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Somatostatin receptors over-expression in castration resistant prostate cancer detected by PET/CT: preliminary report of in six patients.

ABSTRACT: Prostate cancer (PC) is usually characterized by an excellent prognosis, largely due to little biological aggressiveness and the power of hormonal deprivation therapy. In spite of these favorable characteristics, however, a significant quota of patients does not respond to androgen deprivation therapy (ADT) and develop a progressive disease. Castration-resistant prostate cancer (CRPC) is defined by disease progression in spite of ADT. This progression may show any combination of a rise in serum prostate-specific antigen (PSA), clinical and radiological progression of pre-existing disease, and appearance of new metastases. This event is a striking change in the clinical scenario, since the power of treatment for CRPC patients with distant metastases is very limited. Somatostatin is a hormone produced by neuroendocrine cells. Its distant effects are mediated by the binding to five specific receptors, which are the most striking parameter for neuroendocrine. Various synthetic somatostatin agonists able to bind to the receptors have been synthesized during the past two decades for diagnostic and therapeutic purposes. Octreotide, the most popular of these, is widely used to treat patients affected by neuroendocrine tumors. A number of researches carried out in the past evaluated the possible neuroendocrine differentiation (NED) of PC cells in the castration resistant phase. If proved, the presence of a specific class of receptor on cell's surfaces should give a potentially biological target to be used for therapy. However, these studies led to contradictory results. Aim of our phase III diagnostic trial was to study "in vivo" the over-expression of somatostatin receptors (SSTRs) in CRPC patients by PET/CT after the administration of the somatostatin analog [(68)Ga-DOTANOC,1-Nal(3)]-octreotide labeled with (68)Ga. Every area of increased uptake corresponding to a metastasis detected with other methods was considered as SSTRs expressing. False positivity to SSTRs expression was considered those localizations with a suspicious uptake not confirmed by other radiologic procedures. On the other hand, metastatic lesions lacking the radiopharmaceutical's uptake were considered not SSTRs expressing metastases. The preliminary results in 6 of the 67 patients scheduled by our phase III trial showed metastases with a variable SSTRs expression in 2 patients.

SUBMITTER: Savelli G

PROVIDER: S-EPMC4486921 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Somatostatin receptors over-expression in castration resistant prostate cancer detected by PET/CT: preliminary report of in six patients.

Savelli Giordano G Muni Alfredo A Falchi Roberta R Zaniboni Alberto A Barbieri Roberto R Valmadre Giuseppe G Minari Chiara C Casi Camilla C Rossini Pierluigi P

Annals of translational medicine 20150601 10

Prostate cancer (PC) is usually characterized by an excellent prognosis, largely due to little biological aggressiveness and the power of hormonal deprivation therapy. In spite of these favorable characteristics, however, a significant quota of patients does not respond to androgen deprivation therapy (ADT) and develop a progressive disease. Castration-resistant prostate cancer (CRPC) is defined by disease progression in spite of ADT. This progression may show any combination of a rise in serum ...[more]

PMID: 26207238

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Project description:Prostate cancer (PC) is one of the most frequently diagnosed cancers and a leading cause of cancer-related deaths in Western society. Current PC therapies prevalently target the functions of androgen receptor (AR) and may only be effective within short time periods, beyond which the majority of PC patients progress to castration-resistant PC (CRPC) and metastatic disease. The role of estradiol/estradiol receptor (ER) axis in prostate transformation and PC progression is well established. Further, considerable efforts have been made to investigate the mechanism by which somatostatin (SST) and somatostatin receptors (SSTRs) influence PC growth and progression. A number of therapeutic strategies, such as the combination of SST analogs with other drugs, show, indeed, strong promise. However, the effect of the combined treatment of SST analogs and estradiol on proliferation, epithelial mesenchyme transition (EMT) and migration of normal- and cancer-derived prostate cells has not been investigated so far. We now report that estradiol plays anti-proliferative and pro-apoptotic effect in non-transformed EPN prostate cells, which express both ERα and ERβ. A weak apoptotic effect is observed in transformed CPEC cells that only express low levels of ERβ. Estradiol increases, mainly through ERα activation, the expression of SSTRs in EPN, but not CPEC cells. As such, the hormone enhances the anti-proliferative effect of the SST analog, pasireotide in EPN, but not CPEC cells. Estradiol does not induce EMT and the motility of EPN cells, while it promotes EMT and migration of CPEC cells. Addition of pasireotide does not significantly modify these responses. Altogether, our results suggest that pasireotide may be used, alone or in combination with other drugs, to limit the growth of prostate proliferative diseases, provided that both ER isoforms (α and β) are present. Further investigations are needed to better define the cross talk between estrogens and SSTRs as well as its role in PC.

