Neuroendocrine neoplasms (NENs) are highly heterogeneous and relatively rare tumors, which may occur at different sites of the body.[1,2] The most common primary sites of NENs are the stomach, intestine, and pancreas, which account for 70% of all NEN cases. According to the WHO classification of tumors, gastric, intestinal, and pancreatic NENs are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). NETs are further divided into grades 1, 2, and 3. Somatostatin analogs (SSAs) are indicated to inhibit tumor growth and treat symptoms related to hormone hypersecretion. Thus, SSAs can be used to treat functional and non-functional NETs. In this paper, the latest advance in the treatment of NENs with SSAs has been reviewed, providing a reference for clinical practice.
A manual systematic search of electronic databases (PubMed, Web of Science, and EMBASE) from 1991 to May 2021 was conducted. Search terms included “neuroendocrine tumor*”, “neuro-endocrine neoplasm*”, “Somatostatin receptors”, “Somatostatin analogs”, “first line”, “second line”, “octreotide”, and “Lanreotide”. We did not impose restrictions on language or types of articles or any exclusion criteria. We also included abstracts of the conference and clinical trials in clinicaltrials.gov/. We summarized all the evidence to yield this article.
SSTR is the most important therapeutic target for NENs
The definition and therapeutic methods of NETs have constantly been strikingly updating. Treatments for carcinoid tumors in the earlier period had been only conventional chemotherapeutic regimens. Expression of somatostatin receptors (SSTRs) was found as a common feature of NETs in subsequent studies. There are 5 subtypes of SSTRs, namely, SSTR 1 to 5. SSAs bind to SSTRs to exert a therapeutic effect. However, the affinity of SSAs to different types of SSTR varies: octreotide and lanreotide, the first-generation SSAs, have a higher affinity to SSTR2 and SSTR5, but a lower affinity to SSTR3 (SSTR 2+++, SSTR 5++); pasireotide, the second-generation SSAs, has a good affinity to SSTR 1, 2, 3, 5 ++~+++.[6–10] Given the specific binding between SSAs and SSTRs, SSTR is considered the most important therapeutic target for NETs.
In the past decade, several phase 3 randomized controlled clinical trials have demonstrated that SSAs could control the symptoms of functional NETs and inhibit the progression of nonfunctional NETs. Due to these benefits, SSAs have been approved for the treatment of both functional and non-functional metastatic NETs. The availability of SSAs has noticeably prolonged the survival of metastatic NETs patients. The median survival of NETs patients with distant metastases from 1973 to 1987 (before the marketing of octreotide) was only 18 months. In contrast, from 1988 to 2004 (after the marketing of octreotide), the median survival of NETs patients was significantly prolonged to 39 months.
Current usage of SSAs
Antiproliferative roles of SSAs in metastatic GEP-NETs are verified by RCTs
At present, SSAs are mainly used to treat GEP-NETs to control symptoms and tumor proliferation. Although SSAs were first used in functional NENs several decades ago, there has long been concerning about their antiproliferative roles in NENs due to a lack of evidence. It was not until the publication of 2 phases 3 prospective, multi-center, randomized controlled trials, PROMID and CLARINET, that the antiproliferative roles of SSAs in NEN were confirmed, along with their benefits in delaying the progression of functional and non-functional NETs.[12,13]
In PROMID trial, 85 treatment-naive patients with metastatic midgut NETs (Ki-67 < 2%) were enrolled, who were randomly assigned into octreotide Long-acting release (LAR) group or placebo group. Median time to tumor progression in the octreotide LAR and placebo groups was 14.3 and 6months, respectively. Besides, compared with the placebo group, a higher stable disease rate (66.7% vs 37.2%) was achieved in the octreotide LAR group. However, partial response was only achieved in 1 patient in each group.
In CLARINET study, 204 patients with non-functional pancreatic NETs (Ki-67< 10%) were included, who were randomly assigned into the lanreotide autogel (ATG) group (120 mg/4 weeks) and placebo group. At the end of treatment, the median progression-free survival (mPFS) (not reached vs 18 months) and stable disease rate (65.1% vs 33.0%) in the lanreotide ATG group were significantly higher than those of the control group. However, partial response was achieved in none of the patients in either group.
