European Journal of Cardiovascular Medicine

Prostate cancer is the most prevalent tumour among males globally, with a rising incidence observed in recent years [1]. The incidence of PCa in India ranges from 3.38-5.39%.[2] Tumour recurrence or residual presence following prostatectomy, radiation, or other local treatment modalities poses a significant challenge in the management of prostate cancer. Typically, post-therapeutic recurrence following prostatectomy or external beam radiation therapy is identified by prostate-specific antigen (PSA) levels of > 0.2 ng/mL in two consecutive tests, referred to as biochemical recurrence[3].

Morphologic imaging approaches demonstrate significant limitations: sensitivity for detecting local recurrence ranges from 25% to 54% with transrectal ultrasonography or CT, & is substantially enhanced with functional MR imaging methods [4,5]. The sensitivity for detecting lymph node metastases with CT or MR imaging is reported to range from 30% to 80% [6]. Ultra-small iron oxide particles have demonstrated efficacy; nevertheless, they have yet to receive approval from regulatory bodies[7].

Prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein found in various tissues, including the prostate, kidney, small intestine, & both the central & peripheral nervous systems. [8, 9] PSMA is highly expressed in the human prostate, with levels exceeding those in most other tissues by a factor of one hundred. In cancer, its expression is elevated & it has been identified as the second-most upregulated gene in prostate cancer, with an increase of 8- to 12-fold compared to noncancerous prostate tissue[10]. This elevated expression is being pursued as a target for therapeutic & imaging applications. Recently, labelling protocols have been established to tag PSMA ligands with ⁶⁸Gallium (⁶⁸Ga), rendering them appropriate for PET/CT imaging.

The identification of prostate cancer lesions by PET imaging of the Prostate-Specific Membrane Antigen (PSMA) has achieved significant therapeutic relevance in recent years. Hybrid PET-CT imaging with ⁶⁸Ga-PSMA ligand can reveal lesions indicative of prostate cancer with superior contrast. ⁶⁸Ga-PSMA PET/CT shown improved efficacy in identifying prostate cancer at low PSA levels, attributed to its high sensitivity & specificity, as well as its ability to present lymph nodes with enhanced contrast compared to ¹⁸F choline-based PET/CT. [11]

Aim Of The Study

The aim of present study was “to evaluate the role of ⁶⁸Ga labelled Prostate-Specific Membrane Antigen (PSMA)ligand hybrid PET/CT in Primary & Recurrent Carcinoma Prostate for lesion characterisation, lymph node involvement & skeletal & liver metastases”.

The prospective study was conducted at a large tertiary centre during the period of June 2015- January 2016. Ethical clearance was taken from ethical committee of the centre.

A total of 100 male patients with a clinical suspicion or diagnosis of prostate cancer having any of the following characteristics were included in the study.

• Suspected Carcinoma Prostate with increase of tumor marker PSA.
• Initial staging in biopsy proven cases.
• Restaging after radiotherapy.
• Suspected recurrence of tumor or metastasis with rising serum PSA levels after radical prostatectomy or radiotherapy(Biochemical recurrence).
• Radiotherapy
• Theranostics using ¹⁷⁷Lu-PSMAendoradiotherapeutic treatment in patients with metastatic & castration resistant disease.
• Suspected prostate cancer despite negative biopsy, such as in the planning of a new, targeted biopsy.

Study Procedure

In our centre, radiolabelling of PSMA ligand with ⁶⁸Ga is done using on-site commercially available ⁶⁸Ge/⁶⁸Ga generator (itg) & synthesis module as per standard operating procedure supplied by the manufacturer & there was no need for a cost-intensive cyclotron. (Figure 1).No fasting or special patient preparation was required prior to the study. Dose of 3-4mci ⁶⁸GaPSMA is injected intravenously. The tracer was well tolerated. Whole body PET imaging & non contrast CT scan (Hybrid PET/CT) was done on 6 slice PET-CT machine one hour after injection. 

Early imaging is possible with 68GaPSMA’s short half-life (68 minutes), good labelling chemistry, quick background clearance, & high-resolution PET pictures.
Analysis of images: Software & a Siemens workstation were used for image analysis. When at least one focus of anomalous strong uptake was seen, as determined by eye inspection and/or SUV measures, the scan was considered positive, indicating active disease or recurrence/relapse. PCa is favoured by focally high PSMA overexpression or avidity in the prostate gland. Severe avidity in the liver, skeleton, & lymph nodes indicates metastases. The liver, kidneys, spleen, colon, bladder, & salivary & lacrimal glands all exhibit normal physiological uptake.

Statistical analysis

Version 25 of the Statistical Package for Social Sciences (SPSS) was used for data management & analysis. When appropriate, means, standard deviations, & ranges were used to summarise numerical data. Numerical values & percentages were used to display categorical data. The information was collected, analysed, & arranged. Using accepted standards, the hybrid PET/CT’s sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), & accuracy in identifying prostate cancer were calculated.[12]

For the study, 100 male patients with a median age of 69 years (range: 37-90 years) were chosen.  All images showed good resolution and lesions had a great target-to-background ratio. As seen in graph 1, 32 patients were referred for clinical suspicion, 24 for initial staging, & 44 for examination of recurrence.

