99mTc-PSMA Intraoperative Use – Part 1

99mTc-PSMA Radioguided Surgery in Prostate Cancer: A Comprehensive Review of Intraoperative Strategies, Limitations, and Innovation – Part 1

I. Summary

99mTechnetium-Prostate-Specific Membrane Antigen (99mTc-PSMA) Radioguided Surgery (RGS) represents a significant advancement in the surgical management of prostate cancer (PCa), particularly for recurrent disease and lymph node metastases (LNM). This technique capitalizes on the consistent overexpression of Prostate-Specific Membrane Antigen (PSMA) on prostate cancer cells, enabling real-time, intraoperative detection and precise resection of malignant tissue using a gamma probe. It serves as a valuable adjunct to conventional imaging and surgical methods, with the primary objective of improving oncological outcomes by enhancing the completeness of tumor removal during salvage surgery.

Studies report high sensitivity and specificity in detecting PSMA-avid lesions, including micrometastases as small as 3mm, which are often missed by traditional imaging. The procedural framework typically involves the preoperative intravenous administration of a 99mTc-labeled PSMA ligand, followed by intraoperative detection facilitated by a gamma probe. Short-term outcomes have indicated promising rates of biochemical response, characterized by significant Prostate-Specific Antigen (PSA) reduction, and extended treatment-free survival intervals. Despite these compelling benefits, the method is still considered experimental, and ongoing research is crucial to establish its long-term impact on patient outcomes and to standardize protocols for clinical integration.

II. Introduction to Prostate-Specific Membrane Antigen (PSMA) and 99mTc-PSMA

Prostate Cancer: Current Diagnostic and Surgical Challenges

Prostate cancer (PCa) continues to be a major global health concern, ranking as one of the most common cancers in men, with a steadily increasing incidence worldwide.¹ Despite significant advancements in diagnostic and therapeutic strategies, persistent challenges impede optimal patient management, particularly concerning the accurate detection and staging of the disease, especially in scenarios of recurrence or metastatic dissemination.¹ MRI is valuable for characterizing the primary lesion within the prostate and for local staging; its accuracy in predicting lymph node involvement is considerably lower than that of PSMA PET.⁶ A significant clinical challenge is the occurrence of positive surgical margins (PSMs) after radical prostatectomy (RP), which are detected in 11% to 38% of patients and are strongly associated with an elevated risk of biochemical recurrence or distant metastases.² These limitations underscore the need for more sensitive and precise intraoperative tools to ensure complete tumor removal and improve patient prognosis.

PSMA as a Molecular Target in Prostate Cancer

Prostate-Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein characterized by a large extracellular domain. This protein is markedly overexpressed on the surface of prostate cancer cells, often exhibiting levels 100- to 1000-fold higher than in benign prostate tissue or most other normal organs.¹ The expression of PSMA has been observed to increase with higher cancer stage and Gleason grade, particularly in metastatic and androgen-resistant PCa, positioning it as an exceptionally valuable biomarker for both diagnostic imaging and targeted therapeutic interventions.² While primarily associated with PCa, PSMA can also be expressed in the neovasculature of certain other solid tumors, such as renal cell carcinoma, bladder transitional cell carcinoma, and colon cancer, and at weak-to-moderate levels in some normal tissues, including the kidneys, salivary glands, small intestine, testis, and bladder.¹ Despite this broader expression, its remarkable sensitivity and specificity for prostate cancer, especially in metastatic contexts, firmly establish PSMA as a dedicated and highly effective target for molecular imaging and therapy in PCa management.¹²

99mTc-PSMA: Radiopharmaceutical Characteristics and Mechanism of Action

99mTc-PSMA refers to a class of PSMA ligands specifically engineered and labeled with Technetium-99m (99mTc), a gamma-emitting radionuclide widely used in nuclear medicine.¹⁰ These radiopharmaceuticals, exemplified by agents like 99mTc-PSMA-I&S (Imaging & Surgery) 99mTc-PSMA-1404 or 99mTc-PSMA-T4, are designed to bind with high affinity and specificity to the active site of the PSMA protein on cancer cells.^{7, 8, 10, 17}

