The incidence of pancreatic neuroendocrine tumors is increasing year by year, and the clinical presentation and prognosis vary widely. There is no standard treatment for progressive pancreatic neuroendocrine tumors, and the 5-year survival rate is less than 30%. The 12th World Congress of Gastrointestinal Oncology focused on the latest findings of targeted drugs such as everolimus and sunitinib for the treatment of pancreatic neuroendocrine tumors. The incidence, classification and prognosis of pancreatic neuroendocrine tumors have been considered to be low, only 1.4% of tumors of exocrine glandular origin of the pancreas, and the prognosis is better than that of pancreatic cancer, but recent autopsy results have confirmed that the incidence of pancreatic neuroendocrine tumors is 10% of that of pancreatic cancer. The pancreatic neuroendocrine tumors are divided into two categories according to the presence or absence of function: 1) functional neuroendocrine tumors; 2) non-functional neuroendocrine tumors. Functional neuroendocrine tumors are easily detected early because they secrete some hormones such as insulin, gastrin, vasoactive intestinal peptide, glucagon, serotonin and growth inhibitory hormone, while for those non-functional neuroendocrine tumors, they will be detected only when the tumor grows and produces pressure symptoms. WHO classifies pancreatic neuroendocrine tumors into 3 categories: well-differentiated neuroendocrine tumors; well-differentiated neuroendocrine carcinomas and poorly differentiated neuroendocrine carcinomas. Most pancreatic neuroendocrine tumors are scattered, and there are some tumors associated with familial diseases, such as multiple neuroendocrine tumor I, cerebral retinal angiomatosis, neurofibromatosis I and tuberous sclerosis. Pancreatic neuroendocrine tumors are usually considered to be slow growing and inert proliferating, but they are prone to distant metastasis except for insulinoma (85% benign). Localized pancreatic neuroendocrine tumors account for only 14%, regional metastases for 22%, and distant metastases for 64%. The 5-year survival rate for confined pancreatic neuroendocrine tumors is 60%-100%, for regional lesions 40%, for distant metastases 25%, and for poorly differentiated neuroendocrine tumors the median survival time is only 10 months. Treatment principles Surgical resection is the only radical means for limited pancreatic neuroendocrine tumors. The 5-year survival rate for patients who can be surgically resected can reach 80-100%. However, most tumors develop distant metastases, and achieving R0 resection is clinically beneficial for patients with metastases. For neuroendocrine tumors with liver metastases, surgery can reduce the tumor load and prolong survival, in addition to radiofrequency ablation, hepatic artery chemoembolization (TACE), and liver transplantation for those patients who cannot have liver tumor resection. The standard medical treatment for pancreatic neuroendocrine tumors is growth inhibitor analogs and a-interferon. Growth inhibitor analogs not only reduce symptoms, but also have anti-tumor activity and also improve quality of life. The PROMID study showed that growth inhibitor analogs versus placebo prolonged progression-free survival (PFS) by 14.3 months and 6 months for both functional and nonfunctional neuroendocrine tumors, respectively; disease stabilization (SD) could reach 66.7% and 37.2%. In addition, the study also pointed out that patients with resection of the primary tumor and liver metastases undergoing tumor reduction could gain more benefit. Therefore, growth inhibitor analogs remain important therapeutic agents for neuroendocrine tumors. Chemotherapy Pancreatic neuroendocrine tumors have a high malignant aggressive behavior once the disease progresses. The low efficiency of chemotherapy for well-differentiated neuroendocrine tumors, only about 10%, is due to the low mitotic index (KI-67 less than 2% in most patients) and high expression of Bcl-2 and mdr in well-differentiated neuroendocrine tumors; while the efficiency is higher in poorly differentiated neuroendocrine tumors. Chemotherapeutic agents such as streptomycin, fluorouracil, and adriamycin can be used alone or in combination to treat pancreatic neuroendocrine tumors. Cisplatin in combination with etoposide can be effective up to 67% for poorly differentiated neuroendocrine tumors. The efficacy of temozolomide is dependent on the level of O6methylguanine DNA