Project description:ObjectivesWhole body [18F]-fluorodihydrotestosterone positron emission tomography ([18F]FDHT PET) imaging directly targets the androgen receptor and is a promising prognostic and predictive biomarker in metastatic castration-resistant cancer (mCRPC). To optimize [18F]FDHT PET-CT for diagnostic and response assessment purposes, we assessed how count statistics and reconstruction protocol affect its accuracy, repeatability, and lesion detectability.MethodsWhole body [18F]FDHT PET-CT scans were acquired on an analogue PET-CT on two consecutive days in 14 mCRPC patients harbouring a total of 336 FDHT-avid lesions. Images were acquired at 45 min post-injection of 200 MBq [18F]FDHT at 3 min per bed position. List-mode PET data were split on a count-wise basis, yielding two statistically independent scans with each 50% of counts. Images were reconstructed according to current EANM Research Ltd. (EARL1, 4 mm voxel) and novel EARL2 guidelines (4 mm voxel + PSF). Per lesion, we measured SUVpeak, SUVmax, SUVmean, and contrast-to-noise ratio (CNR). SUV was normalized to dose per bodyweight as well as to the parent plasma input curve integral. Variability was assessed with repeatability coefficients (RCs).ResultsCount reduction increased liver coefficient of variation from 9.0 to 12.5% and from 10.8 to 13.2% for EARL1 and EARL2, respectively. SUVs of EARL2 images were 12.0-21.7% higher than EARL1. SUVs of 100% and 50% count data were highly correlated (R2 > 0.98; slope = 0.97-1.01; ICC = 0.99-1.00). Intrascan variability was volume-dependent, and count reduction resulted in higher intrascan variability for EARL2 than EARL1 images. Intrascan RCs were lowest for SUVmean (8.5-10.6%), intermediate for SUVpeak (12.0-16.0%), and highest for SUVmax (17.8-22.2%). Count reduction increased test-retest variance non-significantly (p > 0.05) for all SUV types and normalizations. For SUVpeak at 50% of counts, RCs remained < 30% when small lesions were excluded. Splitting data reduced CNR by median 4.6% (interquartile range 1.2-8.7%) and 4.6% (interquartile range 1.2-8.7%) for EARL1 and EARL2 images, respectively.ConclusionsReducing [18F]FDHT PET acquisition time from 3 min to 1.5 per bed position resulted in a repeatability of SUVpeak (bodyweight) remaining ≤ 30%, which is generally acceptable for response monitoring purposes. However, EARL2 reconstruction was more affected, especially for SUVmax whose repeatability tended to exceed 30%. Lesion detectability was only slightly impaired by reducing acquisition time, which might not be clinically relevant in mCRPC.

Project description:UnlabelledConventional imaging modalities (CIMs) have limited sensitivity and specificity for detection of metastatic prostate cancer. We examined the potential of a first-in-class radiofluorinated small-molecule inhibitor of prostate-specific membrane antigen (PSMA), N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-l-cysteine ((18)F-DCFBC), to detect metastatic hormone-naïve (HNPC) and castration-resistant prostate cancer (CRPC).MethodsSeventeen patients were prospectively enrolled (9 HNPC and 8 CRPC); 16 had CIM evidence of new or progressive metastatic prostate cancer and 1 had high clinical suspicion of metastatic disease. (18)F-DCFBC PET/CT imaging was obtained with 2 successive PET scans starting at 2 h after injection. Patients were imaged with CIM at approximately the time of PET. A lesion-by-lesion analysis of PET to CIM was performed in the context of either HNPC or CRPC. The patients were followed with available clinical imaging as a reference standard to determine the true nature of identified lesions on PET and CIM.ResultsOn the lesion-by-lesion analysis, (18)F-DCFBC PET was able to detect a larger number of lesions (592 positive with 63 equivocal) than CIM (520 positive with 61 equivocal) overall, in both HNPC and CRPC patients. (18)F-DCFBC PET detection of lymph nodes, bone lesions, and visceral lesions was superior to CIM. When intrapatient clustering effects were considered, (18)F-DCFBC PET was estimated to be positive in a large proportion of lesions that would be negative or equivocal on CIM (0.45). On follow-up, the sensitivity of (18)F-DCFBC PET (0.92) was superior to CIM (0.71). (18)F-DCFBC tumor uptake was increased at the later PET time point (~2.5 h after injection), with background uptake showing a decreasing trend on later PET.ConclusionPET imaging with (18)F-DCFBC, a small-molecule PSMA-targeted radiotracer, detected more lesions than CIM and promises to diagnose and stage patients with metastatic prostate cancer more accurately than current imaging methods.

Dataset Information

Somatostatin receptors over-expression in castration resistant prostate cancer detected by PET/CT: preliminary report of in six patients.

Publications

Somatostatin receptors over-expression in castration resistant prostate cancer detected by PET/CT: preliminary report of in six patients.

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