PReCedeNT trial: Phase III randomised-controlled open-label trial of Lutetium - 177 Peptide Receptor Radionuclide Therapy (PRRT) Plus Chemotherapy Versus PRRT alone in FDG-avid, Well-Differentiated Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP-NETs)

Synopsis

 Scientificbackground and rationale

Neuroendocrine tumors (NETs) are a heterogeneous group ofmalignancies ranging from well-differentiated, slowly growing tumors to poorlydifferentiated neoplasms, which are aggressive and less frequent (1).Neuroendocrine cells have the ability to express several peptide receptors inhigh volumes, especially somatostatin receptors, which are heptahelicalG-protein–coupled glycoprotein transmembrane receptors. In the most recent SEERregister (SEER-17), more than half of all NETs, i.e. 61%, weregastroenteropancreatic neuroendocrine tumors (GEP-NETs), with the highestfrequency being found in the rectum (17.7%), the small intestine (17.3%), andthe colon (10.1%) [2]. The tumor biology varies with the location of theprimary tumors as well as with the grade and staging of the tumors. Themalignant potential ranges from the most benign types of tumor to smallintestinal tumors and up to neuroendocrine carcinoma (NEC) with very malignantbehavior [3]. The tumors are graded according to the classification system ofthe World Health Organization (WHO), wherein a new classification system isjust being accepted. The tumors are divided into grade 1 NET (NET-G1), with aproliferation <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 aKi-67 of >20% as well (unpublished data). Of note, the difference betweenNET-G3 and NEC-G3 is mainly the degree of differentiation. NET-G3 arewell-differentiated tumors, often with expression of somatostatin receptors.NEC-G3 are poorly differentiated tumors that usually lack expression ofsomatostatin receptors.

NETs are characterized by a general lack of symptoms untilthey are in advanced phase, and early biomarkers are not as available anduseful as required. Heterogeneity is an intrinsic, pivotal feature of NETs thatderives from diverse causes and ultimately shapes tumor fate.(4) The differentlayers that conform NET heterogeneity include a wide range of distinctcharacteristics, from the mere location of the tumor to its clinical andfunctional features, and from its cellular properties, to the core signalingand (epi)genetic components defining the molecular signature of the tumor. Theimportance of this heterogeneity resides in that it translates into a highvariability among tumors and, hence, patients, which hinders a more precisediagnosis and prognosis and more efficacious treatment of these diseases.

Heterogeneity can be assessed objectively by molecularimaging techniques. Patients withwell-differentiated GEP NETs undergo imaging with Ga-68-DOTATOC PET/CT (DOTAPET/CT), which is somatostatin-receptor (SSTR)-specific imaging tracer. PET/CTwith  68Ga-DOTA-peptides has beenreported to present a higher sensitivity for the detection ofwell-differentiated, less aggressive NETs than CT or scintigraphy (5,6). On theother hand, 18F-FDG PET/CT is preferred for more aggressive, lessdifferentiated NETs as there is emerging evidence that the presence ofincreased expression of GLUT (glucose-transporter) receptors in NETs highlightsan increased propensity for invasion and metastasis, and an overall poorerprognosis (7). In fact, a strong association has recently been shown betweenhigher 18F-FDG uptake and worse outcome even in patients withwell-differentiated or low-grade tumors, with provision of prognosticinformation independently of the mitotic rate (8). Accordingly, 18F-FDG has animportant role in managing patients with NETs because of its high prognosticvalue and its higher sensitivity in delineating disease extent, especially inaggressive and high-grade and aggressive intermediate-grade tumors (9). WhileDOTA PET avidity is a feature of well-differentiated disease, FDG avidity tendsto be associated with more aggressive, de-differentiated disease (10). Grade 1NET tend to be DOTA-avid but negative on FDG PET, whereas grade 3 NEC generallyshow the opposite imaging phenotype. Grade 2 NET may demonstrate uptake of bothtracers. Irrespective of pathological grade, the distribution of these tracersmay not be spatially concordant, with some lesions having either DOTA or FDGavidity, but not both. This highlights the limitations of relying onhistopathological grade from a single biopsy site to predict disease behaviour.Despite the prognostic utility of pathological grading, FDG PET positivity hasbeen consistently shown to be independently associated with a poor prognosis.(11)

SSTR expression on the surface of NET enablesthe use of somatostatin analogues labelled with particle-emitting radionuclidesfor targeted peptide receptor radionuclide therapy (PRRT)

NETTER-1 trial has established Lu-177 PRRT(Peptide Receptor Radionuclide Therapy) as standard of care in treatment ofmetastatic well-differentiated GEP NETs.(12) However, FDG positivity in thesetumors suggests presence of aggressive phenotypes and warrants simultaneous useof chemotherapy.(13) Strosberg et.al, (14) have shown exceptionallyhigh and durable response rate with combination of capecitabine andtemozolomide in metastatic well, or moderately differentiated pancreaticneuroendocrine tumor. Combination of PRRT and chemotherapy, that is,temozolomide-capecitabine (CAP-TEM) has been therefore effective in patientsshowing SSTR and GLUT receptor expression on Ga-68 DOTA PET and FDG PETrespectively.(15) Kong et al studied a retrospective cohort of 52 patients selected for treatmenton the basis of somatostatin-receptor imaging without spatially discordantFDG-avid disease. All patients received conventional PRRT regime, inaddition oral capecitabine was added after every PRRT cycle. Clinical, biochemical and imagingresponse was assessed after completion of induction treatment of combination ofPRRT and chemotherapy. Combination of PRRT and chemotherapy was well toleratedwith negligible grade 3/4 toxicities. After a median follow-up period of 36months, the median OS was not achieved with a median PFS of 48 months. At 3 monthsafter completion of combination of PRRT and chemotherapy, 2% of patients showeda complete anatomical response, 28% a partial response, 68% stable disease, andonly 2% progression. On FDG PET/CT, 27% achieved a complete metabolic responseduring the follow-up period. A biochemical response (>25% fall inchromogranin-A levels) was seen in 45%. (16) These results established the effectiveness ofcombination of PRRT and chemotherapy which is now practiced routinely. However,there is no prospective study to establish this treatment regime. We thereforepropose to prospectively evaluate combination of PRRT and chemotherapy inpatients with well-differentiated NETs, in systematic manner to generate reliable conclusion with regards to thistreatment regimen for intermediate to high grade NETs.

Study designType 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 of8-12 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 of6-8 weeks

Plus

CAP-TEM Protocol:

Day 1: Oral Capecitabine 1500 mg/m2, per oral, twice dailywithin 15 min of food for 14 days, followed by 2 week rest period

Day 10-D14: Oral Temozolomide 20 mg/m2 per oral, daily dosefor 5 days as a single dose with a glass of water at bed time. To be takenempty stomach at least 30 min before or 2 hours after meal.