Richard Paul Baum

Prostate-specific membrane antigen (PSMA) is overexpressed in a majority of prostate cancer cells, which has led to the development of radiolabeled small-molecule inhibitors of PSMA for molecular imaging and targeted radioligand therapy. ¹⁷⁷Lu-labeled PSMA, with therapeutic β-emission and concomitant γ radiation, permits posttherapy imaging for the assessment of biodistribution and uptake in tumors and normal organs, as well as dosimetry. We report a patient with prostate cancer and metastatic lymph nodes–related lower extremity lymphedema, who presented with dermal backflow and soft-tissue uptake in the lower extremity on posttherapeutic whole body scan after intravenous ¹⁷⁷Lu-PSMA treatment.

The widespread use of 68Ga for positron emission tomography (PET) relies on the development of radiopharmaceutical precursors that can be radiolabelled and dispensed in a simple, quick, and convenient manner. The DATA (6-amino-1,4-diazapine-triacetate) scaffold represents a novel hybrid chelator architecture possessing both cyclic and acyclic character that may allow for facile access to 68Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr3]octreotide (TOC), a somatostatin subtype 2 receptor (SST2)-targeting vector for imaging and functional characterisation of SSTR2 expressing tumours. The radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex natGa(III) and 68Ga(III). Competition binding assays of [natGa]Ga-DATA-TOC or [natGa]Ga-DOTA-TOC against [125I-Tyr25]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST2,3,5 receptor subtypes (HEK293-hSST2/3/5 cells). First in vivo studies were performed in female NMRI-nude mice bearing SST2-positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST2-specific tumour-targeting of [68Ga]Ga-DATA-TOC and its overall pharmacokinetics versus the [68Ga]Ga-DOTA-TOC reference. A direct comparison of [68Ga]Ga-DATA-TOC with the well-established PET radiotracer [68Ga]Ga-DOTA-TOC was additionally performed in a 46-year-old male patient with a well-differentiated NET (neuroendocrine tumour), representing the first in human administration of [68Ga]Ga-DATA-TOC. DATA-TOC was labelled with 68Ga with a radiolabelling efficiency of > 95% in less than 10 min at ambient temperature. A molar activity up to 35 MBq/nmol was achieved. The hSST2-affinities of [natGa]Ga-DATA-TOC and [natGa]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC50 values. In mice, [68Ga]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [68Ga]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two 68Ga-radiotracers, but with a higher tumour-to-liver contrast for [68Ga]Ga-DATA-TOC. [68Ga]Ga-DATA-TOC was prepared, to a quality appropriate for in vivo use, following a highly efficient kit type process. Furthermore, the novel radiopharmaceutical was comparable or better than [68Ga]Ga-DOTA-TOC in all preclinical tests, achieving a higher tumour-to-liver contrast in a NET-patient. The results illustrate the potential of the DATA-chelator to facilitate the access to and preparation of 68Ga-radiotracers in a routine clinical radiopharmacy setting.

The aim of this study was to assess the safety, tolerability and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT) using lutetium-177 (¹⁷⁷Lu) labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC) and a single functioning kidney before PRLT. Methods: Sixteen patients (age 53-78 y, mean age 64.7 ± 6.5 y) with a single functioning kidney received PRLT with ¹⁷⁷Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen and electrolytes) were prospectively documented in a structured database and analyzed prior to each PRLT cycle and in follow-up. Renal function was further quantified by measuring TER using ^99mTc-MAG3 renal scintigraphy. Treatment-related adverse events (AEs) were graded according to the CTCAE v.5.0. Kaplan-Meier analysis was performed to obtain the progression-free survival and overall survival. Results: The median administered activity was 22.1 GBq (range 15.4-33.8 GBq). Calculated radiation-absorbed doses of kidney per cycle were 5.3 ± 2.1 Gy (0.81±0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% patients, including G1 renal impairment in 25.0% and G2 in 18.8%. G1 and G2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3 % and 12.5% after the second cycle. No G3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in both tubular extraction rate (TER) and the ratio of to lower limit TER (TER/TERLoLi) after the last cycle of treatment (p>0.05). The median PFS was 8.1 months based on both EORTC and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 months (range 5.8-45.3 months). Conclusion: In patients with a single functioning kidney, ¹⁷⁷Lu-PSMA-617 radioligand therapy is feasible, seems to be effective and is very well tolerated without any signs of acute or subacute nephrotoxicity during a mean follow up of nearly 2 years (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues has been shown to be highly efficacious concerning progression-free survival and response rates in patients with advanced, progressive, well-differentiated, somatostatin-receptor–positive neuroendocrine neoplasm. We report here delayed response of a midgut neuroendocrine neoplasm patient, who had stable disease after 4 cycles of PRRT and over a long period of 5 restaging admissions with excellent quality of life (full working hours), persisting for 3 years of follow-up, and presented as further partial remission according to both Response Evaluation Criteria in Solid Tumors and EORTC criteria, respectively, 36 months after the last PRRT cycle.

