title: Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate.
abstract: Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival.
  
  
  METHODS
  We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with (177)Lu-octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan-Meier curve method (log-rank test) and multivariate analysis (P < 0.05).
  
  
  RESULTS
  The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3-33.7) and 55 mo (95% confidence interval, 48.8-61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1-3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively.
  
  
  CONCLUSIONS
  The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient's performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2-in particular, between G1 (Ki-67 index of 1%-2%) and low-range G2 (Ki-67 index of 3%-10%)-provides prognostic stratification.
authors.affiliation: Department of Nuclear Medicine, University Hospital, Bonn, Germany.
authors.forename: Samer
authors.initials: S
authors.lastname: Ezziddin
authors.forename: Mared
authors.initials: M
authors.lastname: Attassi
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Yong-Hing
authors.forename: Hojjat
authors.initials: H
authors.lastname: Ahmadzadehfar
authors.forename: Winfried
authors.initials: W
authors.lastname: Willinek
authors.forename: Frank
authors.initials: F
authors.lastname: Grünwald
authors.forename: Stefan
authors.initials: S
authors.lastname: Guhlke
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Biersack
authors.forename: Amir
authors.initials: A
authors.lastname: Sabet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms / Q000401:mortality / Q000532:radiotherapy*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000401:mortality / Q000532:radiotherapy*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000532:radiotherapy*; D049268:Positron-Emission Tomography / Q000379:methods; D011379:Prognosis; D011868:Radioisotopes / Q000627:therapeutic use*; D018000:Receptors, Peptide / Q000737:chemistry*; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000401:mortality / Q000532:radiotherapy*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C554548:177Lu-octreotate; D019394:Ki-67 Antigen; D011868:Radioisotopes; D018000:Receptors, Peptide; D015282:Octreotide
keywords: 177Lu-octreotate; gastroenteropancreatic tumors; neuroendocrine tumors; peptide receptor radionuclide therapy; tumor grading