Cycles Of Peptide Receptor Radionuclide Therapy Research Articles

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.

Surgery in combination with peptide receptor radionuclide therapy is effective in metastatic neuroendocrine tumors and is definable by blood gene transcript analysis.

e15697 Background: Neuroendocrine tumours (NET) of the pancreas (PNET) or small bowel (SBNET) 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) in a substantial number of non-surgical patients with advanced NET. Our aim was to prospectively determine the efficacy of a combination of radical loco-regional surgery and PRRT in patients with metastasised NET. Methods: A set of inclusion criteria was defined (e.g. G1/G2 NET, initial tumour diagnosis, treatment naïve patient, stage IV NET, positivity on 68Ga DOTA- PET/CT, eligibility for surgery and PRRT). Patients underwent PRRT within 3 months following surgery. Follow-up included biochemistry and imaging. In a sub-cohort, blood-based neuroendocrine gene transcript analysis of 51 genes (NETest) was used to define the effectiveness of treatment. Outcome measures included 5-year overall survival (OS) and PFS from initial diagnosis. Results: Twenty-five patients (5 PNET, 20 SBNET) met eligibility criteria and were included. There were 13 men (52%) and mean age was 57.1 years. All patients with SB NET underwent right hemicolectomy, terminal ileal resection and mesenteric lympadenectomy. In all PNET patients only limited pancreatic resection was required. The median number of PRRT cycles was 4 (range 2-6). Post-treatment mortality was 0%. Surgical morbidity was 12% (all Clavien-Dindo grade 1). Transient grade 1 toxicity occurred post-PRRT in 40%. NETest scores were increased in 8 patients (100%) pre-operatively and decreased in all following treatment. NETest decreases correlated with diminished tumour volume (R2=0.37, p=0.02). Median follow-up was 48 months (range 12-72months). Five-year OS was 90% and 5-year PFS was 84.3%. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.

Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study.

Peptide receptor radionuclide therapy (PRRT) with 177Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course. Thirty-six patients underwent 122 fixed-IA 177Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6 ± 2.4GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2 ± 5.5, 1.3 ± 0.8, and 114 ± 66Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle. In the P-PRRT regime, cumulative IA could have been increased to 43.7 ± 16.5GBq over four induction cycles (10.9 ± 5.0GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5 ± 2.5, 1.63 ± 0.61, and 163.4 ± 85.9Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68-2.64-fold; P = 0.0013). By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity.

The Impact of Radiological Response to Peptide Receptor Radionuclide Therapy on Overall Survival in Patients With Metastatic Midgut Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced neuroendocrine tumors (NET); however, long-term survival data are scarce. The aim of this study is to determine long-term survival in patients with metastatic midgut NET, according to response to PRRT. One hundred thirty-three consecutive patients with progressive metastatic midgut NET underwent PRRT. Response at 1 year post PRRT was classified as partial response, stable disease, disease progression, or death. Survival was assessed according to response to PRRT, and predictors of overall survival (OS) and progression-free survival (PFS) were identified. At 1 year post PRRT, 9% had partial response, 50.4% stable disease, 10.5% disease progression, and 30.1% were dead. The OS was 33.5, and PFS was 28.5 months. Predictors of disease progression/death were chromogranin A greater than 10 ULN (OR, 4.6; P = 0.007) and hepatic tumor load greater than 50% (OR, 5; P = 0.004). There was no difference in OS between patients with partial response and those with stable disease post PRRT. In multivariate Cox regression, predictors of OS were number of PRRT cycles (HR, 0.33; P < 0.0005), hepatic tumor load greater than 50% (HR, 3.46; P = 0.01), and outcome at 1 year post PRRT (HR, 21.37; P < 0.0005). Predictors of PFS were number of PRRT cycles (HR, 0.39; P < 0.0005), previous resection of liver metastases (HR, 3.56; P = 0,023), and hepatic tumor load greater than 50% (HR, 3.06; P < 0.0005). Patients with progressive metastatic midgut NET who achieved stable disease at 1 year post PRRT had similar OS with those with partial response. Hepatic tumor burden was a strong predictor of response to PRRT, PFS, and OS.

