CHEN Luo-hai1, LIANG Yun2, CHEN Jie2(1.Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 2.Neuroendocrine Tumor Center, Fudan University Cancer Hospital, Shanghai 200032, China
Funds: National Natural Science Foundation of China (82141104)
Corresponding author: Chen Jie
E-mail:[email protected]
Chen Jie
He is the chief expert of neuroendocrine tumors in the Affiliated Cancer Hospital of Fudan University
Director of the Neuroendocrine Tumor Center of Fudan University Cancer Hospital
Director of the Department of Neuroendocrine Oncology, Fudan University Cancer Hospital
Member of the Advisory Board of the European Society of Neuroendocrine Oncology (ENETS).
Member of the Neuroendocrine and Endocrine Oncology Group of the European Society for Medical Oncology (ESMO).
Member of the Medical Advisory Board of the International Union of Neuroendocrine Oncology (INCA).
Chairman of the Neuroendocrine Tumor Committee of the Chinese Anti-Cancer Association
He is the leader of the Neuroendocrine Oncology Group (CSNET) of the Pancreatic Cancer Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Tumor Endocrinology Committee of the Chinese Anti-Cancer Association
Deputy head of the Gastrointestinal Hormone and Neuroendocrine Oncology Group of the Chinese Society of Gastroenterology
Vice Chairman of the Pancreatic Neuroendocrine Tumor Committee of the Pancreatic Disease Branch of the Chinese Medical Doctor Association
Member of the Rare Oncology Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Director of the Chinese Anti-Cancer Association
Director of the Chinese Society of Pancreatic Diseases
Executive Director of Shanghai Anti-Cancer Association
ENETS 官刊Journal of Neuroendocrinology 高级编委
Journal of Pancreatology 编委
Member of the editorial board of China Oncology
Editorial Board Member of Chinese Journal of Digestion
Neuroendocrine neoplasms (NENs) are a rare type of tumor originating from peptidergic neurons and neuroendocrine cells. It can occur all over the body, and its biological behavior is highly heterogeneous, ranging from inert growth, invasive growth, and even early metastasis, and the biological characteristics and prognosis of NENs at different stages are quite different. In terms of local treatment, two large retrospective studies have established the role of endoscopic ultrasound-guided ablation in insulinoma or neuroendocrine tumor, and the necessity of right hemicolectomy of the appendix with a diameter of 1~2 cm has been denied. In terms of drug therapy, biological therapy, targeted therapy, radionuclide therapy, chemotherapy and immunotherapy have all made progress, and the combination of different drugs has achieved certain efficacy, but most clinical trials are still limited to phase I and II, and phase III studies are relatively lacking. This article will review and summarize the progress of NENs therapy in 2023.
【Keywords】neuroendocrine tumors, endoscopic therapy, drug therapy, immunotherapy
Neuroendocrine neoplasms (NENs) are widely distributed in the human body, and can occur in endocrine organs (anterior pituitary, parathyroid glands, etc.), neural structures (paraspinal sympathetic chain, parasympathetic ganglia, etc.) and multiple organs of the whole body (skin, respiratory tract, digestive tract, etc.) with diffuse neuroendocrine cell system. With the deepening of clinical understanding of NENs, the detection rate of NENs is increasing year by year. In recent years, the pathological classification and grading diagnostic criteria for NENs in various parts have also tended to be improved and unified [1]. According to the degree of pathological differentiation, NENs can be divided into two types: well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC), which are quite different in biological behavior and response to drug treatment. At present, there are few phase III clinical trials for patients with NENs, and they are still mainly large-sample retrospective studies or phase I and II clinical trials. This article intends to summarize the important research results in the field of NENs in 2023, aiming to provide new ideas for the clinical diagnosis and treatment of NENs.
