Since the term “carcinoid tumor” was first introduced by the German pathologist Oberndorfer in 1907, it has been gradually recognized that neuroendocrine tumors (NETs) produce 5-hydroxytryptamine metabolites or active peptides, such as glucagon, insulin, gastrin, corticosteroids, etc., depending on where they occur in the digestive tract or pancreas. gastrin, and corticosteroids. Of these, tumors that secrete hormones that cause clinical symptoms are generally considered functional, while tumors that do not produce hormones, or secrete substances that do not cause hormone-like symptoms, although they may produce symptoms because of differences in tumor size and location, are considered nonfunctional. However, for a long time, clinicians have been confused by the lack of understanding of NETs, which often makes these diseases “difficult to treat” in clinical practice.
The reasons for this situation are mainly the following.
1, low incidence, low exposure to these diseases and lack of experience;
2. Different clinical manifestations, mild symptoms and interval appearances, which make it easy to misdiagnose and miss diagnosis.
3, the nomenclature, staging and classification of the disease are not uniform and perfect, which is not conducive to the development of uniform guidelines for the diagnosis and treatment of NETs.
4. There are few therapeutic means for metastatic NETs and lack of effective therapeutic drugs. Therefore, it is especially important to pay attention to the recognition of GEP NETs. It is estimated that about 50% of patients already have locally advanced or metastatic disease at the time of diagnosis. Therefore, there has been no major improvement in the survival rate of patients with NETs over the past three decades. It is important to fully understand the biological characteristics and clinical features of NETs to help internists to be more alert to NETs, improve the early diagnosis rate, and select reasonable treatment for patients.
Epidemiology: from a rare disease to a “common disease”
NETs were once considered to be a rare disease. However, with the use of diagnostic techniques such as endoscopy and biomarker precision testing, the incidence and prevalence of NETs have increased significantly over the past 30 years. According to the Surveillance Epidemiology and End Results (SEER) database in the United States, there has been a 500% increase in incidence. The prevalence is estimated to be 5.25/100,000. Of these, GEP NETs account for 65-75% of all NETs. In Western countries, although GEP NETs account for only 2% of gastrointestinal malignancies. However, because of the long survival of patients (5-year survival rate 67%), GEP NETs are still the second most common gastrointestinal tract tumor after colorectal cancer.
In recent years, there has been a gradual increase in the number of reports on GEP NETs in China, but they are mainly hospital-based reports. An overview of the diagnosis and treatment of pancreatic neuroendocrine tumors in China was provided by Zhu Pre et al. in 2006. Overall, there is a lack of authoritative epidemiological data on GEP NETs because a nationwide tumor registry system has not yet been established in China, and the epidemiological trends, clinical features, and prevention and treatment status of GEP NETs at this stage are poorly understood, and there is a lack of comparable data information with other countries.
Clinical manifestations: diversity and delay
Because of the prevalence of neuroendocrine cells in the gastrointestinal (GI) tract and pulmonary bronchi and the variety of neuroendocrine cell types, the clinical manifestations of NETs are diverse, and the signs and symptoms are often less typical. Because the secreted bioactive products are associated with clinical symptoms, this is often why they are difficult for patients and physicians to recognize and ignore.
For example, occasional loose stools, intermittent facial flushing, or intermittent abdominal pain are often misdiagnosed as other problems such as gastroenteritis, menopause, or stress bowel disease and go unnoticed for years. In fact, it may be the intermittent secretion of biologically active products by NETs that causes the interstitial appearance of symptoms. In addition, localized tumors causing symptoms such as ill-defined abdominal pain, bloating, and intermittent postprandial discomfort are often misdiagnosed as stress bowel disease, diverticulitis, or peptic ulcers. As a result, short-lived abdominal pain or bouts of facial flushing are often overlooked, while left-sided chest pain is often thought of as a cardiac problem and only cardiac investigations are performed. Therefore, most NETs are found late and have already developed local spread and/or distant metastases, when the only possible curative treatment-i.e., radical surgery-is no longer possible.
