Clinical Response Profile of Metastatic/Advanced Pulmonary Neuroendocrine Tumors to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE

Objectives The aims of this study were to perform multiparametric response assessment of metastatic/advanced pulmonary neuroendocrine tumors (NETs) to Lu-177-DOTATATE peptide receptor radionuclide therapy (PRRT) (clinical, biochemical, molecular/structural imaging, and survival assessment) and to study the relationship between response, mortality, and overall survival with dual-tracer molecular imaging parameters. Methods Twenty-two patients (6 women, 16 men; median age, 44 years; range, 16-72 years) of histopathologically proven pulmonary NETs with metastatic/advanced disease were included and analyzed retrospectively. Lu-177-DOTATATE PRRT was administered using standardized protocol (150 mCi [5.55 GBq] per cycle, cycles repeated at 12-16 weeks' intervals [range, 1-5 cycles; average, 4 cycles]) with amino acid-based renal protection. Assessment with Tc-99m-HYNIC-TOC (in the initial years of PRRT development, n = 11)/Ga-68-DOTATATE PET/CT (presently, n = 11) and F-18-FDG PET/CT (n = 22), symptomatic and biochemical parameters (serum CgA and urinary 5-HIAA levels), and anatomical response using contrast-enhanced CT (after 3 cycles) was part of routine pretreatment and response evaluation. The patients were designated as responders and nonresponders based on predefined response assessment criteria. Kaplan-Meier product-limit method was calculated for overall survival (OS) curve after the first PRRT, and corresponding 95% confidence intervals (95% CIs) were estimated for annual survival at 1, 2, 3, and 4 years. The various prognostic variables were also investigated for association with mortality, OS, and treatment response following PRRT. Results and Conclusions Of 22 patients, 6 had undergone surgical resection of primary tumors. All patients were symptomatic before start of PRRT. Two patients did not qualify for PRRT, and 1 received single cycle with follow-up less than 3 months, hence excluded from the present analysis. Thus, a total 19 patients were analyzed in our study. Symptomatic response following PRRT was observed in 15 (79%) of 19 patients. Based on predefined 3-scale response evaluation criteria, of 19 patients, 12 patients (63%) were finally characterized as responders, and 7 patients (37%) were overall nonresponder to PRRT. All 7 nonresponders had moderate to intense FDG-avid primary lung lesion (SUVmax >5 in 4 of 7 patients), and 5 had FDG-avid metastatic liver disease (SUVmax >5). Peptide receptor radionuclide therapy was well tolerated in all with no major hematologic and renal toxicity (except for 2 patients showing mild grade I renal and hematologic toxicity in the initial cycles and recovery in subsequent follow-up). Seven (37%) of 19 died at the time of analysis. The observed annual OS rates were as follows: 1 year: 94.7% (95% CI, 68.1%-99.2%), 2 years: 66% (95% CI, 35.5%-84.5%), 3 years: 57.7% (95% CI, 28-78.9%), and 4 years: 38.5% (95% CI, 8.1%-69.5%); median OS was 40 months with 39% (95% CI, 13.1%-64.8%). In conclusion, Lu-177-DOTATATE PRRT was found safe and well tolerated in receptor-positive pulmonary NET. FDG positivity appeared to forecast aggressive tumor behavior.