1. Surgical and endoscopic treatment
Radical resection of the tumor is one of the most important aspects of NENs treatment, but it is necessary to select the appropriate resection method and resection scope based on the general condition of the patient, the primary site of the tumor, the functional status, the size of the tumor, the depth of invasion, the grade, the stage and other factors. Endoscopic therapy is mainly used for the treatment of low-grade (G1 and G2) NETs of the stomach, duodenum, and colorectum with a maximum diameter of ≤1 cm in mucosa and submucosa, without lymph node metastases, and lesions [2]. Surgery can compensate for the limitations of endoscopic therapy, and palliative surgery is also an important local treatment for patients with functional NENs with distant metastases.
Insulinoma is a type of tumor in pancreatic NENs. Due to the early onset of insulinoma and the obvious symptoms related to hypoglycemia, 82% of patients with insulinoma are often diagnosed with tumors < 2 cm in diameter. A large, multicenter, retrospective study from Italy explored the efficacy and safety of endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) versus surgical resection for insulinoma [3]. The results showed that the incidence of adverse reactions (18.0%vs. 61.8%), the incidence of serious adverse reactions (0%vs. 15.7%), and the length of hospital stay (3.0 dvs. 11.1 days) in the EUS-FRA group were better than those in the surgical resection group, and there was no recurrence in the patients in the surgical resection group, and 15 patients in the EUS-FRA group (16.9%) ), 11 of whom underwent EUS-FRA again and 4 patients underwent surgical resection. This suggests that EUS-FRA is safer than surgery in patients with insulinoma, and the overall outcome is satisfactory.
Compared with insulinoma, there has been a great controversy about whether non-functional small pancreatic NETs (<2 cm in diameter) require early intervention and treatment options. A single-center retrospective study from South Korea compared endoscopic ultrasound-guided ethanol ablation (EUS-EA) and surgery for non-functional micropancreatic NETs [4]. The results showed that the EUS-EA group was superior to surgery in terms of the incidence of early adverse reactions (0%vs. 1.2%), late adverse reactions (3.4%vs. 10.1%), and length of hospital stay (4.0 days: 14.1 days), while there was no significant difference in disease recurrence rate and overall survival (OS) between the two groups. Combining the above two large retrospective studies, endoscopic ultrasound-guided ablation is also a safe and effective treatment for insulinoma and small pancreatic NETs.
Clinically, appendiceal NET is rare, and it is generally found incidentally after appendicitis. It is still inconclusive whether the right colon needs to be further enlarged and resected in patients with appendix NET, especially for appendix NETs with a diameter of 1~2 cm, which is currently controversial. A multicenter retrospective study from Europe included a total of 278 patients with NET appendiceal NET with a diameter of 1~2 cm, including 163 patients who underwent appendectomy alone (appendectomy group) and 115 patients who underwent right hemicolectomy (right hemicolectomy group) [5]. Based on histopathological risk factors, it was estimated that 12.8% of patients in the appendectomy group had lymph node metastasis, but the potential metastasis was missed due to the absence of lymph node dissection, and there was no significant difference in OS between the appendectomy group and the right hemicolectomy group, with a 10-year OS rate of 92% and 91%, respectively. Pathological grade G2, lymphovascular invasion, and depth of mesoappendal invasion were not related to the patient's OS. The results of this study confirmed that right hemicolectomy was not necessary for 1~2 cm appendiceal NET. In view of the rarity of appendix NET, prospective clinical trials are difficult to carry out, and this study provides good evidence support for the surgical treatment range of 1~2 cm appendix NET.
2. Medication
Drug therapy for NENs includes drugs that resist tumor proliferation and alleviate hormone-related symptoms or syndromes, and it is necessary to conduct a comprehensive analysis of the patient's tumor location, functional status, pathological classification and grade, somatostatin receptor expression level, tumor burden, and disease progression status before treatment, so as to formulate an appropriate drug treatment plan [2]. Drugs to alleviate hormone-related symptoms or syndromes are currently relatively well-established and the overall effect is acceptable, and there are no breakthroughs in 2023. Anti-tumor proliferative drugs for the treatment of NENs are currently the focus of research, mainly including biological therapy, molecular targeted therapy, chemotherapy, radionuclide therapy and immunotherapy.