417P Availability and Utility of Functional Imaging (FI) and Peptide Receptor Radionuclide Therapy (PRRT) in the CommNETS Collaboration (Australia, Canada and New Zealand)

Background The use of FI and PRRT is integral to the management of neuroendocrine tumors (NETs). Considerable global variability exists in access to and utility of FI and PRRT. Methods A survey of PRRT centres within CommNETS was conducted to explore the use of FI and PRRT. Two companion surveys were completed by the lead in nuclear medicine and medical oncology per site. Descriptive and inferential statistical methods including nonparametric analyses were performed to evaluate differences in accessibility and availability, models of care, protocols and funding. Results 16 surveys were sent to the 8 PRRT centres across CommNETS (Aust: 6, Canada: 2, NZ: 0). Response rate was 100%. All were academic centres reviewing 110 new and 140 followup patients per month. All centres had access to Octreotide scans, but in Australia this has been superseded by tandem Gallium68 (Ga) and 18Fluorine (FDG) positron emission tomography (PET) scans to stage and assess biology and heterogeneity of NETs. GaPET scans were not available in Canada. Although FDGPET was unfunded for NETs within CommNETS, it was routinely ordered (63%) for grade 2 or 3 NETs. To assess response, 63% used GaPET scans at 6month intervals and 38% ordered both Ga and FDGPET scans. PRRT was only available on clinical trial in Canada. Lutetium177 was the standard PRRT isotope at all centres for most indications. Radiosensitising chemotherapy was used in 5 centres (not in Canada) capecitabine (45%) or capecitabine and temozolomide (36%). Four cycles of PRRT was universal but intervals varied between every 8 weeks (50%), 6 weeks (25%) or 10 weeks (25%), usually without maintenance therapy (63%). Considerable variation existed regarding concurrent somatostatin analogue usage, determination of renal function, dosimetry, dose adjustments and minimum haematological parameters. Only five sites recorded quality of life outcomes. Conclusions This is the first survey to assess the availability and utility of FI and PRRT within CommNETS. Future collaborative efforts will try to improve access and share knowledge between experienced and upcoming PRRT centres to develop standard operating procedures and cooperative trials. Legal entity responsible for the study CommNETs Collaboration Funding CommNETs Collaboration Disclosure All authors have declared no conflicts of interest.

Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics.

To assess the performance of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) and correlate it with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. Fifty patients (M : F 33 : 17, age: 26-71 years) with histopathologically confirmed metastatic/inoperable NETs who had undergone at least three cycles of PRRT with Lu-DOTATATE were included in the analysis. As part of the pretreatment evaluation, they underwent either Tc-HYNIC TOC (n=40)/Ga-DOTATATE PET (n=10) or fluorine-18-fluorodeoxyglucose (F-FDG) PET-computed tomography (CT). Response was assessed after three and five cycles PRRT on the basis of three parameters: (a) symptomatic and subjective scale, (b) biochemical tumor marker level, and (c) objective imaging (F-FDG/Ga DOTATATE PET/CT, Tc-HYNIC TOC, ceCT), and was categorized using predefined criteria (detailed in methods). Stable disease on imaging assessment with response on symptomatic or biochemical tumor marker scales or both were included in the responder group. The study population was broadly classified into (a) metastatic GEP-NET with known primary (n=43 i.e. 86%), which was further subclassified according to the site of primary and (b) those with unknown primary (n=7 i.e. 14%). Symptomatic response: 96% of patients showed a symptomatic response or improvement in health-related quality of life, irrespective of tumor proliferation index, dual tracer imaging characteristics, and response or progression of disease in the scan. Biochemical tumor marker response: 83% of scan responders showed a decrease, 10% showed a stable value, and 7% showed an increase in tumor marker levels. Among the scan nonresponders, 67% patients showed a corresponding increase in the tumor marker level, 22% patient showed a decrease, whereas 11% showed stable values. Scan response: 31 out of total 50 patients (62%) showed a partial scan response with either a decrease in the number of somatostatin receptor (SSTR)-positive lesions or metabolic activity in F-FDG/Ga-DOTATATE PET-CT or both, 10 patients (20%) showed stable disease, and nine patients (18%) showed progressive disease. The higher objective partial scan response documented can be explained by the introduction of the F-FDG-PET/CT parameter as a determinant criterion. Among the responders category (n=41), 32 (78.04%) showed discordance between F-FDG-PET/CT-based and SSTR-based imaging, whereas eight out of nine patients with nonresponse category (88.89%) showed concordance between SSTR-based imaging and F-FDG-PET/CT. Conversely, 32 of 33 patients (96.97%) with SSTR/F-FDG discordance and nine out of 17 (52.94%) with concordance were finally classified as responders, whereas the remaining, that is, 1/33 (3.03%) in the 'discordant' category and 8/17 (47.06%) with imaging concordance were classified as nonresponders, respectively. Our data show that high pretherapy F-FDG maximum standardized uptake values were associated with increased chances of treatment refractoriness in GEP-NETs. However, symptomatic improvement was observed in most cases irrespective of grade and F-FDG uptake. High pretherapy F-FDG maximum standardized uptake value in both low-grade and high-grade NET predicted a poor outcome and was associated with disease progression. Introduction of F-FDG-PET/CT parameter as a determinant of response classification increases the percentage of objective scan responders among patients with grades I and II GEP-NETs as F-FDG activity was observed to decrease before SSTR-based imaging and more frequently compared with the latter.