transferase, with low levels responding well to treatment. No significant efficacy has been seen with temozolomide alone, but the prospect of combining it with capecitabine and bevacizumab is promising. Targeted agents There is no standard treatment for pancreatic neuroendocrine tumors that progress with chemotherapy. Neuroendocrine tumors are vascular rich tumors and there are multiple targets for targeted drug action, such as high level expression of EGF, PDGF, IGF-1, VEGF and sVEGFR. In recent years the targeted drugs everolimus (EverolimusRAD001) and sunitinib have shown good efficacy in clinical studies of pancreatic neuroendocrine tumors. RAD001 RAD001 is a derivative of the signal transduction inhibitor rapamycin, which targets mTOR, a multifunctional signal transduction protein that receives signals from multiple upstream pathways and transmits information through multiple downstream pathways, acting as a trophic sensor and monitor of cellular metabolic status. It regulates protein synthesis and ultimately cell growth and cell proliferation (including angiogenesis) as well as survival. An important aspect of the antitumor effect of RAD001 is its ability to act on tumor cells directly by inhibiting tumor cell growth and indirectly by inhibiting angiogenesis and displaying anti-angiogenic properties. In recent clinical studies, it has been developed as a single agent or in combination with other anticancer drugs for cancer treatment, showing excellent efficacy. A phase II study of RAD001 evaluated the efficacy and survival of 5 mg or 10 mg once daily in combination with 30 mg of long-acting octreotide every 4 weeks for the treatment of hypo-mediated pancreatic neuroendocrine tumors. The results showed 22% efficacy, 42% stable (SD) patients, and mPFS of 60 weeks, and prior octreotide treatment did not affect patients’ PFS. Yao et al. reported a phase II clinical study of daily oral RAD001 in chemotherapy-naïve progressive pancreatic neuroendocrine tumors (RADIANT-1), which focused on evaluating the efficacy of RAD001. Patients were divided into 2 groups according to whether they received octreotide previously or not. 115 patients in group A: RAD001 10 mg/d continuous oral: 45 patients in group B: RAD001 10 mg/d continuous oral combined with long-acting octreotide 30 mg/4 weeks intramuscular. Efficacy evaluation was performed every 3 months according to the evaluation criteria for solid tumors, and patients with high baseline chromogranin A (CgA) and neuron-specific enolase (NSE) expression were tested once a month. Results: 11 patients (9.6%) in group A achieved partial remission (PR), 78 (67.8%) were stable (SD), 16 (13.9%) progressed (PD), and mPFS was 9.7 months; 2 patients (4.4%) in group B had PR, 36 (80%) had SD, and no PD, and mPFS was 16.7 months. patients with early response to CgA or NSE The combination of octreotide and RAD001 had no effect on each other’s drug exposure, and most of the drug side effects were the mild to moderate adverse effects previously reported as common with RAD001. This study concluded that daily oral administration of RAD001 with or without octreotide not only improved objective efficiency but also prolonged PFS in progressive pancreatic neuroendocrine tumors that had failed prior systemic chemotherapy and were well tolerated by patients. In this conference, Yao et al. reported (O-0028) the phase III randomized, placebo-controlled study of RAD001 versus placebo for the treatment of progressive pancreatic neuroendocrine tumors (RADIANT-3). This study compared the efficacy of RAD001 10 mg1/day in combination with best supportive care versus placebo in combination with best supportive care for pancreatic neuroendocrine tumors that progressed within 12 months with the primary study endpoint of PFS. 410 patients were enrolled in this trial, 207 in the RAD001 group and 203 in the placebo group. RESULTS: The RAD001 group reduced the risk of disease progression by 65%, the median PFS was 2.4 times higher in the RAD001 group than in the placebo group (11.04 months versus 4.6 months), and an estimated 34.2% of patients in the RAD001 group were able to achieve a PFS of 18 months compared to 8.9% of patients in the placebo group. The most common adverse events in both the RAD001 and placebo groups were stomatitis, 53.9% and 12.3%, respectively, and the incidence of grade 3/4 adverse events was 53.9% in the RAD001 group compared to 38.9% in the placebo group, with the most common