2.1 Biological Therapy
Biological therapy mainly includes interferon-α and long-acting somatostatin analogues (SSAs), among which the application of interferon-α has gradually decreased in recent years, and it is mainly used for combination drug therapy of refractory functional NENs. At present, the most commonly used long-acting SSAs are octreotide and lanreotide hydrogels, which have been confirmed in the application of gastroenteropancreatic NETs as early as the PROMID [6] and CLARINET [7] studies, and are also the preferred anti-tumor proliferative drugs for gastroenteropancreatic NETs with a Ki67 index (a marker of cell proliferation) < 10%. However, the use of long-acting SSAs in thoracic NETs lacks prospective study data. A phase II prospective, single-arm trial (ATLANT study) from a multicenter in Italy explored the efficacy and safety of Lanreotide hydrogel in combination with temozolomide in lung and thymus NET [8]. The study required patients to undergo somatostatin receptors (SSTRs) scintigraphy, including octreotide scan or 68Ga-labeled somatostatin analogue positron emission tomography/computed tomography (PET/CT), within 1 year prior to enrollment screening. A total of 40 patients (including 36 lung NET and 4 thymic NETs) were included in the study, of which 35 patients had positive SSTRs scintigraphy, 4 patients had negative SSTRs scintigraphy, and 1 patient had unknown SSTRs scintigraphy, and the results showed that the 9-month disease control rate (DCR) was 35%, and the median progression-free survival (progression-free) was achieved survival, PFS) was 37.1 weeks, and treatment-related adverse reactions occurred in 72.5% of patients, but only about 10% of patients experienced adverse reactions above grade 3. In this study, patients were given a relatively long duration of PFS and were well tolerated, but larger controlled trials are needed to confirm the efficacy of this regimen.
2.2 Molecularly targeted therapy
At present, the molecularly targeted drugs used for NENs are mainly divided into two categories, one is a mammalian target of rapamycin (mTOR) inhibitor, which is represented by everolimus, and the other is a tyrosine kinase inhibitor (TKI), which is represented by sunitinib and surufatinib. New research results will be announced in 2023 for both types of drugs. A Nordic multicenter phase II, single-arm clinical trial investigated the efficacy and safety of everolimus in combination with temozolomide as a first-line treatment for advanced high-grade gastroenteropancreatic NENs [9]. The study included 37 patients with a Ki67 index of <55%, including 26 NET and 9 NEC patients, and the results showed that the objective response rate (ORR) of NENs patients was 30%, and the median PFS time was 10.2 months, of which the 6-month DCR of NET patients was 77%, the median PFS time was 12.6 months, and the incidence of grade 3~4 adverse reactions was 43%; The 6-month DCR of NEC patients was 22%, the median PFS time was 3.4 months, and the incidence of grade 3~4 adverse reactions was 38%, and the quality of life score of patients did not decrease significantly during the treatment period. Given the limited number of options currently available for high-grade NENs, a phase III controlled trial will be conducted in the future, which will promote the clinical application of this regimen. For TKI drugs, the 2023 annual update of the study results is cabozantinib. Preliminary results from a multicenter phase III, placebo-controlled clinical trial of cabozantinib in the treatment of advanced NET were presented at the 2023 annual meeting of the European Society for Medical Oncology (ESMO) [10]. A total of 193 patients with non-pancreatic NETs and 93 patients with pancreatic NETs were included in the study, and cabozantinib significantly extended the median PFS time to non-pancreatic NETs (8.2 months versus 3.2 months) and pancreatic NETs (13.7 months versus 3.0 months) compared with placebo. These results suggest that cabozantinib has a good prospect in patients with advanced NET.
In addition to the above two types of molecularly targeted drugs, there are also some new drug studies in pan-solid tumors that include patients with NET. A newly published phase I study explored the safety and potential role of a new targeted drug that promotes apoptosis, cysteine protease precursor activation complex 1 (PAC-1), in pan-solid tumors [11]. The study included 48 patients, including 5 patients who failed NET after multiple lines of therapy, and found that 2 patients achieved partial response (PR) and 3 patients achieved stable disease (SD). This suggests that PAC-1, a new target drug, may have potential efficacy in NET patients who have failed multiple lines of therapy, and warrants further clinical trials.