The impact of 177Lu-octreotide therapy on 99mTc-MAG3 clearance is not predictive for late nephropathy.

Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of 99mTc-mercaptoacetyltriglycine (99mTc­-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq 177Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m2 before PRRT (baseline) and 221 ± 45 ml/min/1.73 m2 after a median follow-up of 370 days. The age-corrected decrease (mean: −3%, range: −27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=−0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by 99mTc-MAG3­clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.

Initial Experience With Gallium-68 DOTA-Octreotate PET/CT and Peptide Receptor Radionuclide Therapy for Pediatric Patients With Refractory Metastatic Neuroblastoma.

Pediatric patients with refractory neuroblastoma have limited therapeutic options. Neuroblastoma may express somatostatin receptors (SSTRs) allowing imaging with 68Ga-DOTA-Octreotate (GaTATE) positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT). We reviewed our experience with this theranostic combination. GaTATE studies (8 patients; 2 to 9 years old) were reviewed and compared with 123I-MIBG or posttreatment 131I-MIBG studies. Immunohistochemistry (IHC) for SSTR subtype 2 was performed in 5 patients. Four patients received PRRT. GaTATE PET showed additional disease in 38% (3/8 patients), and upstaged 1 patient by detecting marrow involvement. IHC detected SSTR 2 in all patients assessed. Six patients were deemed suitable for PRRT on imaging. Four patients received 17 cycles of palliative PRRT (10 111In-DOTATATE; 5 177Lu-DOTATATE; 1 combined 111In and 177Lu-DOTATATE; 1 combined 177Lu and 90Y-DOTATATE) with no significant toxicity attributed to PRRT. All had objective responses. Two survivors are now 40 and 56 months from PRRT commencement. GaTATE PET was positive in a high proportion of patients with refractory neuroblastoma, correlating with SSTR 2 on IHC, with additional disease identified compared with MIBG imaging. PRRT seems safe, feasible, with responses observed in patients with progression despite multimodality treatment. These data support ongoing clinical trials in such patients.

177Lu-DOTATATE PRRT in Patients with Metastatic Neuroendocrine Tumor and a Single Functioning Kidney: Tolerability and Effect on Renal Function.

Our objective was to assess the renal toxicity profile of (177)Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with a metastatic neuroendocrine tumor (NET) and a single functioning kidney. This was a retrospective analysis of NET patients who had undergone (177)Lu-DOTATATE PRRT at a large tertiary-care center. All patients selected for the study had somatostatin receptor-positive NETs, had received at least 3 cycles of (177)Lu-DOTATATE PRRT, and had a documented single functioning kidney. The analyzed parameters included patient characteristics, metastatic burden, renal characteristics at diagnosis and during therapy, and nephrotoxic factors. For the renal assessment, the following characteristics were studied before each PRRT cycle: glomerular filtration rate (GFR) as estimated by (99m)Tc-diethylenetriamine pentaacetic acid renography, effective renal plasma flow (ERPF) as measured by (99m)Tc-ethylenedicysteine renography, and blood urea and serum creatinine levels. Renal toxicity was evaluated using version 4.0 of the Common Terminology Criteria for Adverse Events (NCI-CTCAE score). The percentage reduction in GFR and ERPF was also assessed. Filtration fraction was calculated to clarify whether there was a relatively greater reduction in one index of renal function than in the other. At the time of analysis, 6 patients met the inclusion criteria, having received between 3 and 5 cycles of therapy with a cumulative activity of 16.6-36.2 GBq. The duration of follow-up ranged from 12 to 56 mo. The overall toxicity profile (as per the NCI-CTCAE score) showed no acute renal toxicity in any patient. Regarding overall chronic renal toxicity, 3 patients had none, 1 patient had grade II, and 2 patients had grade I. All patients with overall chronic renal toxicity showed compromised renal function at the outset (baseline). The 2 patients with grade I chronic renal toxicity after PRRT had grade II at baseline and gradual improvement over the subsequent cycles. One patient with grade II at baseline showed transient worsening to grade III after the first cycle followed by gradual improvement and a return to baseline after the second cycle. Only 2 patients showed a reduction in GFR (5.3% in one and 13.84% in the other). Four patients showed a reduction in ERPF (31.4% in the patient with the greatest reduction), and all had a rise in filtration fraction signifying that tubular parameters were more affected than glomerular parameters. With proper renal protection and dose fractionation, it is feasible to use (177)Lu-DOTATATE PRRT in patients with NET and a single functioning kidney. Further studies are required to assess the long-term renal consequences of changes in ERPF and filtration fraction in these patients.

