In this study, we reported our 4 years’ experience in PRRT with 177Lu-DOTATATE in patients with NETs. We evaluated the clinical efficacy and safety of PRRT in 16 patients with NET.
In the recent decades, after it has been demonstrated that NETs can be detected with radiolabeled somatostatin analogues such as 68Ga-DOTATATE PET/CT and 99mTc-octreotide, PRRT has been introduced as a therapeutic option for NETs, especially in patients who were refractory or progressive to conventional therapeutic modalities such as surgery, somatostatin analogues therapy and chemotherapy. From time of introducing, several studies have been performed for evaluation of clinical efficacy and safety of PRRT [2, 3, 7, 8, 10-13]. In a phase 3 trial, efficacy and safety of 177Lu-DOTATATE therapy in advanced and progressive midgut NETs in comparison with somatostatin analogues therapy (control group) had been evaluated which resulted in 18% response rate in PRRT group in comparison with 3% in the control group. In the evaluation of survival, 14 and 26 death occurred in the PRRT and control group, respectively. . In another study, efficacy of PRRT with 90Y- or 177Lu-DOTANOC as another somatostatin analogue had been evaluated in patients with NET which revealed moderate toxicity in 8/20 patients. In addition, of 20 patients underwent PRRT, a partial remission was found in 5 patients, stable disease in 11 patients, and tumor progression in 4 patients .
In our study, according to RECIST, of 20 evaluated patients, PR was found in 11, CR in 2, SD in 1 and PD in 2 patients which demonstrated favorable efficacy of PRRT in treatment of patients with NET. In concordance to our results, E. Abou Jokh Casas et al reported effectiveness of PRRT in 69% of patients with NETs. However, they reported progression in 25% of patients . Dik J. Kwekkeboom et al evaluated effectiveness of PRRT with 177Lu-octreotide as a radiolabeled somatostatin analogue in patients with metastasized or inoperable endocrine gastroenteropancreatic tumors that resulted in among 131 treated patients, CR in 2%, PR in 26%, minor response in 19%, SD in 35% and PD in 18% of patients . Also, in another study, they evaluated efficacy of 177Lu-octreotide in larger group of patients with gastroenteropancreatic neuroendocrine tumors. They reported that of 310 treated patients, CR was observed in 2%, PR in 28%, minor response in 16%, SD in 35% and PD in 20% of patients . It should be mentioned that these results compare favorably to chemotherapy reports in these patients. Previous studies showed PR and CR in less than 20% of patients. In addition, PRRT showed better outcome than chemotherapy in OS, duration of the response and toxicity [14-16].
In this study, we evaluated physical condition and change in QOL of patients with assessment of KPS and ECOG scores. Our results indicated that after treatment, KPS and ECOG were significantly improved compared to before treatment which revealed improvement in QOL of treated patients. In concordance with our results, Saima Khan et al evaluated QOL of patients with NETs underwent PRRT with 177Lu-octreotide in different aspects including KPS. They reported that after PRRT overall QOL significantly improved. In addition, in evaluation of KPS, they indicated that KPS significantly improved in patients responded to PRRT and deteriorated in patients progressed after PRRT . In another study, QOL was assessed with EORTC QLQ-C30 questionary completed after each cycle of PRRT indicated overall QOL was significantly improved after PRRT. In analyzing specific aspects of QOL, they reported significant improvement in emotional functioning, pain and diarrhea .
The median OS in this study was 23 months for all patients and death occurred in 18% (3/16) of patients. There was no significant difference concerning OS compared to several baseline characteristics of patients which may be due to the small sample size and low number of events. Abou Jokh Casas E et al reported that several factors can affect the OS after PRRT with 177Lu-DOTATATE in patients with metastatic NETs including toxicity in previous treatment, tumor grade and presence of bon lesions . In another study, it has been shown that in patients with grade 1 and 2 gastroenteropancreatic NET, PRRT resulted favorable response and long term outcome indicated that tumor grade is the most powerful predictive factor in OS .
According to the CTCAE, in this study, approximately 75% of patients developed PRRT related toxicity. Most common toxicity was anemia which occurred in 10/16 patients including grade 2 in 3 and grade 1 in 7 patients. Leucopenia developed in 6 including grade 2 in 3 and grade 1 in 3 patients, nephrotoxicity of grade 1 in 2 and thrombocytopenia of grade 1 in 2 of patients. In a study, it has been reported that during PRRT, hematological toxicity had been observed in 38.8% of patients . A multicenter study evaluated 450 patients with NETs, it has been revealed that PRRT has rare serious adverse events including leukopenia of grade 3 in 1.1% and thrombocytopenia of grade 3 in 1.3%, and grade 4 thrombocytopenia was observed in only one patient .
This study has some limitations. First, the major limitation is small sample size and relatively short follow-up period time that for confirmation of results, very larger number of patients and longer follow-up time is needed. Second, for more accurate decision, it was better to compare PRRT with other therapeutic methods such as chemotherapy and somatostatin analogues therapy, but it was not possible in this study. Third, beside to evaluation of treatment response with imaging modalities, it was better measure chromogranin A (CgA) as a NETs marker.