Abstract
Background
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogenous malignancies that require well-designed trials to develop effective management strategies. This cross-sectional study aimed to illustrate the current landscape of clinical trials in GEP-NENs to provide insights for future research.
Materials and methods
We reviewed all clinical trials registered on ClinicalTrials.gov between 1 January 2000 and 31 December 2021 with GEP-NEN in the ‘condition or disease’ field.
Results
We included 206 eligible trials. Most trials enrolled less than 50 patients (59.8%) and were sponsored by institutions other than government or industry (67.0%). Most trials were conducted in high-income countries (86.6%) and countries located in Europe (30.1%) or Northern America (29.6%). The overall result reporting rates of GEP-NEN trials was 41.4%, and the median time from primary completion to result reporting was 101 months. Characteristics that improved the reporting of results included larger sample size, tumor differentiation specification for inclusion, progression-free survival as primary endpoint, industry sponsorship, and multicenter or multinational participation (all P < 0.05). Compared with trials registered between 2000 and 2011 (n = 28), trials registered between 2012 and 2021 (n = 178) were more likely to specify the Ki-67 index for inclusion (68.0% vs 35.7%, P = 0.002) and to be conducted outside Europe or Northern America (16.4% vs 3.7%, P = 0.02), while the sample size and the sponsorship did not change significantly.
Conclusions
Novel management options have been explored for GEP-NENs with more specific inclusion criteria during the past two decades. More efforts are needed to promote international collaborations in clinical trials and enhance timely result dissemination.
Introduction
Neuroendocrine neoplasms (NENs) are a group of heterogenous malignancies that arise in the diffuse neuroendocrine system (1). Gastroenteropancreatic (GEP) system is the most common origin of NENs (2, 3). The incidence of GEP-NENs has increased during the past two decades (2). The estimated incidence of GEP-NENs was 3.56 per 100,000 in 2017 in the USA, which could be an underestimate for current incidence as the classification of NENs has been continuously updated since then (3, 4, 5). More than one-fifth of GEP-NEN patients have metastatic disease at diagnosis, and they generally have a poor prognosis (3, 6, 7). Several breakthroughs have been achieved in the systemic treatment of GEP-NENs, including the clinical application of long-acting release somatostatin analogs (SSAs), the multitarget tyrosine kinase inhibitor (TKI) sunitinib, mammalian target of rapamycin (mTOR) inhibitors, and peptide receptor radionuclide therapies (PRRTs) to inhibit tumor growth (8, 9, 10, 11, 12, 13). A multitarget TKI surufatinib has also showed promising efficacy in the Chinese population, which requires further confirmation in large clinical trials of other population (14, 15). However, there is still an unmet need for effective management strategies.
Well-designed trials can improve the efficiency of clinical research, especially for uncommon malignancies like GEP-NENs. Efforts have been made to optimize the design of GEP-NEN trials in the past two decades. The classification system of GEP-NENs has been continuously updated, and the National Cancer Institute (NCI) has made key recommendations on the design of NEN clinical trials in 2011 (4, 15, 16). However, a previous study still reported limited clinical benefit of current systemic treatment for GEP-NENs (17). A comprehensive and quantitative illustration of the chronological changes and the current landscape of GEP-NEN trials can provide insights into improving the quality of clinical trials. A previous study has analyzed characteristics of NEN trials between 2000 and 2020, which only included completed phase 2 or 3 trials with publications (18). However, early phase trials, ongoing trials and unpublished trials may reflect valuable information, especially defects in current research landscape (19, 20). Besides, the scope of all NEN trials in the study may introduce additional heterogeneity.
Therefore, we conducted this cross-sectional study to comprehensively illustrate the current landscape and chronological changes of clinical trials in GEP-NENs. We hope that this study will provide insights for future design and implementation of GEP-NEN trials.
Materials and methods
This cross-sectional study aimed to illustrate the current landscape and chronological changes of clinical trials in GEP-NENs. This study was conducted according to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guideline and was exempt from institutional board review because it only involved publicly available and deidentified data (21).
Data source and selection criteria
We obtained records of all clinical trials registered on https://clinicaltrials.gov/ on 1 April 2022 using the Aggregate Content of ClinicalTrials.gov (AACT) database (22, 23). We restricted our analysis to trials registered between 1 January 2000 and 31 December 2021, and the ‘condition or disease’ fields were GEP-NEN. The registration date was defined as the ‘first posted’ date of the trial. Both the well-differentiated neuroendocrine tumors (NETs) and the poorly differentiated neuroendocrine carcinoma (NECs) were included. To identify all eligible trials, we used a combination of location keywords and NEN keywords to search all conditions synonymous with GEP-NENs according to the World Health Organization (WHO) classification, including gastrointestinal, pancreatic, gastrointestinalpancreatic, gastrinoma, insulinoma, glucagonoma, and midgut NEN (Supplementary Table 1, see section on supplementary materials given at the end of this article) (4, 5). For trials that only include NENs and did not specify tumor locations in ‘condition or disease’ fields, we manually searched ClinicalTrial.gov and included trials that mentioned GEP-NENs in the eligibility criteria. We only included interventional trials. Two investigators (KLY and JRL) independently selected the eligible studies, and a third investigator (CMB) resolved all discrepancies.
Data collection
We used the aggregated content of the AACT database to analyze the characteristics of GEP-NEN trials. The leading sponsor of the trial was categorized into four types according to the definition of ClinicalTrials.gov: industry, the National Institutes of Health (NIH), other government or network, and other institutions. For the geographic region, if a trial was conducted in more than one country, we defined it as a multinational trial; otherwise, the geographic region was designated as USA or Canada, Europe or other regions according to the country in which the trial was conducted. The economic status of each country was defined according to the World Bank income grouping (24).