Metastatic Neuroendocrine Tumor with Extensive Bone Marrow Involvement at Diagnosis: Evaluation of Response and Hematological Toxicity Profile of PRRT with (177)Lu-DOTATATE.

The aim of this study was to evaluate the response and hematological toxicity in peptide receptor radionuclide therapy (PRRT) with lutetium (177Lu)-DOTA-octreotate (DOTATATE) in metastatic neuroendocrine tumor (NET) with extensive bone marrow metastasis at the initial diagnosis. A retrospective evaluation was undertaken for this purpose: Patients with NET with extensive diffuse bone marrow involvement at diagnosis who had received at least three cycles of PRRT with 177Lu-DOTATATE were considered for the analysis. The selected patients were analyzed for the following: (i) Patient and lesional characteristics, (ii) associated metastatic burden, (iii) hematological parameters at diagnosis and during the course of therapy, (iv) response to PRRT (using a 3-parameter assessment: Symptomatic including Karnofsky/Lansky performance score, biochemical finding, and scan finding), (v) dual tracer imaging features [with somatostatin receptor imaging (SRI) and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT)]. Based on the visual grading, tracer uptake in somatostatin receptor (SSTR)-positive bone marrow lesions were graded by a 4-point scale into four categories (0-III) in comparison with the hepatic uptake on the scan: 0 - no uptake; I - clear focus but less than liver uptake; II - equal to liver uptake; and III - higher than liver uptake]. Hematological toxicity was evaluated using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 score. A total of five patients (age range: 26-62 years; three males and two females) with diffuse bone marrow involvement at the diagnosis was encountered following analysis of the entire patient population of 250 patients. Based on the site of the primary, three had thoracic NET (two patients bronchial carcinoid and one pulmonary NET) and two gastroenteropancreatic NET (one in the duodenum and one patient of unknown primary with liver metastasis). Associated sites of metastases included the liver (n = 5), breast (n = 1), and aortocaval nodes (n = 1). On baseline diagnostic study [68 Ga-DOTANOC/TATE or the technetium (99mTc)-hydrazinonicotinamide (HYNIC)-tektrotyd (TOC)], tracer uptake in the bone marrow in all patients was Grade III. At the time of analysis, the patients received three to four cycles of PRRT and a cumulative dose of 16.1-25.6 GBq with a follow-up duration ranging 10-27 months. The response as assessed by three parameters: (i) Symptomatic: All patients (except for one) reported excellent symptomatic palliation and better quality of life with improvement of Karnofsky/Lansky scores; the single case with nonresponse had shown symptomatic response in the initial 6 months following which he had a progressive disease and death at 18 months (ii) biochemical: Three patients had shown more than 50% reduction in the serum chromogranin level, one had shown increase but had demonstrated clinical evidence of response with radiologically stable disease while the other who had shown slight increase of chromogranin A (CgA) level had shown progressive disease thereafter (iii) radiological: Three patients demonstrated partial response (on FDG-PET/CT), one patient had stable disease and one patient had progressive disease following initial clinical response. As per the NCI-CTCAE score, only one patient had persistent Grade I anemia without any deterioration with the administered dose at the time of analysis. FDG uptake in the bone marrow metastatic lesions showed no obvious FDG avidity on visual assessment except for two patients (low-grade FDG uptake). Interestingly, the associated metastatic lesions [except for patient I with Mib1 labeling index (LI): 1-2%], demonstrated high FDG avidity. Thus, we observed that the majority (in our series four out of five patients, i.e. 80%) of the patients had excellent symptomatic response with at least stabilization of the disease at a follow-up period of 10-27 months. The single patient who had a progressive disease also had a good symptomatic response in the initial 6 months from the first dose of PRRT. Despite the extensive bone marrow involvement, no hematological toxicity was observed (only one patient showed Grade I anemia), suggesting that PRRT is well-tolerated by this particular subgroup.