Candidates For Peptide Receptor Radionuclide Therapy Research Articles

Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy

BackgroundSomatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. MethodsThe effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. ResultsPyrosequencing of cell lines illustrated differential methylation indices – BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign −3.75,p < 0.01). ConclusionGuadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.

Modern hybrid imaging of neuroendocrine tumors (clinical lecture)

Background. Neuroendocrine tumors are a group of tumors arising from neuroendocrine cells that have biologically active properties. The onset of neuroendocrine tumors may be associated with the presence of multiple neuroendocrine neoplasia syndromes type 1. According to world statistics, the number of neuroendocrine tumors has increased fivefold in the last 30 years. This is likely to be due to improved detection, including advances in hybrid imaging techniques. Positron emission and single photon emission tomography, combined with computed tomography using somatostatin analogues (DOTA conjugate) labeled with 68Ga, 64Cu-SARTATE and scintigraphy with 99mTc-tectrotide are of most interest. The combination of anatomical and functional diagnostic methods allows to diagnose patients at an early stage of the disease and to influence the further prognosis and outcome of the disease. The urgency of the problem of neuroendocrine tumors is caused by the multidisciplinary nature of the pathology and the lack of screening programs. Purpose – to conduct the review of modern hybrid imaging techniques used for diagnosis, staging, and monitoring neuroendocrine tumors. Materials and methods. The analysis of full-text publications, which were selected by literature search in foreign databases (PubMed, Scopus, ScienceDirect-Elsevier) for the period 2003–2020, was performed. Results and discussion. During the analytical review of the literature the experience of application of modern methods of diagnostics of neuroendocrine tumors in Ukraine and abroad is analyzed. The choice of radiopharmaceutical drugs and tracers is considered. Positron emission computed tomography with DOTA conjugates has been shown to be the new «gold standard» in the imaging of neuroendocrine tumors with sensitivity and specificity well above 90 %. This method is able to detect early bone l esions not visible on CT or MRI and has a positive effect on stage determination and subsequent treatment. An assessment of the receptor status of neuroendocrine tumors for the selection of candidates for peptide-receptor radionuclide therapy is presented. Conclusions. Hybrid imaging plays a key role in diagnosis, determination of stages, choice of treatment and further monitoring of neuroendocrine effects. Innovative technologies based on somatostatin receptors also advance molecular diagnostics and therapy of neuroendocrine tumors, which improve the quality of life of lots of patients. Awareness of this disease can reduce the delay in diagnosis and facilitate expert multidisciplinary care.

The role of baseline Ga-68 DOTATATE positron emission tomography/computed tomography in the prediction of response to fixed-dose peptide receptor radionuclide therapy with Lu-177 DOTATATE.

To describe the role of baseline gallium (Ga)-68 DOTATATE positron emission tomography (PET)/computed tomography (CT) in the prediction of the response to peptide receptor radionuclide therapy (PRRT) using lutetium (Lu)-177 DOTATATE. Analysis was made of baseline Ga-68 DOTATATE PET/CT images of 29 patients (17 females and 12 males; mean age: 50.7 ± 14.6 years) with metastatic neuroendocrine tumors who received PRRT with Lu-177 DOTATATE. Maximum standardized uptake values (SUVmax) of reference lesions and their ratios to physiological uptake organs were calculated. The relationship between these values and the radiological response was analyzed. Partial response was observed in 8 (28%) patients, stable disease in 18 (62%) patients, and progressive disease in 3 (10%) patients. Mean SUVmax of reference lesions was calculated as 23.8 ± 20.5 (min-max: 5.1-87.3). There was no significant correlation between radiological responses and SUVmax of reference lesions and their ratios to other organs. Baseline Ga-68 DOTATATE PET/CT helps to show somatostatin receptor expression status and disease stage in patients who are candidates for PRRT. However, SUVs do not have a role in the prediction of treatment response.

Significant impact of transient deterioration of renal function on dosimetry in PRRT

Peptide receptor radionuclide therapy (PRRT), with (90)Y-DOTATOC and (177)Lu-DOTATATE as most clinically used radiopeptides, is widely used in the management of metastatic neuroendocrine tumors. With respect to radiation dosimetry, the kidneys are the critical organ for (90)Y-DOTATOC. Renal irradiation is significant because of reabsorption of the radiopeptide from the proximal tubuli and the resulting retention in the interstitium, mainly in the inner cortical zone. The high energy and consequently wide range in tissue of the yttrium-90 beta particle result in high absorbed doses to the kidney cortex and medulla. Accurate renal dosimetry can help minimizing radiation nephropathy. We report a case of a 69-year-old candidate for PRRT with an acceptable kidney function at the time of screening. When performing (111)In-octreotide pretreatment dosimetry 3 weeks later, we observed a drastic deterioration in kidney function, caused by undisclosed non-steroidal anti-inflammatory drug intake. The calculated kidney biological effective dose (BED) was 153 Gy after four projected cycles. PRRT was canceled as our full-course BED limit is 37 Gy and the patient was switched to morphine analgesics. Renal function normalized after 3 months and repeated dosimetry yielded an acceptable kidney BED of 28 Gy after four projected cycles (7 Gy/cycle). This case emphasizes that acute kidney insufficiency can yield toxic kidney doses in a single therapy cycle, with an inherent risk of persistent renal insufficiency. All clinical factors which might influence kidney function should be verified at screening and before PRRT administration.

Does the Pretherapeutic Tumor SUV in 68Ga DOTATOC PET Predict the Absorbed Dose of 177Lu Octreotate?

Selection of candidates for peptide receptor radionuclide therapy (PRRT) is increasingly based on receptor positron emission tomography (PET) imaging, including the common tracer 68Ga DOTATOC. However, no studies have yet compared standardized uptake values (SUVs) and absorbed doses in this field. We retrospectively analyzed a consecutive cohort of 21 patients with 61 evaluable tumor lesions undergoing both pretherapeutic 68Ga DOTATOC-PET/CT (Biograph Duo [Siemens Medical Solutions, Erlangen, Germany]; PET acquisition, 75.3 ± 15.4 minutes postinjection; 117.3 ± 33.9 MBq 68Ga DOTATOC) and PRRT with Lu octreotate (7.47 ± 1.39 GBq; intratherapeutic tumor dosimetry with serial whole-body scans; 1, 2, and 4 days postinjection) at our institution. SUVs were compared with the tumor-absorbed doses per injected activity (D/A0) of the subsequent first treatment cycle. The correlation of SUV and D/A0 was r = 0.72 (SUVmean) and r = 0.71 (SUVmax), both P < 0.001. Pancreatic origin and hepatic localization were associated with higher D/A0, and chromogranin A level and Ki-67 index had no influence on SUV or D/A0. High-SUV lesions (SUVmean >15; SUVmax >25) resulted in high D/A0 (>10 Gy/GBq) in 66.7% to 70.8% and low D/A0 (<5 Gy/GBq) in only 8.3% to 12.5% on subsequent PRRT. The mentioned low D/A0 range, on the other hand, was achieved by all lesions with SUVmean <7 or SUVmax <9. Somatostatin receptor PET imaging may predict tumor-absorbed doses. The ability to indicate insufficient target irradiation by a low SUV could aid in selection of appropriate candidates for PRRT. However, larger series are needed to confirm and validate these initial findings.