Grading and classification of GEP NETs
GEP NETs, especially pancreatic NETs (pNETs), are often classified according to the biological and clinical characteristics of islets of Langerhans cells originating from the pancreas. In contrast, tumors originating from chromium-like cells of the GI tract are often referred to as carcinoid or gastrointestinal NETs (GI NETs). pNETs account for 45% of all GEP NETs. They are classified as non-functional pNETs, insulinomas, gastrinomas, glucagonomas, diastolic intestinal peptide tumors, and growth inhibitor tumors, in order of incidence, according to the substance produced. In addition, carcinoid tumors, both primary and metastatic, produce and secrete 5-hydroxytryptamine. Carcinoid syndromes induced by the released hormone include flushing, diarrhea, bronchospasm, and, in later stages, carcinoid heart disease.
The nomenclature and classification of NETs has long been confusing due to the lack of understanding of this group of diseases, and the term “carcinoid”, which implies “benign”, has been used for NETs. There are several clinical pathological classifications based on the organ of origin, tumor function, proliferation index, vascular invasion, and tumor size. These different classifications have led to more or less confusion in the staging of tumors.
The most commonly used and referenced classification is the WHO GEP NET classification. This method classifies tumors into highly differentiated neuroendocrine tumors (WEDT), benign pancreatic adenomas, well-differentiated neuroendocrine carcinomas (WDEC) in low-grade malignant carcinoid tumors, and well-differentiated pancreatic endocrine carcinomas and poorly differentiated neuroendocrine carcinomas (PDEC) based on the biological behavior of the tumor.
Well-differentiated tumors differ from highly malignant neuroendocrine carcinomas both morphologically and clinically. Highly malignant tumors are highly aggressive and sensitive to platinum-based regimens, whereas well-differentiated GEP NETs are relatively resistant to chemotherapy. In order to define tumors with similar characteristics, standardized classification systems and biomarkers are necessary. However, because of patient heterogeneity, it is actually difficult to compare the results of different clinical studies.
Treatment of GEP NETs
It is generally accepted that neuroendocrine cells are hormone-producing cells. Hormone secretion is regulated by G protein-coupled growth inhibitors and receptors. Activation of these receptors by ligands, i.e. endogenous growth inhibitors, leads to inhibition of adenylyl cyclase, which results in a decrease in intracellular cAMP and activation of K+ and Ca2+ channels, ultimately resulting in a decrease in intracellular Ca2+ concentration. This biochemical process prevents the cytostatic effect of intracellularly produced peptides. However, the half-life of endogenous growth inhibitors is very short (<3 min).
Synthetic analogues such as octreotide and lanreotide are commonly used clinically, and these drugs have an extended duration of action and require subcutaneous injections 2-3 times per day. To avoid multiple injections, long-acting release (LAR) formulations of octreotide and lanreotide have been developed, but with very low objective efficiency, previously thought to control symptoms only, the new concept is that these drugs not only reduce symptoms, but also have antitumor activity. Their antitumor activity can be divided into direct and indirect actions.
The direct action is through binding to cell surface receptors, stimulating growth inhibitor receptors, increasing P53 and Bax to induce apoptosis, blocking Ras/Raf/MAPK, PI3K/AKT/mTOR to inhibit tumor proliferation, and avoiding the production and release of growth factors and paracrine growth hormone. Indirect effects are mediated by inhibition of growth factor receptor expression, stimulation of the immune system, and inhibition of angiogenesis.
Growth inhibitors inhibit the release of several preangiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), and basic fibroblast growth factor (b-FGF). Growth inhibitors also act by inhibiting the release of alpha-interferon from T cells and disrupting tumor-induced immunodeficiency.