Two independent investigators (KLY and JRL) manually recorded details of purpose, interventions, and eligibility criteria of each trial from ClinicalTrials.gov. The purpose was defined as diagnosis, symptom control, tumor growth inhibition according the study description and the interventions of the trial. The interventions were categorized into drugs and procedures. We recorded the requirement of NEN differentiation status and Ki-67 index or tumor grade in the eligibility criteria of each trial. To facilitate analysis, we further classified the tumor grade requirements of each trial into three categories: well-differentiated NET, NEN with certain Ki-67 index regardless of differentiation status, and poorly differentiated NEC.
The Food and Drug Administration Amendments Act (FDAAA) of 2007 required sponsors of applicable trials to report results on ClinicalTrials.gov within 1 year of completion (25). Thus, we analyzed the result reporting status of trials with tumor growth inhibition purpose, and the anticipated primary completion date (the date when trials finished collecting data for primary endpoints) was before 31 December 2020. We confirmed the result reporting status of each trial from three sources as previously reported: the result section of ClinicalTrials.gov, the automatically linked publication of ClinicalTrials.gov, and PubMed and Embase databases by searching the NCT identifier (20, 26). Conference abstracts were excluded because of the premature nature. We recorded the earliest result reporting date. A third author (CMB) resolved all discrepancies during the data collection process.
Statistical analysis
We performed all statistical analyses using R version 4.1.0 (https://cran.r-project.org/bin/windows/base/old/4.1.0/). The characteristics of trials were analyzed using descriptive statistics. We analyzed chronological changes of trials by dividing them into two time periods: 1 January 2000 to 31 December 2011 and 1 January 2012 to 31 December 2021. We compared the categorical variables using the chi-squared test or the Fisher’s exact test if indicated. The continuous variables were compared using the Wilcoxon rank sum test. The result reporting status was analyzed as time-to-event data using the Kaplan–Meier method. We defined the result reporting time as the time from the primary completion date to the earliest reporting date. For studies that did not report results, the follow-up time was calculated as the time from primary completion date to 31 December 2021. We identified trial characteristics that could affect result reporting using the log-rank test. Studies that reported the result before registration were excluded from analysis. Missing values were excluded from analyses. All statistical tests were two-sided, and P <0.05 was considered statistically significant.
Results
Overview of characteristics of GEP-NEN trials
We identified 206 eligible trials registered on ClinicalTrials.gov between 1 January 2000 and 31 December 2021 (Supplementary Fig. 1). Table 1 summarizes the characteristics of trials. Most trials were phase 0 to 2 trials (76.7%) and were single-arm trials (64.6%). Randomization (23.3%) and blinding (7.3%) were used in a small proportion of trials. The leading sponsors for most trials were institutions other than NIH or industry (67.0%). Regarding the overall status, 107 trials (51.9%) were still ongoing, 58 trials (28.2%) were completed, and 25 trials (12.1%) were terminated prematurely. The most common reason for trial termination was slow recruitment (12/25 (48.0%)). More than half of the NEN trials had finished enrollment (51.9%), and most of them had enrolled less than 50 patients (64/107 (59.8%)). Most trials had a tumor growth inhibition purpose (82.5%). Among these trials, 66 trials (38.8%) used objective response rate as the primary endpoint, and 47 trials (27.6%) used progression-free survival (PFS).
Characteristics of all GEP-NEN clinical trials (n = 206).
| Characteristics | n (%) |
|---|---|
| Phase | |
| Phase 0–1 | 32 (15.5) |
| Phase 1/2–2 | 126 (61.2) |
| Phase 2/3–3 | 22 (10.7) |
| Phase 4 | 7 (3.4) |
| N/A | 19 (9.2) |
| Primary purpose | |
| Tumor growth inhibition | 170 (82.5) |
| Diagnosis | 26 (12.6) |
| Symptom control | 10 (4.9) |
| Enrollment status | |
| Actual | 107 (51.9) |
| Anticipated | 97 (47.1) |
| N/A | 2 (1.0) |
| Actual enrollment, median (IQR) | 29 (12–62) |
| Actual enrollment (n)a | |
| <50 | 64 (59.8) |
| 50–100 | 17 (15.9) |
| >100 | 17 (15.9) |
| N/A | 9 (8.4) |
| Allocation | |
| Single arm | 133 (64.6) |
| Non-randomized | 25 (12.1) |
| Randomized | 48 (23.3) |
| Blinding | |
| Blind | 15 (7.3) |
| Open label | 191 (92.7) |
| Lead sponsor | |
| Industry | 49 (23.8) |
| NIH | 11 (5.3) |
| Other government or network | 8 (3.9) |
| Other institution | 138 (67.0) |
| Number of participating centers | |
| Single center | 91 (44.2) |
| Multicenter | 115 (55.8) |
| Geographic regions | |
| USA or Canada | 61 (29.6) |
| Europe | 62 (30.1) |
| Other | 36 (17.5) |
| Multinational | 33 (16.0) |
| N/A | 14 (6.8) |
| Overall statusb | |
| Ongoing | 107 (51.9) |
| Stopped early | 25 (12.1) |
| Completed | 58 (28.2) |
| Other | 16 (7.8) |
| Reason for termination c | |
| Slow recruitment | 12 (48.0) |
| Sponsor decision | 5 (20.0) |
| Unreached primary endpoint | 3 (12.0) |
