Abstract Purpose Pancreatic neuroendocrine tumors are uncommon slow-growing tumors that are often lost to surgery once multiple metastases develop and are poorly treated with chemotherapy and radiotherapy. Peptide receptor radionuclide therapy is a new approach, and in this paper, the efficacy of 90Y-growth inhibitor analog ([90Y C(DOTA)0,Tyr3]octreotate, 90Y-DOTATATE) was observed. Methods Six patients with progressive pancreatic neuroendocrine tumors were diagnosed as growth inhibitor receptor positive tumors by growth inhibitor receptor imaging. 90Y-DOTATATE cumulative dose was calculated at 7.4 MBq/m2 and each completed three to five treatments with an interval of 6 to 9 weeks. 90Y-DOTATATE was administered over 30 minutes by sedation, with lysine infusion before and after dosing. Adverse effects were evaluated after each single course of treatment using National Cancer Institute grading criteria. Efficacy was evaluated by WHO criteria 8 weeks after completion of the last treatment. One patient had renal impairment, one patient had leukocytosis, and three patients had nausea. Conclusion PPRT is effective in metastatic and inoperable pancreatic neuroendocrine tumors. Five growth inhibitory receptor subtypes (SSTR) have been identified, namely SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5, and most pancreatic neuroendocrine tumor cells overexpress growth inhibitory receptors, of which SSTR2 is the most abundant [1]. Natural growth inhibitors have the same affinity for the five SSTRs, but octreotide has the strongest affinity for SSTR2, and the radioisotopes 111In, 99Tcm, 90Y and 177Lu-labeled octreotide also have a strong affinity for SSTR2. 111In or 99Tcm-labeled growth inhibitor analogs can be used to localize and diagnose neuroendocrine tumors, and 90Y or 177Lu-labeled growth inhibitor analogs can treat neuroendocrine tumors [2]. Peptide receptor radionuclide therapy (PPRT) for neuroendocrine tumors is a new therapy, and we used [90Y C(DOTA)0,Tyr3]octreotate for the first time in China to treat six cases of pancreatic neuroendocrine tumors. 1, Methodology 1.1 Clinical data Six patients with pancreatic neuroendocrine tumors, with a mean age of 47.7 years. Three cases had histopathological confirmation after surgery and three cases had clinical confirmation. 6 cases had liver metastases, two of which were accompanied by bone metastases and one by abdominal metastases. Three cases had been treated with chemotherapy by vein embolization, and all of them were treated with 5-fluorouracil, mitomycin and epi-amycin regimen. one case was treated with octreotide microspheres (selenium) injection. 1.2 Inclusion criteria Firstly, the presence of distant metastases was confirmed by ultrasound, CT, or somatostatin receptor scintigraphy (SRS), and was not amenable to surgical treatment. Secondly, positive SRS results before treatment showed that the tumor overexpressed SSTR2. 1.3 Treatment The patient signed a written informed consent before treatment. 90Y-DOTATATE cumulative dose was calculated at 7.4 MBq/m2 and divided into 3 to 5 treatments at an average interval of 6 to 9 weeks. The method was as follows: 9 g of lysine was added to 500 ml of saline intravenously and dosed in approximately 1.5 hours. After that, 90Y-DOTATATE was dissolved in 100 ml of saline and finished in 30 minutes by intravenous drip. Finally, 15 g of lysine was added to 750 ml of saline and the drip was finished in about 2 hours. Observe in isolation ward for 2 days and watch for changes in condition. 1.4 Follow-up Routine blood and urine, liver and kidney function and corresponding serum tumor markers were measured before treatment. After treatment, blood and urine routine was checked weekly, liver and kidney function was checked every 2 weeks, and serum tumor markers were measured. The efficacy of the treatment was determined according to WHO standards, and the adverse effects were evaluated according to the National Cancer Institute Grading Criteria (NCIGC). 