Growth suppressor receptors (SSTR)1-5 are known to be present on the surface of neuroendocrine cells. Octreotide and lanreotide bind tightly to SSTR-2 and SSTR-5, while having little effect on other receptors. A prospective randomized study with planned enrollment of 162 advanced, well-differentiated carcinoid tumors was conducted in Germany. This was the first prospective, randomized, placebo-controlled study of octreotide LAR for metastatic neuroendocrine midgut tumors (PROMID) with the primary study endpoint of TTP. unfortunately, only 85 patients were enrolled in eight years. The results showed a significantly longer TTP in the octreotide group compared to placebo (15.6 vs. 5.9 months, P=0.00072). This indicates that octreotide has antitumor activity against highly differentiated GI NETs compared to placebo.
Highly proliferative GEP NETs (Ki-67>20%) are considered to be tumors with aggressive behavior, fast growth rate, and will disseminate early. Therefore, there are quite a few studies exploring chemotherapy for GEP NETs. The earliest application was platinum-based drugs combined with VP-16, with an efficiency of 53%-67%, but the remission period was not long (8-9 months) and the survival was <16 months. Studies of chemotherapeutic drug combinations have focused on streptozotocin in combination with other drugs. The first randomized clinical study comparing streptozotocin alone with streptozotocin + 5fu in 82 cases of pnet resulted in a better outcome in the combination group than in the single agent group, with an efficacy rate of 63% 26="" vs.="" os="">2 years.
An ECOG-initiated study comparing streptozotocin + adriamycin, streptozotocin + 5Fu, or chlorambucil monotherapy in 105 cases of advanced islet cell carcinoma showed that streptozotocin + adriamycin was superior to streptozotocin + 5Fu, with an efficacy rate of 69% vs. 45% (P=0.05), a TTP of 20 months vs. 6.9 months (P=0.001), and a survival of 2.2 The E1281 trial is the largest clinical study conducted for GEP NETs. A total of 249 advanced carcinoid tumors were randomly assigned to the adriamycin + 5Fu, or streptozotocin + 5Fu group, and a total of 176 cases were analyzed for efficiency. The results showed no difference in the efficiency (15.9% vs. 16%) and PFS (4.5 months vs. 5.3 months) between the two groups. However, survival was longer in the streptozotocin+5Fu group than in the adriamycin+5Fu group (24.3 months vs. 15.7 months, P=0.0267).
Commonly used drugs such as adriamycin, DTIC, paclitaxel, doxorubicin, gemcitabine, topotecan, temozolomide, or pemetrexed as monotherapy for well-differentiated GEP NETs have been studied extensively, but with limited clinical benefit. Because well-differentiated GI NETs are less symptomatic, growth inhibitor analogs are often chosen as first-line therapy, while chemotherapy has little effect in metastatic patients and is only used as treatment for patients with significantly accelerated disease progression or uncontrolled hormonal growth. The standard chemotherapy regimen for well-differentiated advanced GEP NETs has not been defined. In contrast, chemotherapy may be the first-line treatment of choice for poorly differentiated, or rapidly progressing, GEP NETs.
As early as the 1980s, alpha-interferon was tried for the treatment of GEP NETs. studies at that time suggested that alpha-interferon was used to block cells in the G0 and G1 phases, inhibit growth factor production, anti-angiogenesis, and induce activation of the immune system through direct action. Unfortunately, previous treatments have mainly been a combination of alpha-interferon and the growth inhibitor analogs octreotide or lantiotide. Three randomized clinical studies comparing alpha-interferon versus octreotide + alpha-interferon, alpha-interferon versus lantriptyline + alpha-interferon, and octreotide versus octreotide + alpha-interferon have shown a trend toward improved survival with combination therapy. However, there is no clear evidence that the efficacy of alpha-interferon combined with growth inhibitors is superior to that of monotherapy. Because of the much greater toxicity of combination therapy than monotherapy and the lack of clear clinical benefit, α-interferon combined with growth inhibitors for advanced NETs is not recommended as a guideline. However, alpha-interferon monotherapy can be recommended for patients who have failed other treatment options.