| N/A | 5 (20.0) |
| Has a DMC | |
| Yes | 91 (44.2) |
| No | 86 (41.7) |
| N/A | 29 (14.1) |
| Histopathological specification in eligibility criteria | |
| Differentiation specification | 138 (67.0) |
| Ki-67 or grade specification | 131 (63.6) |
| Not specified | 56 (27.2) |
| Histopathological requirement for trial inclusion | |
| NET | 125 (60.7) |
| NEN with certain Ki-67 index | 11 (5.3) |
| NEC | 14 (6.8) |
| Not specified | 56 (27.2) |
| Primary efficacy endpointd | |
| Progression-free survival | 47 (27.6) |
| Objective response rate | 66 (38.8) |
| Overall survival | 3 (1.8) |
| Other | 64 (37.6) |
| Treatment regimend | |
| Drug | 153 (90.0) |
| SSA | 20 (11.8) |
| Targeted therapy | 74 (43.5) |
| Immunotherapy | 20 (11.8) |
| Immune checkpoint inhibitor | 16 (9.4) |
| Other immune modulators | 4 (2.4) |
| Chemotherapy | 38 (22.4) |
| PRRT | 35 (20.6) |
| Procedure | 27 (15.9) |
| Surgery | 3 (1.8) |
| Radiotherapy | 3 (1.8) |
| Locoregional therapy | 20 (11.8) |
| Ablation | 7 (4.1) |
| TAE | 4 (2.4) |
| TACE | 4 (2.4) |
| TARE | 5 (2.9) |
| Other (intraperitoneal chemotherapy) | 1 (0.6) |
aThe denominator was the number of trials that had finished enrollment (n = 107); bThe ‘ongoing’ status includes trials that were ‘not yet recruiting’, ‘recruiting’, ‘enrolling by invitation’, ‘active, not recruiting’, or ‘suspended’ on ClinicalTrials.gov; the ‘stopped early’ status includes trials that were ‘terminated’ or ‘withdrawn’ on ClinicalTrials.gov; cThe denominator was the number of trials that stopped early (n = 25); dThe denominator was the number of trials with tumor growth inhibition purpose (n = 170).
DMC, data monitoring committee; IQR, interquartile range; GEP-NEN, gastroenteropancreatic neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; NIH, National Institute of Health; PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analog; TACE, trans-arterial chemoembolization; TAE, trans-arterial embolization; TARE, trans-arterial radioembolization.
For the eligibility criteria, 138 trials (67.0%) specified tumor differentiation status and 131 trials (63.6%) specified tumor grade or Ki-67 index (Table 1). Miscellaneous inclusion criteria for tumor differentiation or Ki-67 index were adopted in these trials (Supplementary Table 2). Briefly, 125 trials (60.7%) included NETs, and 79 of them (38.3%) investigated grade 1–2 NETs. A total of 11 trials (5.3%) included NENs with certain Ki-67 index regardless of differentiation status, and 14 trials (6.8%) exclusively investigated NECs. Six NEC trials specified mixed neuroendocrine and non-neuroendocrine (MiNEN) tumors in their inclusion criteria: two trials included MiNEN tumors (NCT02215447 and NCT04325425); three trials included NECs mixed with other non-neuroendocrine neoplasms with a prominent (>70%) NEC component (NCT02820857, NCT03591731, and NCT04268121), and one trial excluded MiNEN tumors (NCT03278405).
Regarding the primary purpose, most trials investigated tumor growth inhibition strategies (82.5%), followed by diagnostic trials (12.6%) and trials of symptom control strategies (4.9%) (Table 1). Among the 170 trials investigating tumor growth inhibition strategies, 153 investigated drugs and 27 investigated procedures. Targeted therapy was the most investigated drug type (43.5%), followed by chemotherapy (22.4%), PRRT (20.6%), immunotherapy (11.8%), and SSAs (11.8%). Locoregional therapies (11.8%) were the most investigated procedures to inhibit tumor growth. For diagnostic strategies, 23 of 26 trials evaluated functional imaging tracers in SPECT/CT or PET/CT. In addition, two trials evaluated the diagnostic and predictive value of plasma or urine biomarkers, including circulating tumor cells (NCT02075606), and urine and plasma 5-hydroxyindolacetic acid levels (NCT02826928); one trial evaluated the diagnostic value of dual-energy CT (NCT04993261).
Geographical distribution of GEP-NEN trials
A total of 46 countries conducted GEP-NEN trials in the past two decades (Fig. 1A, Supplementary Table 3). Multinational trials accounted for 16.0% of the total GEP-NEN trials (Table 1). The USA had the largest number of trials (n = 88), followed by France (n = 37), Italy (n = 30), Spain (n = 27), the UK (n = 22), and China (n = 22). Regarding the country income status, high-income countries had the largest number of GEP-NEN trials (86.6%), while upper-middle-income countries (12.7%) and lower-middle-income countries (0.7%) participated less (Fig. 1B). Among the top 10 countries with the largest number of GEP-NEN trials, China was the only upper-middle-income country, while the rest were high-income countries.
(A) The distribution of GEP-NEN trials by country (n = 194). (B) The distribution of GEP-NEN trials by World Bank income (n = 194). (C) The distribution of actual enrollment by geographic region (n = 101). GEP-NEN, gastroenteropancreatic neuroendocrine neoplasm.
Citation: Endocrine Connections 12, 4; 10.1530/EC-22-0441
Among the trials that had finished enrollment, multinational trials had significantly larger sample sizes (median 108.5, all P < 0.05) than those conducted in one country (Fig. 1C). There were no significant differences in sample sizes among studies conducted in the USA or Canada (median 20.0), Europe (median 29.0), and other regions of the world (median 34.0).