The mechanism of action involves the intravenous injection of the 99mTc-PSMA radioligand, which then circulates throughout the body. Due to the high overexpression of PSMA in prostate cancer cells, the radioligand selectively targets and binds to these malignant cells.¹³ Once bound, the 99mTc radionuclide emits gamma rays, which can be detected externally by specialized imaging equipment such as Single Photon Emission Computed Tomography (SPECT)/CT scanners or, crucially for surgical applications, intraoperatively by handheld gamma probes.⁵ This molecular targeting capability allows for the precise visualization and localization of even minute tumor foci that might otherwise elude detection by conventional anatomical imaging techniques.⁵

From a radiopharmaceutical perspective, 99mTc is an optimal choice for intraoperative applications due to its ideal physical decay properties for SPECT imaging, a relatively long half-life of 6 hours versus less than 2 hours with PET tracers, and its inherent cost-effectiveness.¹ A significant advantage over Gallium-68 (68Ga), commonly used in PET imaging, is the more widespread availability of 99mTc, which is readily produced from 99Mo/99mTc generators. These generators are standard equipment in nuclear medicine departments globally, rendering 99mTc-based agents a more accessible option, particularly in regions where PET infrastructure is limited.¹ This broad accessibility of 99mTc-PSMA can significantly contribute to expanding advanced surgical techniques, thereby diminishing disparities in cancer care delivery on a global scale. Policymakers and healthcare systems in emerging economies, in particular, may find substantial benefit in prioritizing the integration of 99mTc-PSMA into national guidelines and infrastructure development to improve prostate cancer outcomes more broadly.

Specifically, 99mTc-PSMA-I&S exhibits a relatively slow whole-body clearance due to its high plasma protein binding, reported at 94%.^{10, 11} This pharmacokinetic characteristic is advantageous as it promotes efficient and sustained tracer uptake in PCa lesions over time, leading to steadily increasing lesion-to-background ratios for up to 21 hours post-injection.^{10, 11} This extended window for optimal tracer accumulation is highly beneficial for both preoperative planning and precise execution of surgical procedures.

III. Clinical Rationale for 99mTc-PSMA Radioguided Surgery

Role of PSMA Imaging in Preoperative Staging and Treatment Planning

PSMA imaging, particularly PSMA PET/CT, has revolutionized the preoperative staging and treatment planning for prostate cancer due to its superior sensitivity and specificity in detecting malignant lesions. It provides invaluable data that enables a multidisciplinary care team to comprehensively assess the severity and extent of the disease, thereby creating a precise map for treatment.⁶ PSMA PET/CT has demonstrated higher accuracy in predicting lymph node involvement compared to CT scans, and greater sensitivity and specificity for distant spread compared to bone scans, while also delivering less than half the total radiation of the CT/bone scan combination.⁶ Consequently, PSMA PET has largely supplanted CT and bone scans for determining oligometastatic and metastatic disease, where access and insurance coverage permit.⁶

The clinical impact of PSMA imaging on treatment decision-making is substantial. Studies have shown that PSMA PET/CT can lead to a major change in management for nearly 50% of patients.¹³ The capacity of PSMA imaging to precisely visualize prostate cancer throughout the body enables clinicians to make more informed treatment decisions and monitor patient response to therapy with greater accuracy.¹³ This level of precision facilitates a more personalized approach to cancer care, guiding targeted therapies and potentially reducing the need for more extensive or systemic treatments that carry higher morbidity, even if long-term outcomes do not yet show a significant difference in biochemical recurrence rates.¹ This represents a fundamental shift towards precision oncology, where treatment is tailored to the specific anatomical and biological characteristics of an individual’s cancer.