16 patients (50%) out of 32 with a clinical suspicion of PCa had focused, strong uptake in the prostate gland that was indicative of the disease. Since the remaining 16 patients had no aberrant uptake, a biopsy was not performed & they were placed on clinical follow-up. Of the 24 individuals with PCa who were referred for first staging, 24 out of 24 (100%) had abnormal prostate gland uptake. Three patients experienced abdominal lymph nodal metastases, while nine patients experienced pelvic lymph nodal metastases. One of these three patients had adrenal metastases, another had severe mediastinal & skeletal metastases, & a third patient had additional skeletal metastases. Skeletal metastases were detected in one patient. 40/44 (90.9%) of the 44 PCa patients with a clinical suspicion of recurrence displayed involvement of the disease site. Local recurrence in the prostate gland or prostatic bed occurs in 26 out of 44 cases. Regional pelvic lymph node metastases were found in 21 of 44 patients. Four patients experienced mediastinal lymph nodal metastases, while six patients experienced abdominal lymph nodal metastases. Skeletal metastases were seen in 21 of 44 patients. Graph 2 illustrates the extensive disease of one patient. [Figure 2-10]

When compared to clinical data, PSA levels, radiological follow-up, & histopathological assessments for tumour recurrence or residual presence, the 68Ga-labeled PSMA-ligand PET/CT showed sensitivity, specificity, positive predictive value, negative predictive value, & overall accuracy of 95.6%, 100%, 100%, 50%, & 97.6%, respectively, as indicated in table 1.

Prostate cancer diagnosis has advanced significantly thanks to the promising method (68Ga-labeled PSMA-ligand PET/CT) [13–15]. This imaging method depends on the fact that PSMA is expressed by most prostate adenocarcinomas & that 68Ga-labeled PSMA-ligand binds to it very well.[16–18]
When compared to clinical data, PSA levels, radiological follow-up, & histopathological evaluations for tumour recurrence or residual presence, the 68Ga-labeled PSMA-ligand PET/CT showed sensitivity, specificity, positive predictive value, negative predictive value, & overall accuracy of 95.6%, 100%, 100%, 50%, & 97.6%, respectively, in our study. These results were similar to those of Afshar-Oromieh et al. [19], who examined 319 prostate cancer patients receiving therapy & undergoing PET/CT imaging using 68Ga-labeled PSMA-ligand. In 42 patients, the PET-CT results were correlated with histopathological examination. The detection of recurrent disease in these patients was found to have a patient-based sensitivity of roughly 88.1% & lesion-based sensitivity, specificity, positive predictive value, & negative predictive value of roughly 76.6%, 100%, 100%, & 91.4%, respectively. Our results are supported by Fitzpatrick et al.'s [20] assessment of 24 studies that looked at the sensitivity & specificity of 68Ga-labeled PSMA-ligand PET/CT in detecting recurrent prostate cancer lesions. The results showed sensitivity & specificity values that ranged from 33% to 93% & above 99%, respectively.

In 90.9% of the patients in our study, 68Ga-labeled PSMA-ligand PET/CT showed tumour recurrence. In contrast, 68Ga-labeled PSMA PET/CT imaging produced a positive diagnosis in 264 (82.8%) and a negative diagnostic in 55 (17.2%) of the 319 patients with prostate cancer receiving treatment that Afshar-Oromieh et al. [21] analysed. In their analysis of 248 patients with prostate cancer who had radical prostatectomy, Matthias et al. [22] discovered that 68Ga-labeled PSMA PET/CT imaging was positive in 222 (89.5%) and negative in 26 (10.5%) of the patients. In a similar vein, 68Ga-labeled PSMA-ligand PET/CT produced a positive diagnosis in 80 (64%) and  a negative diagnostic in 45 (36%) of the 125 prostate cancer patients treated by Mattiolli et al. [19].

All 24 patients with prostate cancer who arrived for first staging in this study had abnormal prostate gland uptake. Three patients had abdominal lymph nodal metastases, while nine patients had pelvic lymph nodal metastases. One of the three patients had further skeletal metastases, another had severe skeletal & mediastinal metastases, & the third had metastases to the adrenal glands. Isolated skeletal metastases was seen in one patient. Local recurrence in the prostate gland or prostatic bed was observed in 26 out of 44 patients. Regional pelvic lymph node metastases were seen in 21 out of the 44 patients. Four of these patients presented with mediastinal lymph nodal metastases, while six patients had abdominal lymph nodal metastases. Of the forty-four patients, bone metastases were seen in twenty-one. One patient had a generalised disease. After radical prostatectomy, 68Ga-labeled PSMA PET/CT imaging revealed local recurrence in in 87 (35.1%) patients, abdomino-pelvic nodal metastases in 130 (52.4%) patients, supra-diaphragmatic nodal metastases in 13 (5.2%) patients, bone metastases in 89 (35.9%) patients, & liver/lung metastases in 13 (5.2%) patients. These results were in agreement with Matthias et al. [22]. The findings of a multicentric study by Mattiolli et al. [19] that used 68GaPSMA PET/CT showed that 38 patients (30.9%) had local recurrence, 55 patients (44.4%) had loco-regional lymph node metastases, 15 patients (12.5%) had extra-pelvic abdominal lymph node metastases, 22 patients (17.5%) had thoracic lymph node metastases, 17 patients (13.6%) had visceral metastases, & 37 patients (29.5%) had bone metastases.

⁶⁸Ga-PSMA hybrid PET/CT demonstrated superior lesion detection in primary & recurrent prostate cancer (PCa). Enhanced identification of primary lesions, together with exceptional contrast in lymph node, skeletal, & hepatic metastases, was observed in patients with suspected PCa, initial staging of confirmed cases, restaging, & recurrence.

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