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20% as well (unpublished data).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.