Abstract
Surgery with a complete tumor removal is the only therapeutic option with a curative approach in a neuroendocrine tumor disease. Recurrent abdominal surgery is associated with inflammation, altered anatomy, and scar tissue and can be challenging [1]. Additionally, tumor lesions can be really small, invisible, or not palpable by the surgeon’s fingers. For that reason, an intraoperative diagnostic tool is necessary because the prior imaging (scintigraphy, PET/CT) has a reduced sensitivity with lower tumor size. Sufficient, preoperative, and intraoperative imaging can provide the surgeon with valuable assistance and also significantly simplify the surgical procedure. Depending on the intraoperative findings, the surgical intervention can be expanded or even significantly reduced.
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Surgery with a complete tumor removal is the only therapeutic option with a curative approach in a neuroendocrine tumor disease. Recurrent abdominal surgery is associated with inflammation, altered anatomy, and scar tissue and can be challenging [1]. Additionally, tumor lesions can be really small, invisible, or not palpable by the surgeon’s fingers. For that reason, an intraoperative diagnostic tool is necessary because the prior imaging (scintigraphy, PET/CT) has a reduced sensitivity with lower tumor size. Sufficient, preoperative, and intraoperative imaging can provide the surgeon with valuable assistance and also significantly simplify the surgical procedure. Depending on the intraoperative findings, the surgical intervention can be expanded or even significantly reduced.
For several decades, nuclear medicine has offered surgery through the PET probes an intraoperative technology that offers these needs. Adams and Baum et al. 2000 report on one of the first PET probe applications in a patient with neuroendocrine neoplasia (NEN) [2]. In 2012, Kaemmerer et al. published data of a first pilot study using a hand-held pet-probe for the diagnostic of a NEN intraoperatively [3]. The data showed a significantly higher rate of tumor detection than the pre-operative Somatostatin-receptor PET/CT (SSTR-PET/CT) and even the surgical palpation (94% vs. 69% vs. 50%) respectively). Sadowski et al. 2015 confirmed the results of Kaemmerer et al. and they showed the suitability of the PET probe for SI-NEN, mesenteric lymph node metastases, and also for multilocular tumors. Not suitable are cases with a pancreatic primary tumor with liver metastases due to relatively high tumor to background counts [1]. In conclusion, the PET probe appears to be a useful tool for the surgeon in patients with small SI tumors, lymph node metastases, and multiple previous operations. New radiotracers will certainly continue to expand the range of applications to other tumor entities in the future. The Netter-1 study proved peptide-related radionuclid therapy (PRRT) in the therapies of neuroendocrine neoplasia. Depending on the initial somatostatin-receptor (SST) distribution and the SUVmax, excellent therapy results can be achieved.
Several studies independently presented the suitability of all 3 SST-peptides for the diagnosis of NEN and presented a significant immunohistochemical correlation between the PET parameters ex vivo and the histological SST receptors of the tumors in vivo [4,5,6].
Additionally, these studies showed that SST-PET/CT results allow conclusions for tumor biology (e.g., differentiation, tumor response), because high SST receptor expression is usually associated with good tumor differentiation and excellent PRRT response. As often said by Prof. RP. Baum, if a tumor has been shown to have good receptor expression, then it is suitable for both receptor-based imaging and PRRT. This “Theranostic“concept is transferable to other tumor entities.
Our research group investigated also other receptors as new tools for further diagnostic and therapeutic approaches. Endothelin-receptor A expression as well as chemokine receptor CXCR4 were evaluated in a large set of NEN [7, 8]. Tumor cells and tumor stroma of NEN were characterized by a very low endothelin-A-expression whereas CXCR4-expression directly correlated with Ki-67 and was more expressed in undifferentiated neuroendocrine carcinoma. With a wide CXCR4-distribution of high-proliferative neuroendocrine tumors and carcinoma the CXCR4 was a very interesting target for diagnostic and therapy. With the cyclic peptide CPCR4–2 labeled with 68Gallium an excellent tracer was developed by the Munich group of Prof. Wester [9]. As expected, the well-differentiated tumors showed no CXCR4 expression, so that imaging was also negative. In contrast, high-proliferative tumors were characterized by preclinically seen high CXCR4-receptor expression, so that the CXCR4-based imaging detected the high-proliferative tumor lesions. The authors recommended [68Ga]Pentixafor PET/CT as non-invasive read-out possibility of CXCR4 endoradiotherapy in advanced SST-negative tumors [10]. CXCR4-imaging presented a bone marrow toxicity as limitation. Later on, this side effect was used for molecular diagnosis of multiple myeloma patients [11]. Our group also presented preclinical data of strong CXCR4 expression in MALT lymphoma patients [12, 13]. New data published by Haug AR. demonstrated a more than 90% and an excellent imaging of the lymphomas by PET/MRT [14].
A high SST expression allows a PRRT, for this reason the SST expression of SCLC was examined as a treatment option. In our preclinical data SST expression was found to be expressed in almost 25% of the cases, so SST-based radionuclide therapy seemed suitable. This therapeutic approach was implemented by an external working group (Lapa C. WĂĽrzburg, Germany). Data published by Lapa C. et al. show that the SST-based PRRT is feasible as limited therapy option for very advanced SCLC patients [15].
Finally, theranostic proof of concept works in different tumor entities and seems to be a milestone on the way to personalized medicine. This way of treatment was strongly influenced by Prof. RP. Baum and made decisive progress.
With the Netter-1 study the PRRT in SI-NEN stage IV demonstrated superiority over SSA mono therapy [16, 17]. Different studies presented data of PRRT with other neuroendocrine tumor primaries. Alsadik et al. showed PRRT data of pancreatic neuroendocrine tumors and reported complete response rates of 2–6% and partial response up to 60% by an overall survival of 53 months and a progression-free survival of 34 months [18].
The removal of local advanced pancreatic neuroendocrine tumors is often limited by vessel involvement. In the last years, several studies presented excellent data which PRRT as a neoadjuvant approach to downsize and downstage tumors receiving resectability. The first case was published by our group and the neoadjuvant PRRT was performed by RP. Baum [19]. Later on, Esther I van Vliet published a series of neoadjuvant-treated pancreatic neuroendocrine tumor cases with an impressive median PFS of 69Â months [20].
The resection of the primary tumors in stage IV neuroendocrine tumor patients is still discussed. But how about the primary resection in SST-positive expressed neuroendocrine tumor patients stage IV, treated with PRRT? Bertani et al. presented data with a median PFS of 70 vs. 30 months (HR 5.1; p = 0.002) and a median OS of 112 vs. 65 months (HR 1.13; p = 0.011) with a benefit for the primary resected patients [21]. Kaemmerer et al. published the largest European study with beneficial results for SI- and pancreatic neuroendocrine tumor patients with a resected primary tumor prior to PRRT with mOS of 142 vs. 80 months (HR 2.91; p < 0.001) and a mOS of 140 vs. 58 months (HR 1.86; p = 0.002) respectivly [22]. Finally, these data underline the synergistic effects of well-performed surgery and responsible nuclear medicine treatment.
Thank you Richard for more than 10Â years of fruitful collaboration, outstanding collegiality, empathetic 24-h patients management, and many inspiring clinical and translational oncological research projects.
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Kaemmerer, D. (2024). Nuclear Medicine and Surgery on the Way to Personalized Medicine. Ten Years of Clinical and Translational Oncology and Research. In: Prasad, V. (eds) Beyond Becquerel and Biology to Precision Radiomolecular Oncology: Festschrift in Honor of Richard P. Baum. Springer, Cham. https://doi.org/10.1007/978-3-031-33533-4_17
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