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues has been proven to be very useful in the management of advanced, well-differentiated neuroendocrine neoplasms (NENs). We present here the pregnancy outcome in a NEN patient, who naturally conceived and gave birth to a healthy baby, after 4 cycles of PRRT administering a cumulative radioactivity of 27.1 GBq. This case underlines that pregnancy and birth without sequelae are possible in patients with NEN who have been treated with PRRT and offers a definitive prospect for patients of reproductive age group who plan conception despite having received or due to undergo PRRT.

Substantial molecular and clinical heterogeneity of high-grade neuroendocrine neoplasms (NENs) G3, all of which were previously referred to as neuroendocrine carcinomas, has been observed. Although data are still limited, somatostatin receptor expression in well-differentiated G3 NENs of the pancreas (according to the new WHO 2017 classification) may enable peptide receptor radionuclide therapy for these patients. We report our treatment experience of a G3 NEN patient with discordant Ki-67 proliferation indices (between primary tumor and the metastases), who had a long survival over a span of 10 years with excellent quality of life and no adverse effects after repeated cycles of PRRT.

To date, limited data are available concerning peptide receptor radionuclide therapy (PRRT) of grade 3 (G3) neuroendocrine neoplasms (NENs) with a Ki-67 proliferation index of >20%. The purpose of this study was to analyze the long-term outcome, efficacy and safety of PRRT in patients with SSTR-expressing G3 NEN. Methods: A total of 69 patients (M=41 males; age 28-81 years) received PRRT with lutetium-177 (¹⁷⁷Lu) and/or yttium-90 (⁹⁰Y) labeled somatostatin analogs (DOTATATE or DOTATOC). Twenty-two patients had radiosensitising chemotherapy. Kaplan–Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS), defined from start of PRRT, including a subgroup analysis for patients with a Ki-67 of ≤55% and >55%. Treatment response was evaluated according to RECIST 1.1 as well as by molecular imaging criteria (EORTC). Short and long-term toxicity was documented (CTCAE v.5.0) using a structured database (comprising over 250 items per patient) and retrospectively analyzed. Results: Forty-six patients had pancreatic, 11 CUP, 6 midgut, 3 gastric, and 3 rectal NEN. Median follow-up was 94.3 months. The median PFS was 9.6 months and median OS was 19.9 months. For G3 NEN with a Ki-67 ≤55% (n = 53), the median PFS was 11 months and median OS 22 months. Patients with a Ki-67 >55% (n = 11), had a median PFS of 4 months and a median OS of 7 months. For those patients with positive SSTR imaging, but no FDG uptake, the median PFS was 24 months and median OS was 42 months. A significant difference was found for both, PFS and OS, with a median PFS of 16 vs 5 months and a median OS of 27 vs 9 months for a SUV_max >15.0 and a SUV_max ≤15.0 on SSTR-PET, respectively. In the group with FDG scored as 3-4, the median PFS was 7.1 months and the median OS 17.2 months. For FDG scored as 0-2, the median PFS was 24.3 months and the median OS 41.6 months. PRRT was well-tolerated by all patients; no grade 3 or grade 4 hematotoxicity occurred and no clinically significant decline in renal function was observed. There was no hepatotoxicity. Conclusion: PRRT was tolerated well without significant adverse effects and is efficacious in G3 NEN with promising clinical outcome, especially in patients with a Ki-67 index of ≤55% and even in patients who have failed chemotherapy. Baseline FDG along with SSTR molecular imaging is useful to stratify those G3-NEN patients with high uptake on SSTR PET/CT and no or minor FDG-avidity, a mismatch pattern which is associated with a better long term prognosis.

Objective: Neurotensin receptor 1 (NTR1) is overexpressed in ductal pancreatic adenocarcinoma, which is still one of the deadliest cancers with a very poor prognosis. Eligible patients were offered radiopharmaceutical treatment with the novel NTR1 antagonist ¹⁷⁷Lu-3BP-227 as salvage therapy. Methods: Six patients with confirmed ductal pancreatic adenocarcinoma who had exhausted all other treatment options received ¹⁷⁷Lu-3BP-227 for evaluation of NTR1 expression in vivo. Three patients received treatment activities between 5.1 and 7.5 GBq. Results: Administration of ¹⁷⁷Lu-3BP-227 was well tolerated by all patients. Kidneys were identified as the dose-limiting organ. The most severe adverse event was reversible grade 2 anemia. One patient achieved a partial response and experienced significant improvement of symptoms and quality of life. This patient survived 13 months from diagnosis and 11 months from start of ¹⁷⁷Lu-3BP-227 therapy. Conclusion: This initial report provides first clinical evidence of the feasibility of treatment of ductal pancreatic adenocarcinoma using ¹⁷⁷Lu-3BP-227.