2.3 Chemotherapy
Chemotherapy is mainly indicated for patients with NET and NEC with high proliferative index. Although temozolomide-based chemotherapy regimens have been recommended by several guidelines for patients with thoracic and pancreatic NET with high proliferative index, there is a lack of prospective studies and there is controversy about the predictive value of methylguanine methyltransferase (MGMT) deficiency in temozolomide. A multicenter prospective randomized controlled phase III clinical trial from the United States compared the efficacy and safety of temozolomide monotherapy (monotherapy) with temozolomide plus capecitabine (combination therapy) in patients with G1 and G2 advanced pancreatic NET [12]. The results showed that the median PFS time in the combination group was significantly better than that in the monotherapy group (23.2 months versus 15.1 months), but there was no significant difference in OS, and the response rate (RR) (39.7%vs. 33.8%) and DCR in the combination group were slightly higher than those in the monotherapy group (83.8%vs. 73.8%) However, there was no significant difference (all P>0.05), and the grade 3 and 4 adverse reaction rates in the combination group were 45%, which was significantly higher than that in the single drug group (22%). As for the correlation between MGMT deletion and efficacy, the study suggests that both low expression of MGMT immunohistochemistry and positive methylation of MGMT promoter are associated with higher RR. At the same time, the results of this study are helpful for clinical screening of patients in urgent need of drug reduction, such as patients with critically resectable pancreatic NET, and can predict whether temozolomide-based chemotherapy regimen can achieve better tumor shrinkage effect by detecting the MGMT deletion status of tumor cells.
Another multicenter phase II clinical trial from France presented the results at the 2023 ESMO Annual Meeting. This study compared alkylating agents (including temozolomide, dacarbazine, and streptozonamycin) with oxaliplatin in 105 NETs and compared the effect of MGMT deficiency on efficacy [13]. The results of the study showed that the ORRs of alkylating agents and oxaliplatin were 18% and 39%, respectively, in patients with MGMT deletion, compared with 56% and 21% in patients with MGMT deletion. This study also suggests that different chemotherapy agents can be selected by MGMT status to improve efficacy.
Etoposide plus cisplatin (EP) or etoposide-carboplatin (EC) is the first-line chemotherapy regimen for advanced or unresectable NEC, but there is no standard second-line treatment option when EP and EC regimens fail. A randomized, uncontrolled, multicenter study from France investigated the FOLFIRI (irinotecan + calcium levonofolinate/leucovorin + fluorouracil) regimen in combination with bevacizumab in patients with advanced gastroenteropancreatic or NEC of unknown primary after failure of EP [14]. The study included a total of 65 patients treated with FOLFIRI plus bevacizumab (combination group) and 68 patients treated with FOLFIRI chemotherapy (chemotherapy group), and the results showed that the ORR of the combination and chemotherapy arms was 25% and 18%, respectively, and the 6-month OS rate was 53% and 60%, respectively, that is, the combination of bevacizumab on the FOLFIRI regimen did not provide OS benefit. However, the study also suggests that FOLFIRI may be used as a second-line option for advanced gastroenteropancreatic NEC or NEC of unknown primary.
The results of the interim study of nab-paclitaxel in combination with bevacizumab were presented at the 2023 annual meeting of the European Neuroendocrine Tumor Society (ENETS) in a multicenter, single-arm, phase II clinical study led by Peking University Cancer Hospital [15]. A total of 47 patients with advanced NEC who failed standard regimen therapy were included in the study, and the results showed that the ORR and DCR were 57.4% and 83%, respectively, and the median PFS and OS time were 7.1 and 14.1 months, respectively, and the RR of NEC was 75% and 64% for gallbladder and gastric NEC, respectively, while the ORR of pancreatic NEC was only 20%, but the number of patients was only 5. From the preliminary results of this study, it can be found that the regimen of nab-paclitaxel combined with bevacizumab has a higher ORR and DCR, and may provide a second-line treatment option for NEC patients who have failed standard therapy.