2. Results Six cases of pancreatic neuroendocrine tumors were examined by CT or ultrasound after the last treatment, and two cases of MR, both of which were glucagonomas; two cases of SD, both of which were gastrinomas; and two cases of PD, one of which was a glucagonoma and one of which was a gastrinoma, were judged according to WHO criteria. The changes of serum tumor markers are shown in Table 2. Case 1 Female, 38 years old, was admitted to the hospital with persistent diarrhea. After clinical diagnosis, she underwent “pancreatic tail and splenectomy”, and the histopathological diagnosis was highly differentiated endocrine carcinoma of the tail of the pancreas with peri-pancreatic lymph node metastasis; CT showed multiple metastatic lesions in the liver, which was inoperable, and was treated with proton pump inhibitor; SRS showed multiple growth inhibitor receptor-expressing lesions in the liver. DOTATATE treatment resulted in a weight loss of 2 kg and a rise in serum gastrin from 180 ng/L to 389 ng/L, but CT showed no change in intrahepatic lesions. Case 2 Female, 38 years old, with recurrent vomiting as the first symptom. Fiberoptic gastroscopy revealed an ulcer in the duodenal bulb, and magnetic resonance imaging (MRI) showed a 5.3-cm diameter mass shadow in the medial segment of the left lobe of the liver. The serum gastrin level was 1000 ng/L, and the clinical diagnosis of gastrinoma with intrahepatic metastasis was made. SRS showed multiple growth inhibitor receptor expressing lesions in the head of pancreas, liver, left rib cage and right femur. 5 courses of 90Y-DOTATATE treatment resulted in a weight loss of 4 kg and MRI showed an enlarged intrahepatic metastasis with a diameter of 11.5 cm, and serum gastrin level remained flat at 1000 ng/L. The disease progressed. Case 3 Female, 48 years old, admitted with diarrhea. CT showed multiple metastases in the liver and tumor emboli in the portal vein, therefore inoperable. The clinical diagnosis: gastrinoma with hepatic metastases, SRS showed high expression of growth inhibitor in the liver. He received 4 courses of 90Y-DOTATATE with proton pump inhibitor acid suppression and gained 4 kg of weight. Gastrin level was 155ng/L and CT showed no change in the size of the intrahepatic metastatic lesion. Case 4 Female, 46 years old, with rash on both lower extremities as the first symptom. Abdominal CT showed multiple intrahepatic metastatic lesions. The histopathological diagnosis was: highly differentiated neuroendocrine carcinoma of the pancreatic body and tail and peripancreatic lymph node metastasis. 4 times of “perfusion chemotherapy of the celiac artery, hepatic artery and superior mesenteric artery” with the regimen of 5-Fu, mitomycin, epi The regimen was 5-Fu, mitomycin, epi-amycin and IL-2, but was not effective. After the injection of octreotide microspheres (Sunlong) 20mg, the wandering necrotizing erythema of the lower limbs, nausea, and unbearable were seen again. after 4 courses of 90Y-DOTATATE treatment, the weight gain was 2kg, the necrotizing wandering erythema disappeared, the pruritus was significantly reduced, the insulin was stopped, and the blood glucose reached a satisfactory level under simple diet control. the CT showed that the diameter of the largest intrahepatic metastasis was reduced from 3.0cm to 1.8cm, glucagon decreased from 580ng/L to 402ng/L, and the disease was in slight remission. Case 5 Female, 51 years old, with rash of both lower extremities, tongue inflammation and stomatitis as the first symptoms. The tumor was located in the tail of the pancreatic body, adhered to the surrounding tissues, and grew exophytically with rich blood supply. Postoperative pathology: pancreatic glucagonoma (pancreatic body). Postoperative abdominal ultrasound: 3 hyperechoic occupancies in the liver, liver metastasis was considered. Two hepatic artery embolization chemotherapy was performed with the following regimen: 5-Fu, mitomycin, and epi-amycin. Upper abdominal CT: multiple intrahepatic metastases disappeared. 