Chronological changes in GEP-NEN trials
The number of GEP-NEN trials increased from 1 in 2003 to 17 in 2021 (Fig. 2). Table 2 shows the comparison of trial characteristics between two decades (January 2000 to December 2011, n = 28; January 2012 to December 2021, n = 178). Compared with trials registered between 2000 and 2011, trials registered between 2012 and 2021 had a significantly higher proportion of diagnostic trials (14.6 vs 0%, P < 0.001) and trials conducted in regions outside Europe, the USA, and Canada (16.4 vs 3.7%, P = 0.02). Regarding the eligibility criteria, a significantly higher proportion of trials specified the grade or the proliferation index of tumor (68.0 vs 35.7%, P = 0.002) between 2012 and 2021 than between 2000 and 2011, and the proportion of trials that did neither specify the differentiation nor the grade numerically decreased (24.7 vs 42.9%, P = 0.08). Among trials that specified the differentiation status or the Ki-67 index of tumor, the distribution of tumor grade requirement did not change significantly (NET: 82.8 vs 87.5%, NEN with certain Ki-67 index: 8.2 vs 0%, NEC: 9.0 vs 12.5%, P = 0.57). The distribution of other trial characteristics did not change significantly between the two decades.
Annual numbers of GEP-NEN clinical trials (n = 206) according to (A) primary purpose and (B) tumor differentiation or Ki-67 index. GEP-NEN, gastroenteropancreatic neuroendocrine neoplasm.
Citation: Endocrine Connections 12, 4; 10.1530/EC-22-0441
Chronological changes of GEP-NEN trials between 2000 and 2021.
| Characteristics | n/total (%)a | P-valueb | |
|---|---|---|---|
| 1 January 2000–31 December 2011 (n = 28) | 1 January 2012–31 December 2021 (n = 178) | ||
| Phase | 0.98 | ||
| Phase 0–1 | 4/28 (14.3) | 28/159 (17.6) | |
| Phase 1/2–2 | 20/28 (71.4) | 106/159 (66.7) | |
| Phase 2/3–3 | 3/28 (10.7) | 19/159 (11.9) | |
| Phase 4 | 1/28 (3.6) | 6/159 (3.8) | |
| Primary purpose | 0.001 | ||
| Tumor growth inhibition | 23/28 (82.1) | 147/178 (82.6) | |
| Diagnosis | 0/28 (0.0) | 26/178 (14.6) | |
| Symptom control | 5/28 (17.9) | 5/178 (2.8) | |
| Actual enrollment, median (IQR) | 33 (18.5–64) | 29.5 (12–64.8) | 0.08 |
| Actual enrollment (n) | 0.94 | ||
| <50 | 15/24 (62.5) | 49/74 (66.2) | |
| 50–100 | 5/24 (20.8) | 12/74 (16.2) | |
| >100 | 4/24 (16.7) | 13/74 (17.6) | |
| Allocation | 0.35 | ||
| Single arm | 15/28 (53.6) | 118/178 (66.3) | |
| Randomized | 8/28 (28.6) | 40/178 (22.5) | |
| Non-randomized | 5/28 (17.9) | 20/178 (11.2) | |
| Blinding | 0.44 | ||
| Blind | 3/28 (10.7) | 12/178 (6.7) | |
| Open label | 25/28 (89.3) | 166/178 (93.3) | |
| Lead sponsor | 0.09 | ||
| Industry | 12/28 (42.9) | 37/178 (20.8) | |
| NIH | 1/28 (3.6) | 10/178 (5.6) | |
| Other government or network | 0/28 (0.0) | 8/178 (4.5) | |
| Other | 15/28 (53.6) | 123/178 (69.1) | |
| Number of participating centers | 0.22 | ||
| Single center | 9/28 (32.1) | 82/178 (46.1) | |
| Multicenter | 19/28 (67.9) | 96/178 (53.9) | |
| Geographic regions | 0.02 | ||
| USA or Canada | 13/27 (48.1) | 48/165 (29.1) | |
| Europe | 6/27 (22.2) | 56/165 (33.9) | |
| Other | 1/27 (3.7) | 27/165 (16.4) | |
| Multinational | 7/27 (25.9) | 26/165 (15.8) | |
| Has a DMC | 0.81 | ||
| Yes | 9/19 (47.4) | 82/158 (51.9) | |
| No | 10/19 (52.6) | 76/158 (48.1) | |
| Histopathological specification in eligibility criteria | |||
| Differentiation requirement | 16/28 (57.1) | 122/178 (68.5) | 0.32 |
| Ki-67/grade requirement | 10/28 (35.7) | 121/178 (68.0) | 0.002 |
| Not specified | 12/28 (42.9) | 44/178 (24.7) | 0.08 |
| Histopathological requirement for inclusion | 0.57 | ||
| NET | 14/16 (87.5) | 111/134 (82.8) | |
| NEN with certain Ki-67 index | 0 (0.0) | 11/134 (8.2) | |
| NEC | 2/16 (12.5) | 12/134 (9.0) | |
aAll missing values were excluded from analysis, and the different denominators were the number of trials with available data of different variables; bThe P values of categorical variables were calculated using chi-squared test or Fisher’s exact test if indicated; the P values of continuous variables were calculated using the Wilcoxon rank sum test.
DMC, data monitoring committee; GEP-NEN, gastroenteropancreatic neuroendocrine neoplasm; IQR, interquartile range; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; NIH, National Institute of Health.
Ongoing GEP-NEN trials
Ongoing GEP-NEN drug trials
Among the 107 ongoing trials, 93 investigated drugs with a tumor growth control purpose. Targeted therapy was the most investigated drug (40.9%), followed by PRRT (31.2%), chemotherapy (25.8%), SSA (15.1%) and immune checkpoint inhibitors (ICI) (14.0%) (Fig. 3A). Different tumor grade eligibility criteria were adopted in these trials (Supplementary Table 4). In brief, 68 trials exclusively included NETs, nine trials included NENs with certain Ki-67 index, and seven trials exclusively investigated NECs. Targeted therapy and PRRT were the most investigated drugs in NETs (Fig. 3B), while chemotherapy trials accounted for the largest proportion of NEN and NEC trials (Fig. 3C and D).
