Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies ranging from well- differentiated, slowly growing tumors to poorly differentiated neoplasms, which are aggressive and less frequent. Neuroendocrine cells have the ability to express several peptide receptors in high volumes, especially somatostatin receptors, which are heptahelical G-protein-coupled glycoprotein transmembrane receptors. In the most recent SEER register (SEER-17), more than half of all NETs, i.e. 61%, were gastroenteropancreatic neuroendocrine tumors (GEP-NETs), with the highest frequency being found in the rectum (17.7%), the small intestine (17.3%), and the colon (10.1%) . The tumor biology varies with the location of the primary tumors as well as with the grade and staging of the tumors. The malignant potential ranges from the most benign types of tumor to small intestinal tumors and up to neuroendocrine carcinoma (NEC) with very malignant behavior. The tumors are graded according to the classification system of the World Health Organization (WHO), wherein a new classification system is just being accepted. The tumors are divided into grade 1 NET (NET-G1), with a proliferation \<3%, NET-G2 with a proliferation between 3 and 20%, NET-G3, which is a new group with a Ki-67 \>20%, and finally NEC-G3, exhibiting a Ki-67 of \>20% as well (unpublished data). Of note, the difference between NET-G3 and NEC-G3 is mainly the degree of differentiation. NET-G3 are well-differentiated tumors, often with expression of somatostatin receptors. NEC-G3 are poorly differentiated tumors that usually lack expression of somatostatin receptors.
NETs are characterized by a general lack of symptoms until they are in advanced phase, and early biomarkers are not as available and useful as required. Heterogeneity is an intrinsic, pivotal feature of NETs that derives from diverse causes and ultimately shapes tumor fate. The different layers that conform NET heterogeneity include a wide range of distinct characteristics, from the mere location of the tumor to its clinical and functional features, and from its cellular properties, to the core signaling and (epi)genetic components defining the molecular signature of the tumor. The importance of this heterogeneity resides in that it translates into a high variability among tumors and, hence, patients, which hinders a more precise diagnosis and prognosis and more efficacious treatment of these diseases. Heterogeneity can be assessed objectively by molecular imaging techniques. Patients with well- differentiated GEP NETs undergo imaging with Ga-68-DOTATOC PET/CT (DOTA PET/CT), which is a somatostatin-receptor (SSTR)-specific imaging tracer. PET/CT with 68Ga-DOTA-peptides has been reported to present a higher sensitivity for the detection of well-differentiated, less aggressive NETs than well tolerated with negligible grade 3/4 toxicities. After a median follow-up period of 36 months, the median OS was not achieved with a median PFS of 48 months. At 3 months after completion of combination of PRRT and chemotherapy, 2% of patients showed a complete anatomical response, 28% a partial response, 68% stable disease, and only 2% progression. On FDG PET/CT, 27% achieved a complete metabolic response during the follow-up period. A biochemical response (\>25% fall in chromogranin-A levels) was seen in 45%. These results established the effectiveness of the combination of PRRT and chemotherapy which is now practiced routinely. However, there is no prospective study to establish this treatment regime. The investigators therefore propose to prospectively evaluate the combination of PRRT and chemotherapy in patients with well-differentiated NETs, in a systematic manner to generate reliable conclusions with regards to this treatment regimen for intermediate to high grade NETs. On the other hand, 18F-FDG PET/CT is preferred for more aggressive, less differentiated NETs as there is emerging evidence that the presence of increased expression of GLUT (glucose-transporter) receptors in NETs highlights an increased propensity for invasion and metastasis, and an overall poorer prognosis. In fact, a strong association has recently been shown between higher 18F-FDG uptake and worse outcome even in patients with well-differentiated or low-grade tumors, with provision of prognostic information independently of the mitotic rate. Accordingly, 18F-FDG has an important role in managing patients with NETs because of its high prognostic value and its higher sensitivity in delineating disease extent, especially in aggressive and high-grade and aggressive intermediate-grade tumors. While DOTA PET avidity is a feature of well-differentiated disease, FDG avidity tends to be associated with more aggressive, de-differentiated disease. Grade 1 NET tends to be DOTA-avid but negative on FDG PET, whereas grade 3 NEC generally shows the opposite imaging phenotype. Grade 2 NET may demonstrate uptake of both tracers. Irrespective of pathological grade, the distribution of these tracers may not be spatially concordant, with some lesions having either DOTA or FDG avidity, but not both. This highlights the limitations of relying on histopathological grade from a single biopsy site to predict disease behavior. Despite the prognostic utility of pathological grading, FDG PET positivity has been consistently shown to be independently associated with a poor prognosis. SSTR expression on the surface of NET enables the use of somatostatin analogues labelled with particle-emitting radionuclides for targeted peptide receptor radionuclide therapy (PRRT) NETTER-1 trial has established Lu-177 PRRT as standard of care in treatment of metastatic well-differentiated GEP NETs. However, FDG positivity in these tumors suggests presence of aggressive phenotypes and warrants simultaneous use of chemotherapy. Strosberg et.al, have shown exceptionally high and durable response rate with combination of Capecitabine and temozolomide in metastatic well, or moderately differentiated pancreatic neuroendocrine tumor. Combination of PRRT and chemotherapy, that is, temozolomide-capecitabine (CAP-TEM) has been therefore effective in patients showing SSTR and GLUT receptor expression on Ga-68 DOTA PET and FDG PET respectively. Kong et al studied a retrospective cohort of 52 patients selected for treatment on the basis of somatostatin-receptor imaging without spatially discordant FDG-avid disease. All patients received conventional PRRT regimen, in addition oral capecitabine was added after every PRRT cycle. Clinical, biochemical and imaging response was assessed after completion of induction. Combination of PRRT and chemotherapy was well tolerated with negligible grade 3/4 toxicities. After a median follow-up period of 36 months, the median OS was not achieved with a median PFS of 48 months. At 3 months after completion of combination of PRRT and chemotherapy, 2% of patients showed a complete anatomical response, 28% a partial response, 68% stable disease, and only 2% progression. On FDG PET/CT, 27% achieved a complete metabolic response during the follow-up period. A biochemical response (\>25% fall in chromogranin-A levels) was seen in 45%. These results established the effectiveness of combination of PRRT and chemotherapy which is now practiced routinely. However, there is no prospective study to establish this treatment regime. The investigators therefore propose to prospectively evaluate combination of PRRT and chemotherapy in patients with well-differentiated NETs, in systematic manner to generate reliable conclusion with regards to this treatment regimen for intermediate to high grade NETs.