The formation of solid tumors must depend on angiogenesis. NETs overexpress VEGF compared to normal tissue. A retrospective study showed that the level of VEGF expression was negatively correlated with PFS. In addition, approximately 70% of GI NETs express PDGF receptor (PDGFR) [11]. Since PDGFR-α is present in both tumor cells and mesenchyme, it suggests that the autocrine loop may favor tumor growth, while PDGFR-β is more strongly expressed in the mesenchyme and capillaries surrounding the tumor. Therefore, PDGFR may be an optimal target for the treatment of such tumors. fGF is another pre-angiogenic factor. It was found that FGF was upregulated in metastatic tumors compared to the primary tumor.
Bevacizumab is a humanized anti-VEGF monoclonal antibody that binds to and disables the A subtype of the VEGF family. A proof-of-concept study of bevacizumab enrolled 44 advanced, highly differentiated GI NETs, and patients were randomized to receive bevacizumab or polyethylene glycol IFN-α-2b (0.5 mg/kg, once/week) for 18 weeks or until tumor progression. By 18 weeks or after tumor progression, patients entered the second phase of the two-drug combination. Results Of the 22 patients in the bevacizumab group, 4 had PR and 17 had SD, while in the polyethylene glycol IFN-α-2b group, none had PR and 15 had SD. the PFS rate at 18 weeks was higher in the bevacizumab group than in the control group (95% vs. 68%, p=0.02).
Sunitinib is a multi-target tyrosine kinase inhibitor targeting VEGFR1-3, PDGFR-α and β, stem cell growth factor receptor (c-Kit), glial cell line-derived neurotrophic factor receptor (RET), and FMS-like TK-3 (Flt-3), with anti-tumor and anti-angiogenic effects. kulke et al. performed a study enrolling 107 Kulke et al. conducted a multicenter phase II clinical study enrolling 107 patients with GEP NETs. The results were 66 advanced pNETs who had previously received systemic therapy with an efficiency of 16.7%, SD of 68.2% and TTP of 7.7 months. Based on the results of this study, a large international multicenter, double-blind phase III clinical study was conducted. This study compared sunitinib 37.5 mg 1/day against placebo for progressive hyperdifferentiated pNETs over 6 months.
Although a pre-determined sample size of 340 cases was required to demonstrate whether the primary study endpoint of PFS was improved, at the time of the first interim analysis, sunitinib was found to significantly prolong PFS compared to placebo (11.4 vs. 5.5 months, p=0.0001). Upon recommendation of the independent data monitoring committee, the study was closed early. Although the weights of this study could not evaluate the difference in OS, Kaplan-Meier analysis showed that sunitinib significantly prolonged OS compared to placebo (p=0.02). Currently, the US FDA has approved sunitinib for the treatment of well-differentiated advanced pNETs.
Upregulation of Raf signaling channels is known to be associated with the development of GEP NETs. Sorafenib was another small molecule first developed to block Raf kinases, targeting VEGFR-2, 3, PDGFR-β, Flt-3, and c-Kit. In a phase II clinical study enrolling 93 patients with advanced GEP NETs, patients treated with sorafenib 400 mg 2/day resulted in a PR rate of 12% and a median PFS of 9.6 months (12.7 months for pNETs and 9.1 months for carcinoid tumors).
Pazopanib is a multi-targeted agent targeting VEGFR1-3, PDGFR-α and β, and c-Kit, with dual anti-tumor and anti-neoangiogenic effects. Recently, a phase II study used Pazopanib 800 mg orally 1/day in combination with octreotide LAR once a month to treat a group of patients with highly differentiated GI NETs and a group of pNETs. As a result, none of the 20 patients with GI NETs were effective, despite a 71% clinical benefit rate at 6 months and a PFS of 12.7 months. In contrast, of the 30 patients with pNETs treated with Pazopanib in combination with octreotide LAR, 5 achieved PR (17%) and the median PFS was 11.7 months.
