European Journal of Cardiovascular Medicine

Neuroendocrine tumors (NETs) are uncommon neoplasms that exhibit highly variable biological behavior, ranging from slow-growing indolent forms to aggressive metastatic disease. Their diagnosis is frequently delayed because the primary tumors are small, clinical manifestations are nonspecific, and secretion of bioactive peptides is inconsistent. Early and accurate localization of primary and metastatic disease is therefore essential to guide curative or palliative treatment decisions, including surgery, systemic therapy, and peptide receptor radionuclide therapy (PRRT).^[1,2]

Most well-differentiated NETs overexpress somatostatin receptors (SSTRs), predominantly subtype 2, which enables receptor-targeted molecular imaging. Gallium-68–labeled somatostatin analogues are short synthetic peptides conjugated with the positron-emitting isotope ⁶⁸Ga through the bifunctional chelator DOTA. These ⁶⁸Ga-DOTA conjugates specifically bind to SSTRs on tumor cell surfaces, allowing high-contrast visualization on PET/CT. Among the available tracers, ⁶⁸Ga-DOTATOC, ⁶⁸Ga-DOTATATE, and ⁶⁸Ga-DOTANOC, each demonstrates high affinity for SSTR2 and excellent sensitivity and specificity for SSTR-positive disease. Choice of tracer is generally dictated by local availability, radiochemistry logistics, and cost considerations. Compared with conventional somatostatin receptor scintigraphy (SRS) using indium-111 or technetium-99m analogues, ⁶⁸Ga-DOTA-peptide PET/CT provides superior spatial resolution, shorter imaging acquisition, lower radiation dose, and improved cost-effectiveness.^[3–6]

Radiolabeled ⁶⁸Ga-somatostatin analogues further offer pharmacokinetic advantages, rapid blood clearance, efficient tissue penetration, and minimal immunogenicity, facilitating whole-body assessment within a single session. These attributes make ⁶⁸Ga-based PET/CT an indispensable tool in the evaluation and management of NETs. Accordingly, the present study investigates the diagnostic utility of ⁶⁸Ga-DOTANOC PET/CT in 100 patients with suspected or confirmed NETs, emphasizing its role in localizing primary lesions, assessing metastatic disease, and detecting recurrence or progression.^[7,8]

AIMS & OBJECTIVES

1. To evaluate the diagnostic accuracy of ⁶⁸Ga-DOTANOC PET/CT in detecting neuroendocrine tumors, with lesion characterization during initial staging and follow-up for suspected residual, recurrent, or progressive disease.

The prospective study was carried out in a large tertiary hospital from May 2023 to May 2024. Approval was granted by the institutional ethics committee, and informed consent was obtained before participation.  A total of 100 patients with suspected NET for initial diagnosis and staging, or previously diagnosed tumors for restaging or recurrence evaluation were included in the study. Of these, 69 were men and 31were women, with an average age of 55 years (range 40–70).

The tracer ⁶⁸Ga-DOTANOC was synthesized following established radiochemistry protocols, eluted from a Ge-68/Ga-68 generator (ITG, Germany), and DOTANOC was labeled with Ga-68 following the recommended procedure. No fasting or dietary restriction was needed prior to the study. Each patient received the compound intravenously, and the tracer was well tolerated. Whole body PET imaging and non contrast CT scan from vertex to mid-thigh were performed on 6 slice Siemens PET-CT scanner one hour after injection. Image reconstruction was done using iterative reconstruction and axial, coronal and sagittal reformatted images were obtained.

Image analysis was performed on a Siemens workstation. Axial PET slices were evaluated alongside corresponding CT and fused PET/CT images. Physiological sites of ⁶⁸Ga-DOTANOC uptake, including the pituitary, thyroid, adrenal glands, pancreatic uncinate process, spleen, kidneys, and gastrointestinal tract, were distinguished from abnormal uptake. Focal tracer accumulation in non-physiological locations or with intensity exceeding background activity was considered abnormal. Anatomical localization of such uptake was confirmed on CT or fused PET/CT images, and focal lesions, including primary and metastatic sites, were assessed semi-quantitatively using Maximum standardized uptake values (SUVmax).

For staging cases, the main outcome was whether the primary tumor could be identified. For restaging, the principal measure was the detection of disease activity, residual, recurrent, or progressive

Statistical Analysis

Analysis was descriptive. Numbers and percentages were reported for categorical variables. Age and other continuous variables were summarized with mean and range. Detection rates for both groups were calculated with 95% exact binomial confidence intervals. Risk differences between staging and restaging groups were described, though no formal hypothesis testing was performed, as the focus was on diagnostic yield rather than comparative accuracy.

