Perspective on Pattern of Failure in Patients with Biochemical Recurrence After PSMA Radioguided Surgery

Prostate cancer, the second most frequent type of cancer in men, presents complex diagnostic and treatment challenges and is a major health care burden (1). The complexity of prostate cancer management ranges from early diagnosis to treatment and follow-up, involving a wide range of medical specialties. In this regard, multidisciplinary management is key to a successful patient outcome (1).

With regard to the role of nuclear medicine in prostate cancer, the advent of prostate-specific membrane antigen (PSMA) ligands both for PET/CT imaging and for theranostic applications is acquiring progressively more relevance in the overall patient journey, from staging to therapeutic indications, having demonstrated efficacy in many of these settings (2,3). The efficacy of imaging tests can be evaluated using different parameters. Fryback and Thornbury proposed a hierarchic model of efficacy (4). When this model of efficacy is applied to PSMA ligand PET/CT, the available evidence is demonstrating patient outcome efficacy in many indications in prostate cancer, as studies are showing that the information it supplies helps guide patient management decisions that lead to better outcomes, increased survival, or improved quality of life (2,3). However, access to some state-of-the-art diagnostic or therapeutic tools inside high-income countries is limited to some regions or even to certain hospitals—those that have higher budgets assigned to the medical specialties offering these latest innovations. Examples of these disimilarities in access to some state-of-the-art health care options, not yet included in international guidelines, are robotic surgery, PET/MRI, and radiopharmaceutical therapy with PSMA ligands. Regarding the last of these, as a particular example, there are regions in northern Europe where radiopharmaceutical therapy with PSMA ligands in prostate cancer is readily available for patients and is applied, when indicated, in everyday clinical practice. In contrast, in southern Europe the situation is very different, with few cases being done, mainly because of budgetary limitations.

Focusing on the subgroup of prostate cancer patients presenting with biochemically recurrent disease and evident metastatic lymphadenopathies, the main management options before the availability of PET/CT with PSMA ligands were to wait and observe or to start systemic therapy, such as androgen deprivation therapy (5). In this subset of patients, the main trend in the last 2 decades has been to validate treatments aimed at eliminating localized disease—generically denominated salvage therapies—through either radiation therapy or surgical interventions. The main eligibility criterion for these salvage therapies is the presence of oligometastatic disease that can be effectively treated, leaving no detectable disease. One surgical intervention is salvage lymph node dissection. This procedure can achieve a complete biochemical response in patients presenting with recurrent prostate cancer with metastatic lymph nodes after an initial treatment consisting of radical prostatectomy (6). However, one of the difficulties of salvage lymph node dissection is dissecting all the metastatic lymph nodes, which is not always easy on the basis of conventional imaging. Apparently normal lymph nodes based on their size and morphology may present metastatic disease detectable only with functional imaging techniques, such as those available in nuclear medicine. In this setting, PSMA ligands bound to ^99mTc, which can be detected intraoperatively with a γ-probe, have been used for radioguided surgery. Preliminary studies presented by the group led by Maurer from Hamburg University Hospital show (a) that PSMA-radioguided surgery increases the detection rate of metastatic lymph nodes in salvage lymph node dissection and also (b) that in patients that achieve biochemical response with prostate-specific antigen (PSA) values lower than 0.1 ng/mL, it prolongs therapy-free survival. The investigators concluded that surgery may be an opportunity to prolong treatment-free survival, but patient selection criteria need to be narrow, taking into account that there should be a limited number of metastatic pelvic lesions, that the PSA values should not be too high (indicating a limited disease burden), and that patients should present favorable overall health conditions and life expectancy (7,8).

In this clinical setting, a study by Schweiger et al., published in The Journal of Nuclear Medicine, analyzed the failure pattern of patients who had undergone PSMA-radioguided surgery (5). This group of investigators, from Hamburg University Hospital, retrospectively evaluated the localization of recurrent disease using PSMA ligand PET/CT in patients presenting biochemical failure after PSMA-radioguided surgery. The 100 patients included in the study had previously undergone PSMA-radioguided surgery and on follow-up presented with biochemical recurrence with PSA values of 2 ng/mL or greater. Once the biochemical recurrence was evident, PSMA ligand PET/CT was performed in 88 of them and PSMA ligand PET/MRI in the remaining 12 patients. Then, these PET findings were compared with PET images obtained before the PSMA-radioguided surgery using the molecular imaging classification for PSMA ligand PET/CT, called miTNM (9). The main finding was that PSMA ligand PET/CT accurately detected and localized recurrent disease, with 53% of patients showing local recurrent disease and/or only local pelvic lymphadenopathic metastases. On this basis, they concluded that PSMA ligand PET/CT could be useful to guide management decisions on local treatments. In particular, in these patients it would potentially mean a second locoregional treatment that could help delay the need to initiate systemic treatment, although further evidence is required (5).

It is known that micrometastatic disease, not detectable with currently available imaging methods, leads over time to biochemical recurrence and then to structural lesions that become evident in imaging. Although PET image resolution has steadily improved over the last 20 y until reaching around 3–4 mm, it still cannot detect micrometastatic disease, a small tumor burden, or tumors with low avidity for the radiopharmaceutical used. As an example, in melanoma, [¹⁸F]FDG PET/CT does not detect micrometastasis (10). Therefore, sentinel node biopsy is indicated for precise lymphatic staging and to rule out lymphatic micrometastasis (11). The sentinel node biopsy concept is already included in the standard of care for melanoma and breast cancer (12–14). In less accessible tumors, such as prostate cancer, the sentinel node biopsy procedure is technically more difficult and performed only in certain centers. As an example of research with the latest technology in this setting, a randomized trial has proven the higher efficacy of sentinel node biopsy in prostate cancer using a hybrid radioactive and fluorescent tracer approach (15,16).

In conclusion, regarding prostate cancer, in the last decade we have witnessed the clinical introduction of diagnostic and therapeutic nuclear medicine procedures with enormous potential, situating nuclear medicine at the core of the multidisciplinary team managing these patients. Given the available evidence, it is reasonable to expect significant growth of the clinical presence of nuclear medicine, from radioguided surgery to PET/CT, PET/MRI, and radiopharmaceutical therapy using PSMA radiopharmaceuticals. We have at hand the opportunity to promote these techniques and contribute to the generation of high-quality evidence, never forgetting the importance of multidisciplinary collaboration in the search for the best possible treatment and care for the individual patient.

• © 2025 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication October 19, 2024.
• Accepted for publication November 14, 2024.