These 2 studies have shown that although SSAs only have a limited role in tumor shrinkage, it can noticeably prolong mPFS and inhibit tumor proliferation, which also shows a favorable safety profile. The findings of these 2 studies provide a reference for the antiproliferative effect of SSAs in NETs.
Antiproliferative roles of SSAs in metastatic GEP-NETs are verified in real-world studies
In 2020, a real-world study conducted at the Dana-Farber Cancer Institute, included 682 patients with well-differentiated metastatic GEP-NETs.[14,18] It was found that the SSA monotherapy was the most commonly chosen first-line regimen in metastatic GEP-NETs (69.7%). Besides, under the first-line setting, in 13.4% of the patients, SSAs were combined with other treatments. Only 9.7% of the patients were prescribed cytotoxic therapy, and over 80% of the patients received SSA-based treatment as the second-line therapy.
GETNE-TRASGU study recruited 535 metastatic, well-differentiated GEP-NETs patients using SSAs monotherapy as the first-line treatment.[15,16] The results showed that the mPFS was 28.7months (95% CI, 23.8–31.1) and the median overall survival (mOS) was 85.9months (95% CI, 71.5–96.7). Meanwhile, predictive factors of SSA as first-line therapy in advanced GEP-NETs were investigated. It was found that PFS was closely related to 9 factors, including Ki-67 index, neutrophil-to-lymphocyte ratio, primary tumor site, liver involvement, peritoneal metastases, bone metastases, alkaline phosphatase, progression status, and symptoms before the use of SSAs.
According to the findings from real-world studies, SSAs are the most chosen drugs in advanced low-grade NENs. In addition, a phase 3, prospective, single-arm, open-label, multi-center clinical trial is ongoing in China, which evaluates the efficacy and safety of lanreotide ATG (120 mg/4 weeks) for advanced gastric, intestinal, and pancreatic NETs G1/G2 with an estimated number of patients to be enrolled of 43.
SSA therapy is the primary first-line therapy for the treatment of NENs recommended by the guidelines
According to several guidelines (eg, ENETS, NCCN, and ESMO), including Chinese Guidelines for the Diagnosis and Treatment of Pancreatic Neuroendocrine Neoplasms, and Chinese Expert Consensus on Gastric, Intestinal and Pancreatic Neuroendocrine Neoplasms, SSAs are recommended as the first-line therapy in metastatic well-differentiated NETs patients (including NETs from the chest, stomach, intestine, and pancreas), especially for SSTR-positive tumor.[19–21]
Clinical problems concerning the usage of SSAs for the treatment of NETs
Are SSAs indicated for metastatic GEP-NETs with Ki-67 ≥ 10%?
Both PROMID and CLARINET studies enrolled patients with a Ki-67 < 10%. It remains controversial whether SSAs are equally effective in controlling tumor progression in those with a Ki-67 ≥ 10%.
In 2020 ENETS, a retrospective study that enrolled 73 pancreatic NETs (pNETs) patients with a median Ki-67 index of 15% (10%–35%) and received SSAs as the first-line therapy was reported. Within a median period of 40.2 months, the mPFS of the patients was 11.9 months, and pNETs G2 and pNETs G3 patients was 12.2 and 4.7 months, respectively (P = .02). The 5-year survival was 64.2%. Additionally, the mPFS of the patients with different liver metastasis burdens (<25%, 26%–50%, 51%–75%, or >75%) was 13.8, 12.4, 6.5, and 6 months, respectively (P = .009).
Based on the results of this study, it might be feasible to apply SSAs as first-line treatment in advanced NETs-G2 patients (including Ki-67 of 10%–20%), especially those with a smaller tumor burden. However, these findings remain to be further verified by prospective studies.
Are SSAs indicated for GEP-NETs with G3 grade?
Due to the high aggressiveness of NET G3, although SSAs showed an antiproliferative effect in NET G1/2 patients, whether SSAs could be applied in NET G3 was unknown. In recent 2 years, several small sample-sized retrospective studies had investigated the issue.
