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Brief Summary
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Synopsis
Scientific
background and rationale
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 (1).
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%) [2]. 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 [3]. 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20% as well (unpublished data).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.(4) 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 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 CT or scintigraphy (5,6). 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 (7). 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 (8). 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 (9). While
DOTA PET avidity is a feature of well-differentiated disease, FDG avidity tends
to be associated with more aggressive, de-differentiated disease (10). Grade 1
NET tend to be DOTA-avid but negative on FDG PET, whereas grade 3 NEC generally
show 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 behaviour.
Despite the prognostic utility of pathological grading, FDG PET positivity has
been consistently shown to be independently associated with a poor prognosis.
(11)
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
(Peptide Receptor Radionuclide Therapy) as standard of care in treatment of
metastatic well-differentiated GEP NETs.(12) However, FDG positivity in these
tumors suggests presence of aggressive phenotypes and warrants simultaneous use
of chemotherapy.(13) Strosberg et.al, (14) 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.(15) 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 regime, in
addition oral capecitabine was added after every PRRT cycle. Clinical, biochemical and imaging
response was assessed after completion of induction treatment of combination of
PRRT and chemotherapy. 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%. (16) 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. We 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. Study design Type of study - Prospective, randomized, open-label ,Patient number - 162 â—
Arm A (PRRT Arm)
Peptide Receptor Radionuclide Therapy with Lu-177-DOTATATE,
180-200 mCi administered intravenously for 4 cycles, at interval duration of
8-12 weeks
â— Arm B (PRRT plus Chemotherapy Arm)
Peptide Receptor Radionuclide Therapy with Lu-177-DOTATATE,
180-200 mCi administered intravenously for 4 cycles, at interval duration of
6-8 weeks
Plus
CAP-TEM Protocol:
Day 1: Oral Capecitabine 1500 mg/m2, per oral, twice daily
within 15 min of food for 14 days, followed by 2 week rest period
Day 10-D14: Oral Temozolomide 20 mg/m2 per oral, daily dose
for 5 days as a single dose with a glass of water at bed time. To be taken
empty stomach at least 30 min before or 2 hours after meal. |