PRRT Versus PRRT Plus Chemotherapy in GEP NET (PReCedeNT Trial)

Neuroendocrine tumours (NETs), better defined as neoplasms (NENs), are a heterogeneous group of neoplasms that range from well-differentiated tumours to more aggressive carcinomas. Peptide receptor radionuclide therapy (PRRT) with Lutetium-177 DOTATATE is the established standard of care for patients with well-differentiated metastatic or locally advanced GEP-NETs. It has demonstrated a significant improvement in outcomes compared to Octreotide LAR, both as a first-line and second-line treatment approach, following the results of NETTER-1 and NETTER-2 trials, respectively. ENETS guidelines recommend the use of Ga-68 labeled DOTANOC/TOC/TATAE imaging only for WHO Grade 1 NET whereas FDG PET is the preferred modality for WHO Grade 3 NEN and NEC. For Grade 2 tumors (Mib index ranging from 3-20%), there are no strong recommendations for the addition of FDG PETCT in existing diagnostic algorithm. FDG PET positivity has been shown to be an independent predictor of shorter progression-free and overall survival in NET patients undergoing peptide receptor radionuclide therapy (PRRT). (8) Consequently, it is imperative to address FDG-avid tumors by integrating PRRT and chemotherapy. There are no strong recommendations for the grade wise management of GEP-NETs particularly grade 2 \& 3. Although recently published NETTER 2 trial substantiated the role of PRRT as a first line treatment for advanced grade GEP-NETs, still there is lack of evidence supporting the addition of chemotherapy in management of GEP-NETs. Given the absence of a prospective study to establish this treatment regimen, we designed a Phase 3 Randomized Controlled Trial to evaluate the combination of PRRT and CAPE-TEM-based chemotherapy in patients with FDG-positive metastatic well-differentiated NETs.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Male or female, age greater than 18 years
* Histopathological diagnosis of GEP-NET, necessarily satisfying all the the criteria below
* Well differentiated G2 (Ki67 : ≥3-20%) OR G3 (ki67- greater than 20-55%), OR
* Well-differentiated G1 (\<3%) with disease progression in last 6 months
* Positive Ga-68-DOTANOC PET/CT, Krennings score \>/=3
* Positive FDG PET imaging, grade 3 or 4 uptake
* Locally advanced/inoperable disease or metastatic disease
* Karnofsky performance-status score of at least 60 or ECOG performance status \</= 2
* Life expectancy greater than 6 months

Exclusion Criteria:

* Serum creatinine level of more than 1.6 mg/dl or a creatinine clearance of less than 50 ml/min
* Hemoglobin level of less than 8.0 g per deciliter
* Red blood cell count noty less than 300,000/cubic millimeter White cell count of less than 2000 per cubic millimeter
* Platelet count of less than 75,000 per cubic millimetre
* Total bilirubin level of more than 3 times the upper limit of the normal range
* Serum albumin level \< 3.0 g/dl
* Treatment with more than 30 mg of octreotide LAR within 4 weeks before randomisation.
* Peptide receptor radionuclide therapy at any time before randomisation
* Pregnancy and Lactation
* Patients with concurrent malignancies

• BACKGROUNDParghane RV, Ostwal V, Ramaswamy A, Bhandare M, Chaudhari V, Talole S, Shrikhande SV, Basu S. Long-term outcome of "Sandwich" chemo-PRRT: a novel treatment strategy for metastatic neuroendocrine tumors with both FDG- and SSTR-avid aggressive disease. Eur J Nucl Med Mol Imaging. 2021 Mar;48(3):913-923. doi: 10.1007/s00259-020-05004-5. Epub 2020 Sep 2. PMID 32876706
• BACKGROUNDNicolini S, Bodei L, Bongiovanni A, Sansovini M, Grassi I, Ibrahim T, Monti M, Caroli P, Sarnelli A, Diano D, Di Iorio V, Grana CM, Cittanti C, Pieri F, Severi S, Paganelli G. Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2021 Sep;48(10):3260-3267. doi: 10.1007/s00259-021-05236-z. Epub 2021 Feb 18. PMID 33604690
• DERIVEDPuranik AD, Dev ID, Yadav S, Rangarajan V, Agrawal A, Basu S, Chaudhari VA, Ramaswamy A, Ostwal V, Bhandare MS, Shrikhande SV, Parghane RV, Bhargava P, Bal MM, Yadav S, Patkar S, Goel M, Purandare NC, Shah S, Choudhury S, Ghosh S, Venkatachalam M. PReCedeNT trial: Phase III randomized-controlled trial of Lutetium - 177 DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) plus Chemotherapy versus PRRT alone in FDG-avid, Well-differentiated Gastroenteropancreatic neuroendocrine tumors (GEP-NETs). BMC Cancer. 2025 Oct 28;25(1):1659. doi: 10.1186/s12885-025-15111-x. PMID 41152774