Senthil Kumar: Systemic Treatment for Advanced/Metastatic Gastrointestinal and Pancreatic Neuroendocrine Tumors

Senthil Kumar, Medical Oncologist at Red Hills Chennai, shared on X:

“Systemic Treatment for Advanced/Metastatic Gastrointestinal and Pancreatic Neuroendocrine Tumors (GEP-NETs)

—

 Classification and Diagnostic Overview

Types:

G1: Ki-67 <3%

G2: Ki-67 3–20%

G3: Ki-67 >20% (Well-differentiated G3 NETs and poorly differentiated NECs)

Functionality:

Functional

Non-functional

Common Sites:

Small intestine, stomach, pancreas, colon, rectum, appendix

Diagnosis:

Histopathology: Confirms NET morphology.

Immunohistochemistry (IHC): Chromogranin A, Synaptophysin, Ki-67 proliferation index.

Imaging: CT, MRI, 68Ga-DOTATATE PET/CT (for SSTR expression)

Molecular Profiling: optional , NGS for MEN1, DAXX, ATRX, mTOR mutations

—

Prognostic and Predictive Factors

Age, Performance Status (PS), Comorbidities

Tumor Grade and Differentiation (Ki-67 index)

Tumor Burden and Disease Tempo

Symptomaticity (due to tumor bulk or hormone secretion) Somatostatin Receptor (SSTR) Expression

Metastatic Spread: Liver, bone, peritoneum involvement

Molecular Alterations: MEN1, DAXX, ATRX, mTOR pathway mutations

—

Surgical and Locally Directed Therapies

Surgical Resection Complete Resection:

Recommended when both primary tumor and metastases are fully resectable.

Incomplete Cytoreduction (Debulking):

Considered if ≥90% of total tumor burden can be removed.

Primary Tumor Resection Alone:

Indicated for symptomatic relief due to bulk, carcinoid syndrome, obstruction, or ischemia.

Liver Metastases Resection/Ablation: Considered for low-volume, unilobar liver disease with preserved liver function and symptomatic burden.

Liver-Directed Therapies

Ablation (RFA/MWA), Surgery, TACE, Radioembolization are effective for hepatic-dominant disease.

Best suited for:

Unilobar, limited liver metastases

Preserved liver function Symptomatic patients (due to bulk or hormone secretion)

Liver Transplantation (OLT):

Investigational in unresectable liver metastases.

—

First-Line Treatment

Somatostatin Analogs (SSAs)

Octreotide LAR (PROMID Trial):

Time to Progression (TTP): 14.3 vs. 6 months (midgut NETs)

Drug: Octreotide LAR (30 mg IM every 4 weeks)

Lanreotide (CLARINET Trial):

Progression-Free Survival (PFS): 32.8 vs. 18 months (non-functional GEP-NETs)

Drug: Lanreotide Autogel (120 mg SC every 4 weeks)

Indication: G1/G2 well-differentiated NETs, SSTR-positive, symptomatic patients

—

Second-Line Treatment

Peptide Receptor Radionuclide Therapy (PRRT)

177Lu-DOTATATE (Lutathera)

NETTER-1 Trial:

PFS: 28.4 vs. 8.5 months Median

OS: 48 vs. 36 months (not statistically significant)

ORR: 18%

Adverse Effects:

Hematologic Toxicity:

Thrombocytopenia, neutropenia, anemia

Renal Toxicity: Nephrotoxicity (mitigated by amino acid infusions)

Nausea, Vomiting Secondary Myelodysplastic Syndrome (MDS)/Leukemia (rare)

Indication: Progressive, SSTR-positive, well-differentiated G1/G2 NETs

NETTER-2 Trial Indication:

Progressive, high-grade (G2/G3) SSTR-positive GEP-NETs.

PFS: Significantly prolonged with PRRT vs. high-dose SSA. (23 vs 8.5 months )

ORR: Higher response rates in earlier use. OS: Data pending.

—  Targeted Therapy Everolimus (mTOR Inhibitor)

RADIANT-3 (Pancreatic NETs):

PFS: 11.0 vs. 4.6 months Median

OS: 44 months (not significant) RADIANT-4 (Non-functional GI/Lung NETs):

PFS: 11.0 vs. 3.9 months Sunitinib (Tyrosine Kinase Inhibitor)

SUN1111 Trial (pNETs):

PFS: 11.4 vs. 5.5 months

ORR: 9.3% Bevacizumab (Anti-VEGF Antibody)

Role: Anti-angiogenic therapy in NETs.

Clinical Trials: Bevacizumab + Octreotide LAR improved PFS over interferon + Octreotide.

ECOG E2211: Studied in combination with CAPTEM.

Usage: Limited to investigational settings.

—  

Third-Line and Refractory Treatment

 Chemotherapy CAPTEM (Capecitabine + Temozolomide)

(G1/G2 Pancreatic NETs) ECOG-ACRIN E2211 Trial:

PFS: 22.7 vs. 14.4 months Median

OS: 58 months (not significant)

ORR: 30–70%. “