Addressing Positive Surgical Margins and Micrometastases

A critical challenge in prostate cancer surgery, particularly radical prostatectomy, is the achievement of negative surgical margins, meaning the complete removal of all cancerous tissue. Positive surgical margins (PSMs) are a known risk factor for biochemical recurrence and metastasis, occurring in a significant proportion of patients.² Conventional techniques, even with preoperative imaging like multiparametric MRI, may still miss microscopic disease or small, atypically localized lesions.²

99mTc-PSMA radioguided surgery (RGS) directly addresses this challenge by providing real-time intraoperative detection capabilities. By preoperatively labeling prostate cancer cells with a radioactive tracer, surgeons can use a gamma probe to identify and remove even very small metastases and lymph nodes containing cancer cells that might otherwise be undetectable by visual inspection or palpation.² Studies have shown that 99mTc-PSMA RGS can detect additional metastases as small as 3mm, which were not visualized on preoperative 68Ga-PSMA-11 PET.¹² This enhanced detection capability is particularly valuable in salvage surgery for recurrent PCa, where reliable identification of small or atypically localized lesions is often challenging.¹² The ability to precisely identify and resect these minute tumor foci contributes to improving the chance of complete tumor removal, thereby minimizing the risk of recurrence and enhancing the overall effectiveness of surgical management.²

IV. Clinical Data on 99mTc-PSMA Radioguided Surgery

Sensitivity, Specificity, and Accuracy

Clinical studies evaluating 99mTc-PSMA RGS in patients with recurrent PCa have reported high diagnostic performance. On a specimen basis, radioactive rating using 99mTc-PSMA has yielded a sensitivity of 83.6%, a specificity of 100%, and an accuracy of 93.0%.²   These figures underscore the technique’s robustness in accurately identifying cancerous tissue during surgery.

Impact on Biochemical Response and Treatment-Free Survival

The application of 99mTc-PSMA RGS in salvage surgery for recurrent PCa has shown promising short-term clinical outcomes. A reduction in PSA levels below 0.2 ng/ml was observed in 20 out of 31 patients in one study.⁵ Furthermore, 41.9% of patients remained biochemical recurrence-free after a median follow-up of 13.8 months, and 64.5% continued to be treatment-free after a median follow-up of 12.2 months.⁵ This suggests that targeted removal of metastatic lesions using RGS can delay disease progression and the need for subsequent systemic treatments.³

Diagnostic Efficacy in Primary Prostate Cancer and Margin Assessment

While predominantly studied in recurrent settings, the utility of 99mTc-PSMA RGS is also being explored in primary prostate cancer, particularly for optimizing lymph node dissection and assessing surgical margins.

Role in Primary Staging and Lymph Node Dissection

99mTc-PSMA RGS is being investigated to improve the intraoperative detection of lymph node invasion (LNI) during primary robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection (ePLND).⁴ The technique aims to assist surgeons in identifying patients with LNI who would benefit from ePLND, potentially optimizing the extent of lymph node removal.¹² Initial studies indicate that robot-assisted 99mTc-based PSMA-radioguided surgery is feasible and safe in the primary setting, thus enhancing the detection of nodal metastases.⁴

Intraoperative Margin Assessment

The detection of positive resection margins is crucial in high-risk prostate cancer to minimize recurrence.⁷ Intraoperative ex vivo PET/CT using [18F]PSMA-1007 has shown promise for margin assessment, with reported sensitivity, specificity, and accuracy of 83%, 100%, and 92%, respectively, using an iterative thresholding method.⁷ While 99mTc-PSMA is primarily used with gamma probes for discrete lesion detection, the broader principle of PSMA-guided margin assessment is under investigation. The development of tools allowing surgeons to visualize cancerous tissue intraoperatively could transform the goal of achieving negative surgical margins and ultimately optimize patient outcomes.^{15, 16} However, challenges remain in reliably distinguishing between positive and close surgical margins with current probe technologies.⁷ Prospective trials are needed to further investigate the value of PSMA-based radioguided surgery for margin assessment in primary PCa.⁷

Comparison with Other Imaging Modalities and Tracers

The landscape of prostate cancer imaging and radioguided surgery involves various modalities and tracers, each with distinct advantages and limitations.