The distribution of drug mechanisms in ongoing (A) GEP-NEN trials (n = 93); (B) GEP-NET trials (n = 68); (C) GEP-NEN trials with certain Ki-67 index (n = 9); (D) ongoing GEP-NEC trials (n = 7). The sum of each treatment strategy may exceed the total number of clinical trials because one trial can evaluate more than one treatment strategy. GEP, gastroenteropancreatic; ICI, immune checkpoint inhibitor; NEC, neuroendocrine carcinoma; NEN, neuroendocrine neoplasm; NET, neuroendocrine tumor; SSA, somatostatin analog; PRRT, peptide radionuclide receptor therapy.
Citation: Endocrine Connections 12, 4; 10.1530/EC-22-0441
We further analyzed the mechanisms of targeted drugs evaluated in ongoing trials (Fig. 4). Multitarget TKIs were most frequently investigated (15 (35.7%)), followed by mTOR inhibitors (8 (19%)), poly ADP-ribose polymerase (PARP) inhibitors (3 (7.1%)), and vascular endothelial growth factor targeted drugs (3 (7.1%)). Other targeted therapies, including cyclin-dependent kinase inhibitors, hypoxia-activated prodrugs, histone deacetylase inhibitors, were also being actively evaluated (Supplementary Table 5).
The distribution of targeted therapies in ongoing GEP-NEN trials (n = 38). The sum of each treatment strategy may exceed the total number of clinical trials because one trial can evaluate more than one treatment strategy. bsAb, bispecific antibody; CDK, cyclin-dependent kinase; DNA-PK, DNA-activated protein kinase; G6PD, glucose-6-phosphate dehydrogenase; GEP, gastroenteropancreatic; HDAC, histone deacetylase; HIF, hypoxia-inducible factor; mTOR, mammalian target of rapamycin; NEN, neuroendocrine neoplasm; SSTR, somatostatin receptor; PARP, poly-ADP-ribose polymerase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
Citation: Endocrine Connections 12, 4; 10.1530/EC-22-0441
Combination strategies were investigated in 54 ongoing trials (Fig. 5). Chemotherapy (n = 25) and targeted therapy (n = 24) were commonly evaluated as combinatorial regimens. Combination chemotherapy (n = 14), chemotherapy combined with targeted therapy (n = 5), and targeted therapy combined with PRRT (n = 5) were most frequently investigated strategies (Supplementary Table 6).
The distribution of combination strategies in ongoing GEP-NEN trials (n = 54) This figure demonstrates the distribution of combination strategies. Different treatment regimens are arranged around the outer circle and distinguished by different colors. The absolute number of different treatment regimens is indicated by their proportion of the outer circle. The combination strategies are shown as paths emerging from one side of the outer circle to another side. The width of certain path indicated the number of certain combination strategy investigated in ongoing trials. GEP, gastroenteropancreatic; NEN, neuroendocrine neoplasm; SSA, somatostatin analog; PRRT, peptide radionuclide receptor therapy.
Citation: Endocrine Connections 12, 4; 10.1530/EC-22-0441
Ongoing GEP-NEN diagnostic trials
There were 14 ongoing trials with a diagnostic purpose. In addition to trials that investigated established functional imaging tracers such as 68Ga-DOTA-D-Phel-Tyr3-octreotate, seven trials investigated novel imaging tracers (Supplementary Table 7). Three trials investigated novel radioactive isotopes with peptide bound to somatostatin receptor 2 (SSTR2), which included one trial that evaluated the alpha-emitter theranostics pair 203Pb/212Pb. Four trials investigated tracers binding to targets other than SSTR2.
Result reporting status of GEP-NEN trials
We included 87 trials in result reporting analysis. At a median follow-up of 48.7 months (95% confidential interval (CI), 37.6–64.9), 36 trials (41.4%) reported results (Fig. 6A). Among them, 27 trials (31.0%) posted results on ClinicalTrials.gov, and 21 trials (24.1%) reported results as publications. The median time from trial primary completion to result reporting was 101 months (95% CI, 37.8-NA). Thirteen trials (14.9%) reported results within 12 months of primary completion, and 28 trials (28/77 (36.3%)) reported results within 24 months of primary completion. Characteristics that positively associated with result reporting included sample size larger than 50, blind design in randomized trials, industry sponsorship, multicenter participation, multinational participation, tumor differentiation requirement in eligibility criteria, and PFS as the primary endpoint (all P < 0.05) (Fig. 6B, C, D, E, F, G and H).
The cumulative result reporting rate of GEP-NEN trials (A) anticipated to be primary completed by December 31, 2020; (B) sample size; (C) blind design; (D) lead sponsor; (E) number of participating centers; (F) region; (G) tumor differentiation requirement in eligibility criteria; (H) PFS as the primary endpoint. GEP-NEN, gastroenteropancreatic neuroendocrine neoplasm; NIH, National Institute of Health; PFS, progression-free survival.
Citation: Endocrine Connections 12, 4; 10.1530/EC-22-0441
Discussion
This study comprehensively illustrates the current status and chronological changes of all registered GEP-NEN clinical trials in the past two decades. Most clinical trials focused on systemic treatment of GEP-NENs, and the number of diagnostic trials increased significantly in the last decade. Current ongoing trials are exploring novel imaging tracers and drug targets. A key advance in the design of GEP-NEN trials is histopathological specification in trial eligibility criteria. However, there are still concerns in the unbalanced geographical distribution, the small sample size, and the low result reporting rate of GEP-NEN trials.