being anemia, hyperglycemia, diarrhea, abdominal pain, stomatitis, platelet The duration of dosing was 38 and 16 weeks in the RAD001 and placebo groups, respectively, and the rate of discontinuation due to adverse events was 17.4% and 3.4%, respectively. Thus, this large phase III clinical study demonstrated a statistically clinically significant improvement in the treatment of progressive pancreatic neuroendocrine tumors with RAD001 compared to placebo, which was well tolerated by patients. Sunitinib sunitinib is an oral, small molecule, multi-kinase inhibitor that has been shown to have direct antitumor activity and inhibit angiogenesis. It produces this integrative effect by interacting with targeted receptors of multiple signaling pathways that underlie tumor growth and survival. The phase III clinical study of sunitinib versus placebo for pancreatic neuroendocrine tumors reported by Niccoli et al. was terminated early due to highly significant efficacy in efficiency, mPFS and overall survival. This study enrolled 171 pancreatic neuroendocrine tumors that progressed within 12 months and randomized 86 patients in the sunitinib group (37.5 mg/d) and 85 patients in the placebo group, both of whom were given concomitant best supportive care. These patients had distant metastases in 95%, 89% were previously treated with surgery, 50% with chemotherapy, and 25% with long-acting octreotide, 49% of which were functional tumors, and the median overall survival time has not yet been reached, however the mPFS was very significantly different, 11.4 months (sunitinib group) and 5.5 months (placebo group), respectively. Adverse effects were tolerated by patients. This conference continues to report the clinical benefit of this study and an exploratory analysis regarding the prognosis of PFS (O-0009). Patients completed the QLQ-C30 questionnaire for safety and quality of life on day 1 and every 4 weeks and at the end of treatment, with significantly more diarrhea (P<0.001) and insomnia (P=0.0372) in the sunitinib-treated group than in the placebo group. For the effect of baseline characteristics analyzed by Cox hazard ratio model, the results showed that regardless of age (<65 versus ≥65 years), sex, race (Caucasian versus non-Caucasian), ECOG score (0 versus 1/2), number of metastases (≤2 versus ≥3) or time from diagnosis to enrollment (<3 years versus ≥3 years), regardless of treatment with growth inhibitor analogs during treatment, regardless of prior The sunitinib treatment group was able to reduce the risk ratio, and the sunitinib group improved PFS compared with the placebo group. Multifactorial analysis showed that only time from diagnosis to enrollment (≥3 versus <3 years) was an independent predictor of PFS (HR 0.603; 95% CI 0.382,0.952; P=0.0299) when this time was adjusted the sunitinib group had significantly better PFS than the placebo group (HR0.374; 95% CI0.234,0.599; P<0.0001). This study concluded that sunitinib not only improved PFS in pancreatic neuroendocrine cancer, but also improved patient quality of life across the board in a subgroup analysis. RAD001 in combination with bevacizumab Yao et al. reported a study of RAD001 in combination with bevacizumab for pancreatic neuroendocrine tumors. 39 patients were randomly assigned to the 21-day cycle 1 RAD001 and bevacizumab groups, and the two drugs were combined in cycle 2. The efficacy rate reached 26%, stability 69%, 3% disease progression, and mPFS of 14.4 months. Functional CT showed that the addition of RAD001 reduced the blood supply to the tumor in patients in the bevacizumab alone group, and the combination resulted in lesion reduction. Chemotherapy in combination with bevacizumab Kunz et al. reported a phase II study of capecitabine and oxaliplatin in combination with bevacizumab for the treatment of progressive neuroendocrine tumors. RESULTS: Of 31 patients with evaluable outcomes, 7 achieved (23%) PR (6 of which were pancreatic neuroendocrine tumors), 22 achieved (71%) SD, and only 2 (6%) PD. median PFS was 13.7 months. In conclusion, the clinical presentation and prognosis of pancreatic neuroendocrine tumors vary widely. surgery is the only curative tool for primary tumors, and survival benefit can be obtained for pancreatic neuroendocrine tumors with liver metastases. Targeted agents such as everolimus and sunitinib alone or in combination with growth inhibitor analogs and cytotoxic agents are a new option for pancreatic neuroendocrine tumors.