1 year later reappeared with linguitis, stomatitis and weight loss. After 4 courses of 90Y-DOTATATE treatment, weight gain of 6 kg, complete disappearance of keratitis and linguitis, and discontinuation of insulin. /L decreased to 816 ng/L, and the disease was in slight remission. Because of the disappearance of the 2 small abdominal lesions, the opportunity was gained for surgery and the 2.7 cm lesion was removed laparoscopically. Case 6 Male, 64 years old, presented with diabetes mellitus. He was clinically diagnosed with glucagonoma, and abdominal CT showed multiple metastases in the liver and bone metastases on bone scan. Without surgical treatment, he had 2 courses of arterial embolization chemotherapy with regimen of 5-Fu, mitomycin, and epi-amycin. sRS showed multiple growth inhibitor receptor high expression lesions in the liver. Because of the poor results of the above therapies, 4 courses of 90Y-DOTATATE were chosen, but weight loss and CT showed an increased number of intrahepatic metastatic lesions after treatment. Case 2 was treated with 5 courses of 90Y-DOTATATE at a cumulative dose of 18.7 GBq. Three months after the last treatment, BUN and Cr began to rise, with BUN of 255 mg/L and Cr of 17 mg/L, consistent with grade 2 nephrotoxicity according to NCIGC criteria. Leukocytes were 3.5×109/L after the 4th treatment , and returned to normal at 9 weeks. In addition, nausea was observed in 3 patients within 24 hours of drug administration, and none of the patients had abnormal liver function. 3, Discussion Pancreatic neuroendocrine tumor cells tend to overexpress growth inhibitor receptors, and growth inhibitor receptor-mediated targeted diagnosis and treatment has become a new technique for the diagnosis and treatment of pancreatic neuroendocrine tumors, and foreign scholars actively advocate PPRT for metastases and inoperable neuroendocrine tumors as the preferred method. Neuroendocrine tumors are a large group of rare tumors, although most of them develop slowly, there is no effective treatment method once they metastasize. In the past 6 years, we treated 25 cases of neuroendocrine tumors, with 1 case in partial remission, 3 cases in mild remission and 16 cases in stable condition. In this paper, among 6 cases of pancreatic neuroendocrine tumors, 2 cases were in mild remission, 2 cases were in stable condition, but 2 cases continued to progress. Although the sample size was small, PPRT treatment achieved some efficacy. Foreign PPRT has experienced a 30-year history. Initially, high doses of [111InCDTPA0]octreotide were used to treat metastatic neuroendocrine tumors with cumulative doses as high as 20-100 GBq. Although some efficacy was achieved, some complications such as leukemia and myelodysplastic syndrome emerged, and the 111In physical properties were not suitable for treatment [7]. The most used 90Y-labeled growth inhibitor analog, 90YCDOTA0-Tyr3-octreotide (90Y-DOTATOC) [2], is attributed to the physical properties of 90Y. 90Y emits pure β-rays with a physical half-life of 2.7 days and an intra-tissue range of 1.2 cm and a maximum energy of 2284 KeV. 90Y-DOTATOC has a superior efficacy. DOTATOC is superior to [111InCDTPA0]octreotide in terms of efficacy, with the number of CR and PR cases reaching 10-30%. However, nephrotoxicity and hematologic toxicity are still possible complications. Compared to 90Y, 177Lu is more suitable for smaller lesions. 177Lu radiates both β- and γ-rays with a physical half-life of 6.7 days. Its maximum beta-radiation energy is 497 keV, with an intra-tissue range of 2 mm. 504 patients with neuroendocrine tumors were treated with [177Lu-DOTA0,Tyr3]Octreotate (177Lu-DOTATATE) at the Erasmus Medical Center in the Netherlands. The efficacy was evaluated in 131 of these patients, with CR in 3 cases (2%), PR in 32 cases (26%), MR in 24 cases (19%), SD in 44 cases (35%), and PD in 22 cases (18%). The side effects of 504 patients were analyzed, and the common side effect remained hematotoxicity, reversible hepatotoxicity occurred in 2 patients, and myelodysplastic syndrome was later diagnosed in 3 patients. Radionuclide labeled growth inhibitor analogs provide an effective treatment for progressive neuroendocrine tumors and, if this approach becomes widely available, will become the treatment of choice for metastatic and inoperable neuroendocrine tumors. However, bone marrow and kidney become important organs for limiting the radiation dose, and controlled clinical studies for different treatment regimens as well as different radionuclides should be conducted to take further measures to reduce side effects and improve the efficacy.