excellent disease stabilization, and symptom palliation with 177Lu-DOTATATE PRRT was documented in these advanced or metastatic NETs of various rare sites.

Outcomes of peptide receptor radionuclide therapy (PRRT) in metastatic grade 3 neuroendocrine tumors (NETs).

e15694 Background:Grade 3 (G3) NETs have a poor prognosis and limited treatment options (usually chemotherapy). PRRT is a potential treatment option if all sites of disease demonstrate high uptake on somatostatin-receptor imaging (SSRI). We retrospectively evaluated the efficacy of PRRT in G3 NETs. Methods: We reviewed records of patients with metastatic G3 NETs (Ki-67 &gt; 20%) who received PRRT at our institution. Patients were treated with up to 5 cycles of PRRT, predominantly 177Lu-DOTA-octreotate. Further maintenance PRRT was administered upon progression if deemed suitable on SSRI. Radio-sensitizing chemotherapy was administered unless contra-indicated. Kaplan-Meier estimate was used to determine median overall survival (OS) and median time to new treatment/death (TNTD) defined from start of PRRT. Subgroup-analysis was performed for patients with Ki67 &lt; 55% and ≥55%. Results: 26 patients with metastatic G3 NET received PRRT; 22 combined with chemotherapy (capecitabine/temozolomide (n = 12), 5-fluorouracil or capecitabine (n = 8), other (n = 2)). 58% were male. The median age was 62 (range 16-78 years). 61% had pancreatic NET, 19% small bowel, 8% lung, 8% unknown primary, 4% rectal. 77% had received at least one line of prior chemotherapy. 54% received prior platinum-based chemotherapy. Median follow-up was 33 months (range 8-83 months). Patients received a median of 4 cycles of PRRT (range 1-15). The estimated median OS from start of PRRT was 18 months: for Ki-67 &lt; 55% (n = 21), 20 months; and Ki-67≥ 55% (n = 5), 9 months. The estimated median TNTD was 12 months: for Ki-67 &lt; 55%, 16 months; and Ki-67≥55%, 4 months. 31% of patients were alive without a change in treatment modality following PRRT. Conclusions: In thispoor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.