THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience

The acronym THERANOSTICS epitomizes the inseparability of diagnosis and therapy, the pillars of medicine and takes into account personalized management of disease for a specific patient. Molecular phenotypes of neoplasms can be determined by molecular imaging with specific probes using positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or optical methods, so that the treatment is specifically targeted against the tumor and its environment. To meet these demands, we need to define the targets, ligands, coupling and labeling chemistry, the most appropriate radionuclides, biodistribution modifiers, and finally select the right patients for the personalized treatment. THERANOSTICS of neuroendocrine tumors (NETs) using Ga-68 labeled tracers for diagnostics with positron emission tomography/ computed tomography (PET/CT), and using Lu-177 or other metallic radionuclides for radionuclide therapy by applying the same peptide proves that personalized radionuclide therapy today is already a fact and not a fiction

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

Peptide 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.In 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.Overall 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.PRRT 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

Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [177Lu] Lu-PSMA-617. A WARMTH multicenter study (the 617 trial)

Please read abstract in the article.This article is part of the Topical Collection on Oncology - GenitourinaryOpen Access funding provided by Projekt DEAL.http://link.springer.com/journal/259am2021Nuclear Medicin

Prognostic Value of 18F-FDG PET/CT in a Large Cohort of Patients with Advanced Metastatic Neuroendocrine Neoplasms Treated with Peptide Receptor Radionuclide Therapy

The objective of this retrospective study was to determine the role of F-18-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with Lu-177- or Y-90-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both Ga-68-DOTATOC/TATE/NOC and F-18-FDG PET/CT before treatment and were followed 3-189 mo. Kaplan-Meier analysis, log-rank testing (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: One hundred ninety-nine patients (40.2%) presented with pancreatic NENs, 49 with cancer of unknown primary, and 139 with midgut NENs, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8, and in other locations in 42. F-18-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were Ga-68-DOTATOC/TATE/NOC-positive. For all patients, the median PFS and OS, defined from the start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive F-18-FDG results predicted shorter PFS (18.5 mo vs. 24.1 mo; P = 0.0015) and OS (53.2 mo vs. 83.1 mo; P <0.001) than negative F-18-FDG results. Among the cases of pancreatic NENs, the median OS was 52.8 mo in F-18-FDG-positive subjects and 114.3 mo in F-18-FDG-negative subjects (P = 0.0006). For all patients positive for F-18-FDG uptake, and a ratio of more than 2 for the highest SUVmax on Ga-68-somatostatin receptor (SSTR) PET to the most F-18-FDG-avid tumor lesions, the median OS was 53.0 mo, compared with 43.4 mo in those patients with a ratio of less than 2 (P = 0.030). For patients with no F-18-FDG uptake (complete mismatch imaging pattern), the median OS was 108.3 mo versus 76.9 mo for an SUVmax of more than 15.0 and an SUVmax of 15.0 or less on Ga-68-SSTR PET/CT, respectively. Conclusion: The presence of positive lesions on F-18-FDG PET is an independent prognostic factor in patients with NENs treated with PRRT. Metabolic imaging with F-18-FDG PET/CT complements the molecular imaging aspect of Ga-68-SSTR PET/CT for the prognosis of survival after PRRT. High SSTR expression combined with negative F-18-FDG PET/CT results is associated with the most favorable long-term prognosis

Salivary Gland Toxicity of PSMA-Targeted Radioligand Therapy with 177Lu-PSMA and Combined 225Ac- and 177Lu-Labeled PSMA Ligands (TANDEM-PRLT) in Advanced Prostate Cancer: A Single-Center Systematic Investigation

Purpose: PSMA-targeted radioligand therapy (PRLT) is a promising treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, a high uptake of the radiopharmaceutical in the salivary glands (SG) can lead to xerostomia and becomes dose-limiting for 225Ac-PSMA-617. This study investigated the sialotoxicity of 177Lu-PSMA-I&amp;T/-617 monotherapy and co-administered 225Ac-PSMA-617 and 177Lu-PSMA-617 (Tandem-PPRLT). Methods: Three patient cohorts, that had undergone 177Lu-PSMA-I&amp;T/-617 monotherapy or Tandem-PRLT, were retrospectively analyzed. In a short-term cohort (91 patients), a xerostomia assessment (CTCAE v.5.0), a standardized questionnaire (sXI), salivary gland scintigraphy (SGS), and SG SUVmax and the metabolic volume (MV) on 68Ga-PSMA-11-PET/CT were obtained before and after two cycles of 177Lu-PSMA-I&amp;T/-617. In a long-term cohort, 40 patients were similarly examined. In a Tandem cohort, the same protocol was applied to 18 patients after one cycle of Tandem-PRLT. Results: Grade 1 xerostomia in the short-term follow-up was observed in 22 (24.2%) patients with a worsening of sXI from 7 to 8 at (p &lt; 0.05). In the long-term cohort, xerostomia grades 1 to 2 occurred in 16 (40%) patients. SGS showed no significant changes, but there was a decline of the MV of all SGs. After Tandem-PRLT, 12/18 (66.7%) patients reported xerostomia grades 1 to 2, and the sXI significantly worsened from 9.5 to 14.0 (p = 0.005), with a significant reduction in the excretion fraction (EF) and MV of all SGs. Conclusion: 177Lu-PSMA-I&amp;T/-617 causes only minor SG toxicity, while one cycle of Tandem-PRLT results in a significant SG impairment. This standardized protocol may help to objectify and quantify SG dysfunction

Optimizing psma radioligand therapy for patients with metastatic castration-resistant prostate cancer. A systematic review and meta-analysis

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT. 17