Neuroendocrine tumors (NENs) are among the most heterogeneous of solid tumors, both in terms of biological characteristics and clinical presentation. Solid tumors are generally named according to the organ of origin of the tumor and pathologically classified according to histological characteristics, while for NENs, multiple clinical nomenclature and classification methods exist. NENs are classified as foregut, midgut, and hindgut NENs based on embryonic origin; lung, pancreatic, and gastrointestinal NENs based on the anatomical site of tumor origin; insulinoma, gastrinoma, glucagonoma, vasoactive intestinal peptide tumor, and growth inhibitory tumor NENs based on secreted peptides and neuroamines; and functional and nonfunctional NENs based on whether the secreted hormone causes clinical symptoms.
The nomenclature and classification of NENs in the chest (including lung and thymus) and gastroenteropancreatic NENs differ according to the pathological histology of the tumors, and those with G1 and G2 differentiation are named typical carcinoid tumors and atypical carcinoid tumors. In contrast, gastroenteropancreatic NETs are collectively referred to as neuroendocrine tumors (NETs). Therefore, the clinical and pathological histological nomenclature of patients with NECs is crucial for physicians to develop treatment strategies. There are many factors that physicians need to consider when developing a treatment strategy, such as the biological characteristics of the tumor itself, clinical staging, and the purpose of treatment.
Specifically, the factors to be considered include.
(1) The stage of the tumor: limited or extensive stage, liver metastasis only or systemic metastasis, resectable or unresectable, large or small tumor load;
(2) The growth rate of the tumor: whether it is in stable or progressive stage, whether the growth rate is fast or slow;
(3)The primary site is the pancreas or non-pancreas;
(4) Grading of the tumor: whether it is well differentiated or poorly differentiated;
(5) Hormonal status: functional or non-functional;
(6) The goal of treatment: to delay the progression or to reduce the load;
(7) side effects of treatment: mild or severe.
Control of symptoms
For symptom control of NETs with hormonal overproduction, growth inhibitory analogs (SSAs) are the main therapeutic agents. Short- and long-acting formulations of octreotide are available, which can be adjusted by increasing the dose of octreotide and shortening the interval between doses, depending on the patient’s symptom relief. Lanreotide is also available in extended-release and long-acting formulations. Both types of SSAs have similar mechanisms of action, mainly a high affinity for the growth inhibitor receptor (SSTR) 2. Pareotide has a high affinity mainly with SSTR1,2,3,5, with a 30-40 fold higher affinity with SSTR1,5 than octreotide and lanreotide. It should be noted that growth inhibitor analogs have the potential to exacerbate the hypoglycemic symptoms of insulinoma by inhibiting the secretion of glucagon.
Inhibition of tumor growth
The first thing that doctors need to clarify is the severity of the disease i.e. the stage of the tumor. For localized stage tumor, radical surgical resection is preferred; for patients with extensive stage that cannot be surgically resected or metastatic, it depends on the degree of tumor differentiation. For well-differentiated (G1 or G2) metastatic patients, tumor reduction surgery can be considered; for well differentiated symptomatic or progressive NETs, systemic therapeutic drugs are often the first choice. The choice of drug therapy is based on the site of tumor origin such as the pancreas or non-pancreas. For pNETs with large tumor load, rapid progression, or symptomatic, chemotherapy can regress the tumor to a greater extent than SSAs and molecularly targeted drugs; and for metastases confined to the liver only, hepatic artery embolization is also an important option.
1. Well-differentiated NETs
(1).SSAs have the function of controlling the symptoms due to excessive hormone secretion, and two phase III clinical studies of PROMID and CLARINET have proved that SSAs have the function of inhibiting tumor growth respectively.
(2) Peptide receptor radionuclide therapy (PRRT) was approved in Europe in the 1990s for the treatment of inoperable and metastatic NETs, with retrospective clinical studies showing an efficiency of 0-37%, but the efficacy of pNETs is better than that of midgut NETs. .
(3), interferon treatment, alpha interferon alone or in combination with octreotide for the treatment of progressive NETs has been studied a lot and has some clinical efficacy, but because of toxicity, especially for patients with liver metastases, it is commonly used in patients who have failed standard therapy.
(4), Sunitinib, which targets VEGF, and everolimus, which targets the mTOR pathway, have each been shown to significantly prolong PFS in patients. both are approved for unresectable locally advanced or metastatic pNETs. because the prolongation of PFS is extremely similar for both classes of drugs, both prolonging it by about 6 months compared to placebo, the clinical choice for pNETs can only be more patient-possible tolerated differently to make a choice. Recently, the RADIANT-4 study demonstrated that everolimus significantly prolonged PFS in non-functioning GI and pulmonary NETs.
(5), Chemotherapy can be used for NETs with high tumor load, rapid progression, or symptomatic. for pNETs, after failure of targeted agents and SSAs, because of the high efficiency of chemotherapy, it is possible to better control symptoms by reducing tumor load. For progressive non-pNETs, chemotherapy may also be considered when no other treatment options are available. Streptomycin and temozolomide are the more commonly used chemotherapeutic agents. Streptozotocin is not available in many countries outside Europe and is more toxic. Therefore, temozolomide combined with capecitabine is more commonly used to treat pNETs and has shown better efficacy and safety.
(6), arterial embolization interventions in the liver are commonly used for treatment of metastatic NETs confined to the liver. It includes embolization therapy alone, chemoembolization, and selective 90Y microsphere internal irradiation.
2, poorly differentiated NECs The current preferred treatment regimen is still platinum combined with VP-16 (e.g., EP regimen). Although this regimen has a rapid onset and high efficiency, the remission period is short. It has been reported that chemotherapy is less effective in NECs with Ki-67<55% compared to NECs with Ki-67≥55% (15% vs. 42%), but patients have a longer survival (14 vs. 10 months). Temozolomide combined with capecitabine is also an effective treatment option for this type of tumor. However, the results of clinical studies comparing these two regimens are lacking.
The increasing number of treatment options for progressive NENs now represents both an opportunity and a challenge for clinicians. How to develop an appropriate treatment strategy for each patient? Only by fully understanding the patient’s tumor site of origin, tumor load, growth rate, hormone secretion status, pathological grading, and the characteristics of various therapeutic options can we tailor the treatment to the patient and turn the challenge into an opportunity for patient benefit.