A study finished in Mayo Clinic enrolled 18 patients with well-differentiated NET-G3, who were prescribed SSA monotherapy with available radiological data for response evaluation. SUVmax was obtained from Ga-68-PSMA PET/CT scan for quantification of the affinity to SSTRs. Rb1 and p53 were evaluated by IHC. The results showed that the mPFS of the patients was 4.4 months and the disease control rate (DCR) was 55%. One-third of the patients achieved a stable disease over 8 months. The duration of stable disease was prolonged for at least 24 months in 3 patients. The results demonstrated favorable effects of SSAs in well-differentiated NET G3 patients.
In 2020 ENETS, the investigators of a retrospective study found that mPFS of the enrolled NETs-G3 patients was 4.7 months. This population benefited less from the SSAs treatment unless the tumor burden was small. Otherwise, other treatments, including PRRT, targeted therapy, or chemotherapy, might be preferred.
Based on available results, the 2021 NCCN guidelines recommended SSAs as the treatment for SSTR-positive and/or symptomatic NETs-G3, but should be restricted to patients with traits of well biological behaviors, slow growth rate, Ki-67<55%, and SSTR-positive status.
In summary, the use of SSA in the treatment of GEPNETs G3 is still controversial and the current evidence is insufficient. SSAs are not recommended as the best first-line therapeutic solution. We have to give full consideration to the expression of SSTRs, progressive behaviors (low Ki-67), and tumor burden in clinical practice.
The ongoing NETTER-2 study is a multicenter, prospective clinical trial that enrolls patients with a Ki-67 of 10%–55%. The 2 cohorts receive SSA dose-escalation or PRRT + SSA treatment separately, and the results of this study hopefully will help in the treatment decision of this special population.
Is dose escalation of SSAs effective after initial disease progression on SSAs?
If GEP-NENs are resistant to SSAs of the standard dose, a common solution is dose-escalation, especially for symptom control. High-dose SSAs may further improve the symptoms with favorable safety. However, there is a lack of evidence on whether high-dose SSAs could further enhance the antiproliferative effect on tumors. Despite that, an increased dose of SSAs was still recommended by the 2016 ENETS Guidelines as second-line therapy for advanced GEP-NETs.
In the NETTER-1 study, second-line therapy was given to patients with advanced midgut NETs who progressed after the treatment of octreotide LAR of the standard dose as the first-line therapy. There were 116 patients in the combination treatment group who were prescribed octreotide LAR 30mg+ 177Lu DOTATATE. Notably, those in the control group were given an increased dose of octreotide LAR (60 mg), mPFS of which was still 8.4 months.
During the 2021 ENETS Conference, Prof Pavel shared findings of a CLARINET FORTE study. It was a phase 2, prospective, single-arm, international study evaluating the efficacy and safety of reducing the interval of interdose (120 mg/14 days) in progressive pancreatic or midgut NETs after the standard dose of lanreotide ATG treatment. The results showed that by reducing the interdose interval, mPFS of the patients with midgut NETs was 8.3 months compared to 5.6 months of the patients with pNETs. The analysis of the subgroup indicated more significant benefits in patients with Ki-67 ≤ 10%, especially for pNET groups (8.0 vs 2.8 months).
In 2020, a study which retrospectively enrolled 140 patients from 13 centers in Italy, analyzed the clinical benefits of high-dose SSAs as second-line therapy. It included well-differentiated GEP-NETs G1 or G2 receiving high-dose SSAs as a later-line therapy (either by increasing the dose or by reducing the interdose interval). The dosing frequency was increased in 95% of the patients. The results showed that the mPFS of the patients who were prescribed high-dose SSAs as a later-line therapy due to progression after the first-line therapy of standard-dose SSAs was as long as 31 months. The mPFS of the patients prescribed highdose SSAs as the second-line therapy was 57 months compared to 22 months of those as the third-/fourth-line therapy. There was no significant difference in mPFS between different subgroups of patients with high-dose SSAs.
According to all the studies above, NETs patients were benefited from an increased dose of SSAs as second-line therapy. Besides, low-grade NETs usually progress slowly, life quality of the patients should also be emphasized. The proven safety of high-dose SSAs is also a prerequisite for its use as a second-line therapy, especially for those with a low Ki-67 and smaller tumor burden.
Is SSA-based combination therapy feasible?