Our study reveals the substantial progress in the diagnosis and treatment of GEP-NENs in the last two decades. The diagnostic trials showed a significant increase between 2012 and 2021, accounting for 14.6% of the total trials in this period. Most trials evaluated the diagnostic value of radiolabeled imaging tracers in functional imaging such as PET/CT and SPECT/CT, which could be attributed to the fact that NETs uniquely express SSTR and other proteins based on their biological origins. Consequently, the SSTR-based PET imaging has been extensively evaluated for the diagnostic efficacy and was recommended as the standard procedure in the diagnosis and evaluation of NENs (27, 28). The advancements of NEN diagnostic techniques may also contribute to the rising incidence of NENs (3). Since SSTR-based PET imaging has established its position in NEN diagnosis, ongoing diagnostic trials focus on novel imaging targets based on the biological functions of GEP-NENs, such as targeting the glucagon-like peptide 1 receptor to detect insulinoma (NCT04185350), and novel radioactive isotopes, such as the alpha-emitter theranostics pair 203Pb/212Pb (NCT05111509).
The number of newly initiated trials of GEP-NENs has increased steadily and remained stable in the last 4 years, and most trials focused on systemic drug treatment. Targeted therapy and PRRT were the major milestones of systemic GEP-NEN treatment in the last decade and are still being intensively investigated in ongoing trials (8, 9, 10, 11, 14, 15). The development of effective treatment strategies requires comprehensive understanding of tumor biology. In the past two decades, there have been advancements in the research on the oncogenesis and the immune microenvironment of GEP-NENs. NETs and NECs are regarded as different entities with distinct molecular landscape, and GEP-NETs of different grades also have different immune microenvironment (29, 30, 31, 32, 33). In addition to the multitarget TKIs and mTOR inhibitors with established efficacy in GEP-NENs, several novel targets are being evaluated in ongoing trials, and the results are worth expecting.
A key advance in the design of GEP-NEN trials is the specification of the trial eligibility criteria. The classification system of GEP-NENs has greatly changed during the past two decades (5). Based on the evolving understanding of NENs, the NCI has made key recommendations on the design of NEN clinical trials in 2011, one of which was that trials should investigate NETs and NECs separately (16). In our analysis, a significantly higher proportion of trials specified the Ki-67 index in the eligibility criteria after 2011, and the proportion of trials that investigated histopathologically non-selected GEP-NENs decreased. In ongoing GEP-NEN trials, well-differentiated NETs and poorly differentiated NECs are investigated separately and treated with drugs of different mechanisms. A previous study analyzing all phase 2–3 NEN trials reported the same trend (18). These changes ultimately reflect the advances in the understanding of the biological heterogeneity of GEP-NENs. Tumors with different Ki-67 index and differentiation status are acknowledged as different biological entities and should be treated differently (29, 30). Nevertheless, our results have also showed that a proportion of ongoing trials only specified the Ki-67 index of NENs rather than the differentiation status. In addition, the concept of MiNEN tumors has aroused concerns in the past two decades (34). Clinical-pathological features of MiNEN tumors originating from digestive system have been reported, which suggested their pathogenesis and management strategies could be different from NENs (35, 36). However, our analysis showed that only a small proportion of GEP-NEN trials have specified MiNEN status in their inclusion criteria. Therefore, the eligibility criteria of GEP-NEN trials should be further refined to reduce potential bias due to participant heterogeneity in clinical trials and help to gain more clinically meaningful results.
Our study highlights several concerns that should be addressed for future GEP-NEN trials. First, the geographic distribution of GEP-NEN trials is unbalanced. Although the number of trials conducted in other regions of the world significantly increased in the last decade, high-income countries located in Northern America and Europe region still dominated the clinical research of GEP-NENs. Although the global epidemiological statistics for GEP-NENs remains incomplete, it is likely that the distribution of GEP-NEN trials does not match the disease burden of each region and that of each ethnicity. Patients from certain regions, especially the lower-middle-income countries, are underrepresented in clinical trials, and the results of these trials may lack generalizability to non-Caucasian populations. This disparity was also reported in analyses of clinical trials of other malignancies (37, 38).
Second, the scale of most GEP-NEN trials restricts acquisition of high-level evidence. Most GEP-NEN trials were single-arm trials with small sample sizes. A previous study addressed the same issue and suggested that the limited clinical benefit of systemic therapies for GEP-NETs was associated with the insufficient enrollment in clinical trials (17). This fact may be attributed to the relatively low incidence of GEP-NENs. In addition, only a small proportion of trials were sponsored by industry, NIH, or other governments and networks. The dominance of individual investigators and institutions may also result in small trials. Our analysis revealed that multinational trials had significantly larger sample sizes. Thus, promoting government sponsorship and international collaborations in clinical trials may help to solve this issue.
Third, the result reporting rate of GEP-NEN trials is low, and there is a long time from primary completion to result dissemination. A previous study reported a result reporting rate of 60.7% for all oncology trials (26). The FDAAA of 2007 required sponsors of applicable trials to report results on ClinicalTrials.gov within 1 year of completion (25). The result reporting status of GEP-NEN trials showed poor compliance with the current regulation. Timely result dissemination of clinical trials can reduce redundant research and avoid unnecessary interventions to patients. This is extremely important for the research of GEP-NENs because of the rarity of the malignancy and the long implementation period of clinical trials. Future regulations and enforcement are required to enhance timely result dissemination of GEP-NEN trials.