Patient Profile

One hundred patients were included in the analysis. The cohort consisted of 69 males and 31 females, with a mean age of 55 years (range: 40–70 years). Among them, 68 underwent initial staging for suspected NET, while 32 underwent restaging after prior diagnosis and treatment.

Initial Staging Group

Of the 68 patients referred for initial staging, 61 showed a positive scan with clear identification of a primary lesion, giving a detection rate of 89.7%. Seven patients (10.3%) did not demonstrate any abnormal uptake and were placed on clinical follow-up.

Lesion distribution revealed the gastrointestinal tract as the most common site (n=51), followed by pancreas (n=11) and bronchus (n=7).

Figure 1: A 60-year-old patient with Pancreatic neuroendocrine tumor (PNET) Fig A. Axial non contrast CT shows an oval well delineated soft tissue attenuating mass lesion involving uncinate process of pancreas with mild perilesional fat stranding Fig B. 68Ga-DOTANOC fused PET/CT image a larger intense avidity in the mass and a smaller uptake medially, likely a tiny metastatic lymph node. Fig.C Axial MIP image show the uptake in the mass

Restaging Group

In the 32 patients undergoing restaging, 18 demonstrated pathological uptake consistent with active disease, while 12 showed no evidence of recurrence or progression. The positivity proportion for restaging was 56.2%.

Figure 2: A 58-year-old female with Caecal neuroendocrine tumor Fig A shows axial contrast enhanced CT scan image with enhancing intraluminal lesion filling cecum and adjoining perilesional fat stranding. An enhancing ileocolic lymph node also seen. Fig B shows fused PET/CT image showing strong uptake in the caecal mass and also in the lymph node

The present prospective study demonstrated that ⁶⁸Ga-DOTANOC PET/CT achieved high rates of primary lesion localization in suspected neuroendocrine tumors and provided clinically significant findings during restaging. The primary detection rate of 89.7% in newly diagnosed patients closely aligns with large European and Indian studies reporting sensitivities between 80% and 95%.^[9] The restaging positivity rate of 56.2% similarly reflects prior reports where more than half of patients under surveillance showed residual or progressive disease.^[10]

Naswa et al. evaluated gastroenteropancreatic NETs in an Indian cohort and reported sensitivity of 96% for ⁶⁸Ga-DOTANOC PET/CT, particularly in detecting small primaries.^[11] Similarly, Pruthi et al. highlighted its role in localizing primaries in patients with metastatic NET of unknown origin, underscoring its utility in complex diagnostic settings.^[12] In Western cohorts, Ambrosini et al. found that ⁶⁸Ga-DOTANOC PET/CT outperformed conventional imaging in both staging and restaging, leading to significant management changes in a considerable proportion of cases.^[13] Our results echo these trends, confirming that DOTANOC provides high contrast imaging and consistent performance across diverse populations. As far as its relevance in Indian clinical practice is concerned, the predominance of gastrointestinal and pancreatic primaries in our cohort is consistent with both global epidemiology and Indian institutional series.^[11,12]

The strengths of this study include its prospective design, clear separation of staging and restaging groups, and uniform imaging protocol. However, limitations must be acknowledged. First, there was no uniform histopathologic confirmation of all lesions, which restricts calculation of sensitivity and specificity; we reported diagnostic yield instead. Lastly, we did not capture the downstream clinical impact, such as changes in surgical planning or initiation of therapy. Future multicenter studies with standardized reporting would be valuable to address these gaps.

For patients with suspected NET, ⁶⁸Ga-DOTANOC PET/CT provides near-comprehensive staging in a single imaging session, guiding surgical and oncologic planning. For restaging, it serves as a reliable arbiter when biochemical markers or conventional imaging yield equivocal results, allowing clinicians to tailor follow-up and therapeutic interventions. These findings reaffirm the role of SSTR-PET/CT as a cornerstone in NET management, and specifically validate DOTANOC as a dependable option in regions where it is most accessible

This prospective study reaffirms the diagnostic value of ⁶⁸Ga-DOTANOC PET/CT across the neuroendocrine tumor spectrum. The tracer demonstrated a high capacity for primary and metastatic lesion localization in suspected cases and those undergoing restaging. Our findings strongly support the continued adoption of ⁶⁸Ga-DOTANOC PET/CT as a first-line molecular imaging tool for staging, restaging, and surveillance of neuroendocrine tumors.

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