A real-world study showed that SSA-based combination therapy was the most common second-line option for GEP-NETs.[14,17] As for the second-line therapies used in this study, 77.9% of the pNETs patients, 96.6% of the midgut NETs patients, and 78.7% of the patients with other primary locations were given SSA-based combination therapy. In these treatments, the drugs used concomitantly with SSAs included cytotoxic agents, everolimus, interferon, and investigational drugs.
SSAs plus the mTOR inhibitors have a synergistic anti-tumor effect. The RADIANT-2 study included 429 low- or mediumgrade advanced NETs patients with a history of carcinoid syndrome. They were randomly prescribed everolimus + octreotide LAR, or placebo + octreotide LAR. The results showed that the mPFS in the everolimus group was 16.5 vs 11.3 months in the placebo group (P = .026), indicating a significant difference with a prolongation of 5.1 months compared with the placebo group, while the risk of disease progression was decreased by 23%. Another research of SSAs plus mTOR inhibitor is the phase 3 clinical trial (STARTER-NET) ongoing in Japan, evaluating the unresectable or recurrent GEP-NETs, which will bring more clinical evidence for the use of lanreotide plus everolimus in NETs treatment.
Recently, Pusceddu et al published a meta-analysis that compared the efficacy of mainstream treatment and mPFS of advanced GEP-NETs. Of the 83 studies, 8 RCTs were chosen, involving 1849 NETs patients, who were randomly divided into SSAs, everolimus, sunitinib, everolimus plus SSAs, and placebo groups. It was demonstrated that all the treatments above were superior to placebo (HR was 0.34 for all SSAs combination, 95% CI 0.24–0.37; HR 0.42 for everolimus plus SSAs, and 95% CI 0.31–0.57; moderate grade of evidence quality). In terms of PFS improvement, everolimus plus SSAs ranked the highest. Among various interventional measures, pasireotide monotherapy and everolimus plus octreotide were the optimal drug therapies. The above-mentioned meta-analysis supported the use of combination treatment in functional and non-functional GEP-NETs patients, and it was pointed out that everolimus plus octreotide was superior.
A study on octreotide LAR plus pazopanib, a tyrosine kinase inhibitor, was a single-arm, multi-center, prospective phase 2 trial published on Lancet Oncology. It included 52 patients with metastatic or locally advanced pNETs G1/G2 and 32 patients with treated or treatment-naive pNETs. They were prescribed pazopanib (800 mg/d) plus octreotide LAR, and the primary endpoint was the overall response rate (ORR). The results showed that the ORR in pNETs patients reached 21.9%, with an mPFS of 14.4 months and an mOS of 25 months.
The use of Axitinib + octreotide LAR was investigated in a phase 2/3 AXINET trial published at the 2021 ASCO-GI Conference. This trial included 256 advanced non-pancreatic NETs G1/G2 patients, among which 126 patients were prescribed Axitinib plus octreotide LAR, and 130 patients were given placebo plus octreotide LAR as the control. The results showed that the mPFS was 17.2 months for patients with Axitinib plus octreotide LAR vs 12.3 months for the controls but without a significant difference in PFS. In contrast, ORR was superior in Axitinib plus octreotide LAR group compared to those given octreotide monotherapy (17.5% vs 3.8%).
The ATLANT study was published in the 2020 ESMO Congress, which represented the application of SSAs combined with chemotherapy in NETs. The phase 2, prospective, single-arm clinical trial investigated the efficacy of lanreotide ATG plus temozolomide in treating unresectable, locally progressive or metastatic, well-differentiated chest NETs. Forty patients (chest 80%, thymus 10%; atypical carcinoid 52.5%) were included in the study, and they were prescribed lanreotide ATG plus temozolomide. The results showed that the DCR at 9 months was 35% and the mPFS was 37.1 months.
SSAs plus PRRT is another important combination treatment regimen, which was used in the NETTER-1/NETTER-2 study as mentioned above.