This study has several limitations. First, NETs and NECs are biologically distinct entities, so including all GEP-NEN trials in this study may introduce heterogeneity and complicate the interpretation of result. However, the classification system of GEP-NENs has been continuously evolving during the past two decades, and our analysis showed that a large proportion of trials did not clarify tumor differentiation or grade in inclusion criteria, which made it difficult to fully separate trials of NETs from NECs. To reduce potential confounding, we separately analyzed ongoing trials of NETs, NENs with certain Ki-67 index, and NECs. Second, we only analyzed trials registered on ClinicalTrials.gov, and clinical trials registered on other platforms were not included. Nevertheless, ClinicalTrials.gov contained more than 80% of all clinical studies in the WHO portal according to previous studies, so we assume this analysis still covered most GEP-NEN trials around the world (23). Third, the ClinicalTrials.gov only serves as a registration platform, which cannot confirm the information integrity and timely update of each trial. Although we manually collected and checked the eligibility, intervention, and publication details of included trials, the missing values could lead to potential bias in data interpretation. Fourth, the results reporting status of analyzed trials may be underestimated, because we used the NCT identifier to search relevant publications. The articles could not be identified if they did not include the identifier in the abstract.
In conclusion, this cross-sectional study comprehensively illustrated the current status and chronological changes of clinical trials in GEP-NENs over the past two decades. Much progress has been made in the diagnosis and systemic treatment of GEP-NENs, and ongoing trials are investigating novel imaging tracers and drug targets. The eligibility criteria of GEP-NEN trials have been refined to focus on more specific patient group. Concerns that should be addressed included unbalanced geographical distribution, small sample size, and low result reporting rate of GEP-NEN trials. More efforts are needed to improve the understanding of the molecular biology of GEP-NENs, promote government sponsorship and international collaborations in clinical trials, and enhance timely result dissemination of studies.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-22-0441.
Conflict of interest
The authors declare no competing interests.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
Conceptualization: JRL, KLY, CMB, YJC; Data curation: KLY, JRL; Original draft writing: KLY; Manuscript review and editing: JRL, KLY, YJC, CMB.
Data availability statement
The data underlying this article will be shared on reasonable request to the corresponding author.
Compliance with ethics guidelines
This study was exempt from formal institutional board review because of its retrospective design and deidentified data.
Acknowledgement
None.
References
- 1↑
Cives M, Strosberg JR. Gastroenteropancreatic neuroendocrine tumors. CA: a Cancer Journal for Clinicians 2018 68 471–487. (https://doi.org/10.3322/caac.21493)
- 2↑
Xu Z, Wang L, Dai S, Chen M, Li F, Sun J, Luo F. Epidemiologic trends of and factors associated with overall survival for patients with gastroenteropancreatic neuroendocrine tumors in the United States. JAMA Network Open 2021 4 e2124750. (https://doi.org/10.1001/jamanetworkopen.2021.24750)
- 3↑
Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T, Yao JC. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncology 2017 3 1335–1342. (https://doi.org/10.1001/jamaoncol.2017.0589)
- 4↑
Rindi G, Inzani F. Neuroendocrine neoplasm update: toward universal nomenclature. Endocrine-Related Cancer 2020 27 R211–R218. (https://doi.org/10.1530/ERC-20-0036)
- 5↑
Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, Ezzat S, de Herder WW, Klimstra DS & Papotti M et al.Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocrine Pathology 2022 33 115–154. (https://doi.org/10.1007/s12022-022-09708-2)
- 6↑
Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015 121 589–597. (https://doi.org/10.1002/cncr.29099)
- 7↑
Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, Dueland S, Hofsli E, Guren MG & Ohrling K et al.Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the Nordic NEC study. Annals of Oncology 2013 24 152–160. (https://doi.org/10.1093/annonc/mds276)
- 8↑
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D & Vinik A et al.Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine 2011 364 501–513. (https://doi.org/10.1056/NEJMoa1003825)
- 9↑
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J & de Vries EG et al.Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine 2011 364 514–523. (https://doi.org/10.1056/NEJMoa1009290)
- 10↑
Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H & Voi M et al.Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016 387 968–977. (https://doi.org/10.1016/S0140-6736(1500817-X)
- 11↑
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH & Jacene H et al.Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine 2017 376 125–135. (https://doi.org/10.1056/nejmoa1607427)
- 12↑
Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF & Bläker M et al.Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of Clinical Oncology 2009 27 4656–4663. (https://doi.org/10.1200/JCO.2009.22.8510)
- 13↑
Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J & Wall L et al.Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 2014 371 224–233. (https://doi.org/10.1056/NEJMoa1316158)
- 14↑