Final results of NET-O2 were presented at the 2023 American Society of Clinical Oncology Annual Meeting in a multicenter phase II clinical trial from the United Kingdom [16]. The study compared the liposomal irinotecan group (liposomal irinotecan, fluorouracil (5-fluorouracil, 5-FU), leucovorin) and docetaxel group as second-line treatment regimens for advanced extrapulmonary NEC, a total of 58 patients were included and randomly assigned to liposomal irinotecan and docetaxel, with 29 patients in each group, and the results showed that the 6-month PFS rate (29.6%vs. 13.8%) and ORR (11.1%vs. 10.3%) in the liposomal irinotecan group (11.1%vs. 10.3%) ) and median PFS (3 months to 2 months) were better than those in the docetaxel group, and the incidence of grade 3 or higher adverse reactions in both groups reached more than 50%, but the quality of life scores of patients in the docetaxel group were lower than those in the irinotecan group. The results of this study suggest that the liposomal irinotecan combination regimen has potential value in advanced extrapulmonary NEC, and further phase III clinical trials are needed to confirm the value of this regimen.
2.4 Radionuclide therapy
Peptide receptor radionuclide therapy (PRRT) is currently recommended for SSTRs-expressing NET patients, and research in recent years has focused on placing PRRT at the forefront of treatment options or expanding the scope of adaptation. Results of a multicenter, single-arm prospective study from Italy presented PRRT as a neoadjuvant therapy at the annual ESMO meeting [17]. A total of 31 patients with resectable pancreatic NET with high-risk recurrence factors were included in the study, of which 26 patients completed 4 courses of 177Lu-DOTATATE, and the results showed that 17 patients had the best tumor efficacy to PR, and finally 29 patients successfully completed pancreatic NET resection. This study provides some basis for neoadjuvant therapy for pNET, but there are no data on postoperative recurrence, and it is inconclusive whether neoadjuvant PRRT can reduce recurrence.
Given that the current prerequisite for PRRT therapy is the expression of SSTRs in the patient's tumor, the interim results of a phase I.b study aimed at upregulating SSTRs expression in tumor cells were presented at the 2023 annual meeting of the UK and Ireland Neuroendocrine Tumour Society (UKI NETS) [18]. The study explored the safety and potential role of SSTRs epigenetic-modifying drugs ASTX727 in patients with NET, a total of 10 patients were included, only 1 patient had adverse reactions of grade 3 or higher, 4 patients were confirmed to have increased SSTRs expression after PET/CT evaluation, and 2 patients started follow-up PRRT therapy. The study may provide hope for further PRRT therapy for NET patients with negative or weak SSTRs expression.
2.5 Immunotherapy
Immune checkpoint inhibitors (ICIs) have limited efficacy in advanced NENs, so in recent years, the mainstream research direction has shifted to the combination of immune checkpoint blockade at different targets or in combination with other types of drugs. An investigator-sponsored study from the United States investigated pembrolizumab [a programmed cell death protein 1 [PD-1 inhibitor] alone or in combination with chemotherapy (irinotecan) for extrapulmonary NEC after treatment failure [19]. The study was divided into two parts, in which patients received pembrolizumab monotherapy (Part A) followed by irinotecan chemotherapy (Part B) if the response was not as expected, and the results showed that the ORR was 7% and 5%, the median PFS time was 1.8 months and 2.0 months, and the median OS time was 7.8 months and 4.8 months, respectively. This suggests that pembrolizumab alone or in combination with irinotecan does not work well in patients with NEC of advanced progressive extrapulmonary origin.