99mTc-PSMA SPECT/CT vs. 68Ga-PSMA PET/CT

Both 99mTc-PSMA SPECT/CT and 68Ga-PSMA PET/CT utilize the PSMA target, but they differ in their radionuclide and imaging technology. 68Ga-PSMA PET/CT is recognized for its high sensitivity and spatial resolution, making it a highly accurate diagnostic tool for localizing recurrent PCa and impacting clinical decision-making.^{6, 13} However, its availability is often limited due to the higher cost of PET equipment and radiopharmaceutical production, especially in countries with emerging economies.³

In contrast, 99mTc-PSMA SPECT/CT offers a more cost-effective and widely accessible alternative.¹ While some studies suggest 68Ga-PSMA PET/CT generally has superior detection rates, particularly for lesions in the prostate bed, 99mTc-PSMA SPECT/CT shows comparable performance for detecting bone metastases and overall good agreement in TNM staging.¹³  For instance, one study found that 68Ga-PSMA PET/CT detected 53 regions compared to 43 by 99mTc-PSMA SPECT/CT, with most differences attributed to lower detection in the prostate bed by SPECT/CT. ¹³ Despite these differences, 99mTc-PSMA SPECT/CT can provide sufficient information to significantly alter treatment intentions and reduce waiting times, especially where PET availability is scarce.¹⁴ This clearly indicates that while PET may offer higher resolution, 99mTc-PSMA SPECT/CT is a valuable and practical tool, particularly in resource-constrained settings.

99mTc-PSMA vs. Conventional Imaging (CT/MRI/Bone Scan)

99mTc-PSMA imaging, whether SPECT/CT or used in RGS, consistently demonstrates superior performance over conventional imaging modalities in detecting small, metastatic prostate cancer lesions.¹ PSMA PET/SPECT directly targets tumor cells at a molecular level, allowing for earlier and more accurate visualization of disease compared to CT, MRI, and bone scans, which rely on anatomical changes or less specific metabolic activity.⁶ For example, PSMA PET has largely replaced CT and bone scans for determining oligometastatic and metastatic disease due to its higher accuracy for predicting lymph node involvement and distant spread, along with lower radiation exposure.⁴ 99mTc-PSMA SPECT/CT, specifically, has shown superiority over 99mTc methylene diphosphonate (99mTc-MDP) SPECT/CT in detecting bone metastases, particularly for small lesions and in patients with low PSA levels, and also provides information on extraskeletal metastases.^{9, 14}

99mTc-PSMA RGS vs. Fluorescence Imaging

Beyond radionuclide detection, other intraoperative imaging techniques are being explored. Fluorescence imaging, particularly near-infrared fluorescence (NIRF) imaging, allows for direct visualization and clear delineation of tumor tissue from healthy tissue.² It offers advantages such as high spatial and temporal resolution and repeated excitation of fluorophores.² However, fluorescence imaging is limited by low tissue penetration depth, as photons are scattered or absorbed within just a few cell layers.² In contrast, radionuclide detection with a gamma probe, as employed in 99mTc-PSMA RGS, is generally not hindered by penetration depth and is considered highly sensitive for intraoperative localization of tumor lesions.² The primary limitation of radionuclide use is the reliance on an acoustic signal, which can lead to inaccurate tumor delineation due to the lack of exact visual representation of the tumor tissue.² This suggests that rather than being competing technologies, these modalities may serve complementary roles. A combination of radiodetection and optical imaging techniques could offer additional value, leveraging the strengths of each to provide both sensitive detection and precise visualization for surgeons.² This integrated approach represents a continuous evolution towards ultra-precise, real-time, image-guided surgery, moving beyond traditional anatomical landmarks to achieve more complete and functionally preserving resections.