Besides, SSAs have been also used as maintenance therapy after the first-line targeted therapy/chemotherapy. The REMINET study in 2021 ENETS Conference concerned with lanreotide ATG as the maintenance therapy for patients with duodenal and pancreatic NETs who achieved partial remission or stable disease after 2 to 6 months of the targeted therapy or chemotherapy. A total of 118 patients were randomly prescribed 120 mg lanreotide ATG or placebo and followed up for 27 months. The results showed that the mPFS was 19.4 months in the treatment group vs 7.6 months in the control group. The median OS was not reached in the treatment group vs 41.9 months in the placebo group.
Could SSAs benefit for pNETs ≤ 2 cm?
Due to the slow growth of pNETs ≤ 2 cm, it remains controversial that these patients need surgical resection or not. ENETS guidelines generally recommend regular follow-up instead of surgical resection. NCCN guidelines 2021 recommend that low-grade sporadic non-functional pNET with a size of <2 cm can undergo surveillance and observation. It is still uncommon about the use of SSAs in these patients.
A trial published during the 2020 ENETS Conference enrolled 41 patients with sporadic non-functional pNETs, among which 24 patients were prescribed SSAs, and 17 patients were given active surveillance (AS). The efficacy of SSAs for sporadic nonfunctional pNETs ≤ 2 cm and patients’ tolerance were investigated. They were followed up for 45.2 months on average. Progressive disease (PD) was not reported in the SSA group, while it was reported in 6 patients in the AS group. The mPFS was significantly longer in the SSA group than that in the AS group (not reached vs 47.9 months) (P = 0.001). Faggiano et al also demonstrated that Lanreotide was more effective than AS in MEN1-related PNET < 2 cm.
It was indicated that for pNETs with a smaller size, SSA treatment is indicated for patients with great surgical trauma or those intolerant of surgery due to age or underlying diseases.
Are SSAs as adjuvant therapy effective for pNETs after radical surgery?
Adjuvant therapy following radical resection has become a primary choice to prevent the recurrence of many tumors. However, there is still a lack of evidence supporting its use in NETs. Given the antiproliferative effect of SSAs on NETs, some researchers have begun to focus on the feasibility of SSAs on postoperative adjuvant therapy for pNETs with high recurrence risk.
Jin et al reported a real-world study from China, in which the long-term follow-up data of 130 patients with pNETs-G2 receiving radical resection were reviewed.[38,39] Among them, 59 patients were given at least 6 months of octreotide LAR adjuvant therapy, and 71 patients have not prescribed any adjuvant therapy. The baseline data showed that the vascular and neural invasion revealed by postoperative pathology (indicating a higher risk) was more common in the octreotide LAR adjuvant therapy group. The follow-up results demonstrated that the disease-free survival (DFS) rate was significantly higher in the octreotide LAR group than in the control group: the 24-month DFS rate was 98.3% vs 88.7% (P = .0371); the 36-month DFS rate was 96.6% vs 85.9% (P = .0498). Long-acting octreotide treatment could reduce the risk of 3-year recurrence of G2 pNET after radical resection (HR = 0.2, P = .044). It was suggested that the postoperative SSA adjuvant therapy might reduce the recurrence rate of pNETs. Despite its retrospective nature, the findings of this study bring novel perspectives and evidence. This was also confirmed by Wang et al However, the findings remain to be further verified by prospective trials with a larger sample size.
SSAs, as the first-line therapy for metastatic low-grade GEP-NETs, have some novel clinical implications. SSAs could prolong the PFS of patients of metastatic GEP-NETs with Ki-67 ≥ 10%, especially those with a lower tumor burden. High-dose SSAs have been proved safe and effective as second-line therapy for the patients after disease progression with a standard doses of SSAs. SSAs combined with targeted therapy or chemotherapy emerged as a common second-line treatment in clinical practice. SSAs may also be considered for unresectable pNETs ≤ 2 cm. When used as a postoperative adjuvant therapy for pNETs with a high recurrence risk, SSAs could also prolong DFS. However, the existing evidence is mostly from retrospective studies remain to be further verified.
All authors were involved in manuscript conception and design. Manuscript writing was performed by Ming Lu, Panpan Zhang and Jianwei Zhang, with the direction and support of Ming Lu and Jie Li. All authors provided critical input for the revision of the manuscript and approved the final version of the manuscript.
Conflicts of interest
The authors declare no conflicts of interest.
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