A prospective, phase II, single-arm clinical trial from Spain explored durvalumab against programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 4, CTLA-4) in combination with tremelimumab monoclonal antibody in advanced gastroenteropancreatic or pulmonary NENs[20]. A total of 27 patients with pulmonary NETs, 31 cases of G1 and G2 gastrointestinal NETs, 32 cases of G1 and G2 pancreatic NETs, and 33 cases of G3 gastrointestinal pancreatic NENs were included, with DCRs of 56.1%, 74.2%, 74.2%, and 59.4%, respectively, but drug RR was only 6.5%. The RR of patients with G3 gastroenteropancreatic NENs was 16.7% for NEC patients and 0% for NET patients, the 9-month OS rate reached 36.1%, and as for safety, the incidence of grade 3 and above adverse reactions in the total population was 29.3%, of which 12.2% were immune-related grade 3 and above adverse reactions. In the study, 9.8% of patients permanently discontinued the drug due to intolerable toxicity. At the 2023 American Association for Cancer Research (AACR) Annual Meeting, Peking University Cancer Hospital presented the results of a Phase I.b dose expansion study of CTLA-4 monoclonal antibody porustobart in combination with toripalimab (PD-1 monoclonal antibody) for the treatment of advanced high-grade NENs [21]. The results of the study showed that among the 16 patients with the evaluation results, the ORR and DCR were 37.5% and 62.5%, respectively, and the ORR and DCR of 11 NEC patients were 36.4% and 72.7%, respectively. From the results of these two studies, the combination of ICIs targeting dual targets may have certain efficacy in high-grade NENs, which is worthy of further investigation.
In addition to the combination of dual-target ICIs, the combination of ICIs with drugs that may have immunomodulatory effects is also one of the strategies currently being used in immunotherapy research. A prospective phase II, single-arm clinical trial from the United States explored the value of nivolumab (PD-1 monoclonal antibody) in combination with temozolomide in advanced NENs [22]. Only 28 patients were included in the study, including 20 with NET and 8 with NEC, and the results showed that the ORR was 35.7%, including 35% for NET and 38% for NEC, and the median PFS and OS time were 8.8 and 32.3 months, respectively. In addition, the study found that after 2 weeks of treatment with this regimen, patients had significantly increased circulating CD8+ T lymphocytes and decreased CD4+ T lymphocytes. For patients whose tumors achieved PR, total T lymphocytes expressing LAG-3 were lower. This study suggests that temozolomide may exert immunomodulatory effects and enhance the efficacy of PD-1 antibodies, and this drug combination warrants further phase III studies. Another pan-solid tumor study explored the role of the PARP inhibitor olaparib in combination with durvalumab (PD-1 monoclonal antibody) in advanced solid tumors [23]. A total of 48 patients were included in the study, of which 1 NEC patient with ATM gene alteration achieved the best efficacy with PR. However, due to the fact that there is only one patient with NEC, this result is far from indicating the effectiveness of the combination drug regimen, and further clinical studies are needed to confirm it.
In addition to the above-mentioned classic ICIs, the interim analysis results of HPN328, a T-cell coupling drug targeting δ-like canonical Notch ligand 3 (DLL3) targeting delta-like canonical Notch ligand 3 (DLL3), were presented at the 2023 ESMO Annual Meeting [24], which may exert a tumor-killing effect by promoting immune cell activation and enrichment. The Phase I and II studies reported the safety and pharmacokinetics of HPN328 in DLL3-expressing small cell lung cancer and other NENs: it was generally highly tolerable, and PR was observed in 2 patients with small cell lung cancer, CR in 1 patient, and PR in 1 patient with NENs. This suggests that the drug has a promising future in NENs.
3. Summary
In 2023, more clinical studies related to NENs will be published or announced, including topical therapies and drug treatments, which are expected to rewrite the treatment strategy of NENs or lead the transformation of NENs treatment ideas. For drug research, the study of the treatment of NENs through the combination of different ICIs drugs or in combination with other types of drugs is also gradually being carried out, which may overturn the previous perception that immunotherapy is ineffective in NENs and make it a potential application direction in the future. In addition, there are also drugs with good effects on NENs in some drug studies of pan-solid tumors, suggesting that the drug development of NENs should expand the thinking and further explore new drugs. However, there are still many therapeutic areas of NENs that have not been resolved in 2023, and there are still few related phase III clinical trials, and we look forward to making greater breakthroughs in 2024.
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