The PI3K/Akt/mTOR channel plays a key role in the regulation of tumor cell proliferation, growth, metabolism, motility and survival. 72 tissue specimens in a retrospective Missiaglia analysis suggested that this channel plays an important role in the formation and progression of pNET. The first mTOR inhibitor for pNET was Temsirolimus. in a phase II study enrolling 36 advanced GEP NETs, the efficacy and SD rates were 6.7% and 60% for pNETs and 4.8% and 57.1% for GI NETs, respectively, with Temsirolimus 25 mg IV once-weekly dosing regimen. The median TTP for GI NETs and pancreatic tumors was 10.6 and 6 months, respectively.
Another phase II clinical study of the oral mTOR inhibitor everolimus (RAD001) evaluated the efficacy of RAD001 in combination with octreotide LAR in 67 advanced hypofractionated and moderately differentiated GEP NETs. The resulting efficiency and SD were 22% and 70%, respectively, and the median OS was 60 weeks. Among the pNETs was 50 weeks. This proof-of-concept study led to the clinical study of RAD001 for advanced NETs, the RADIANT project. The program consists of three trials, of which RADIANT-1 is a phase II clinical study for advanced pNETs. The first group of 115 patients received RAD001 monotherapy at 10 mg/day and the second group of 45 patients received the same dose of RAD001 + octreotide LAR. the first group of RAD001 monotherapy demonstrated activity with an efficacy rate of 9.6%, SD of 67.8% and median PFS of 9.7 months.
Although this study was not designed to compare the results of the two groups, the results suggest that the combination group was more effective with a median PFS of 16.7 months and a clinical benefit rate of 84.4%. the RADIANT-2 study compared octreotide LAR ± RAD001 for advanced carcinoid tumors and resulted in a significantly longer PFS of 16.4 months for octreotide LAR + RAD001 than for octreotide LAR alone at 11.3 months (p=0.026). And RADIANT-3 is a phase III randomized agent-controlled study of RAD001 versus placebo for progressive pNETs. This study compared the efficacy of RAD001 10 mg 1/day in combination with best supportive care versus placebo in combination with best supportive care for pNETs with progressive hypofractionation or intermediate differentiation within 12 months. The trial enrolled 410 patients. Results The RAD001 group reduced the risk of disease progression by 65% and had a median PFS 2.4 times higher than the placebo group (11.04 months versus 4.6 months).
Among several tumor channels being investigated, the insulin-like growth factor receptor (IGFR) is one of the most promising targets for GEP NET therapy. IGFR is overexpressed in NETs and promotes cell growth, inhibits apoptosis, and regulates cell adhesion and motility. Preclinical studies have shown that inhibition of IGFR-1 channels induces apoptosis and cell cycle arrest in NET cell lines.
IGFR-1 acts through PI3K, activating Akt and mTOR. It suggests that IGFR channels may be involved in the resistance of mTOR inhibitors. Blocking both channels has the potential to produce synergistic effects. MK-0646, a monoclonal antibody that blocks IGFR-1, enrolled 25 patients in a small phase II clinical study targeting advanced GI NETs and pNETs, with 5 patients receiving SD greater than 6 months. AMG-479 is a fully humanized, monoclonal antibody in development that targets IGFR-1. In the recently reported phase I dose-escalation trial in metastatic carcinoid tumors, 5 patients were enrolled, 2 achieved PR and 5 had SD of at least 16 weeks.
Conclusion
GEP NETs are composed of a group of tumors with different biological characteristics, pathomorphological and functional features, which makes this group different from other gastrointestinal tumors. When patients present with intermittent episodes of diarrhea, facial flushing, or abdominal pain, the first consultation is often with an internist, which may delay the diagnosis for years if the physician has insufficient knowledge of the disease. The delay in diagnosis in turn leads to the disease progressing from early, to late stages.
This requires the internist to be dynamic, to keep learning, to gain experience, and to fully understand this type of disease in order to guide the patient to the correct diagnosis. Also, because the treatment of this type of tumor includes not only treating the tumor itself but also treating the associated clinical symptoms, it requires multidisciplinary participation and collaboration among pathologists, radiologists, nuclear medicine physicians, surgeons, endocrinologists, and medical oncologists in order for patients to receive appropriate treatment.