Xu J, Shen L, Bai C, Wang W, Li J, Yu X, Li Z, Li E, Yuan X & Chi Y et al.Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. Oncology 2020 21 1489–1499. (https://doi.org/10.1016/S1470-2045(2030493-9)
- 15↑
Xu J, Shen L, Zhou Z, Li J, Bai C, Chi Y, Li Z, Xu N, Li E & Liu T et al.Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. Oncology 2020 21 1500–1512. (https://doi.org/10.1016/S1470-2045(2030496-4)
- 16↑
Kulke MH, Siu LL, Tepper JE, Fisher G, Jaffe D, Haller DG, Ellis LM, Benedetti JK, Bergsland EK & Hobday TJ et al.Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute neuroendocrine tumor clinical trials planning meeting. Journal of Clinical Oncology 2011 29 934–943. (https://doi.org/10.1200/JCO.2010.33.2056)
- 17↑
de Hosson LD, van Veenendaal LM, Schuller Y, Zandee WT, de Herder WW, Tesselaar MET, Klümpen HJ, Walenkamp AME. Clinical benefit of systemic treatment in patients with advanced pancreatic and gastrointestinal neuroendocrine tumours according to ESMO-MCBS and ASCO framework. Annals of Oncology 2017 28 3022–3027. (https://doi.org/10.1093/annonc/mdx547)
- 18↑
Das S, Du L, Lee CL, Arhin ND, Chan JA, Kohn EC, Halperin DM, Berlin J, LaFerriere H & Singh S et al.Comparison of design, eligibility, and outcomes of neuroendocrine neoplasm trials initiated from 2000 to 2009 vs 2010 to 2020. JAMA Network Open 2021 4 e2131744. (https://doi.org/10.1001/jamanetworkopen.2021.31744)
- 19↑
Hunter KE, Webster AC, Page MJ, Willson M, McDonald S, Berber S, Skeers P, Tan-Koay AG, Parkhill A, Seidler AL. Searching clinical trials registers: guide for systematic reviewers. BMJ 2022 377 e068791. (https://doi.org/10.1136/bmj-2021-068791)
- 20↑
Chen R, Desai NR, Ross JS, Zhang W, Chau KH, Wayda B, Murugiah K, Lu DY, Mittal A, Krumholz HM. Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers. BMJ 2016 352 i637. (https://doi.org/10.1136/bmj.i637)
- 21↑
von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP & STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLOS Medicine 2007 4 e296. (https://doi.org/10.1371/journal.pmed.0040296)
- 22↑
Tasneem A, Aberle L, Ananth H, Chakraborty S, Chiswell K, McCourt BJ, Pietrobon R. The database for aggregate analysis of Clinicaltrials.Gov (AACT) and subsequent regrouping by clinical specialty. PLoS One 2012 7 e33677. (https://doi.org/10.1371/journal.pone.0033677)
- 23↑
Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, Tasneem A. Characteristics of clinical trials registered in ClinicalTrials.gov, 2007–2010. JAMA 2012 307 1838–1847. (https://doi.org/10.1001/jama.2012.3424)
- 24↑
The World Bank. World Bank Country and Lending Groups. Washington, DC, USA: The World Bank Group. (available at: https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups)
- 25↑
DeVito NJ, Bacon S, Goldacre B. Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study. Lancet 2020 395 361–369. (https://doi.org/10.1016/S0140-6736(1933220-9)
- 26↑
Liu X, Zhang Y, Li WF, Vokes E, Sun Y, Le QT, Ma J. Evaluation of oncology trial results reporting over a 10-year period. JAMA Network Open 2021 4 e2110438. (https://doi.org/10.1001/jamanetworkopen.2021.10438)
- 27↑
Shah MH, Goldner WS, Benson AB, Bergsland E, Blaszkowsky LS, Brock P, Chan J, Das S, Dickson PV & Fanta P et al. Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network 2021 19 839–868. (https://doi.org/10.6004/jnccn.2021.0032)
- 28↑
Sadowski SM, Neychev V, Millo C, Shih J, Nilubol N, Herscovitch P, Pacak K, Marx SJ, Kebebew E. Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. Journal of Clinical Oncology 2016 34 588–596. (https://doi.org/10.1200/JCO.2015.64.0987)
- 29↑
Zhang WH, Wang WQ, Gao HL, Yu XJ, Liu L. The tumor immune microenvironment in gastroenteropancreatic neuroendocrine neoplasms. Biochimica et Biophysica Acta. Reviews on Cancer 2019 1872 188311. (https://doi.org/10.1016/j.bbcan.2019.188311)
- 30↑
Rindi G, Wiedenmann B. Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine. Nature Reviews. Endocrinology 2020 16 590–607. (https://doi.org/10.1038/s41574-020-0391-3)
- 31↑
Frizziero M, Kilgour E, Simpson KL, Rothwell DG, Moore DA, Frese KK, Galvin M, Lamarca A, Hubner RA & Valle JW et al.Expanding therapeutic opportunities for extra-pulmonary neuroendocrine carcinoma. Clinical Cancer Research 2022 28 1999–2019. (https://doi.org/10.1158/1078-0432.CCR-21-3058)
- 32↑
Shi M, Fan Z, Xu J, Yang J, Li Y, Gao C, Su P, Wang X, Zhan H. Gastroenteropancreatic neuroendocrine neoplasms G3: novel insights and unmet needs. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer 2021 1876 188637. (https://doi.org/10.1016/j.bbcan.2021.188637)
- 33↑
Balanis NG, Sheu KM, Esedebe FN, Patel SJ, Smith BA, Park JW, Alhani S, Gomperts BN, Huang J & Witte ON et al.Pan-cancer convergence to a small-cell neuroendocrine phenotype that shares susceptibilities with hematological malignancies. Cancer Cell 2019 36 17–34.e7. (https://doi.org/10.1016/j.ccell.2019.06.005)
- 34↑
La Rosa S, Sessa F, Uccella S. Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocrine Pathology 2016 27 284–311. (https://doi.org/10.1007/s12022-016-9432-9)
- 35↑
de Mestier L, Cros J, Neuzillet C, Hentic O, Egal A, Muller N, Bouché O, Cadiot G, Ruszniewski P & Couvelard A et al.Digestive system mixed neuroendocrine-non-neuroendocrine neoplasms. Neuroendocrinology 2017 105 412–425. (https://doi.org/10.1159/000475527)
- 36↑
La Rosa S Challenges in high-grade neuroendocrine neoplasms and mixed neuroendocrine/non-neuroendocrine neoplasms. Endocrine Pathology 2021 32 245–257. (https://doi.org/10.1007/s12022-021-09676-z)
- 37↑
Trapani D, Curigliano G, Alexandru E, Sternberg CN. The global landscape of drug development for kidney cancer. Cancer Treatment Reviews 2020 89 102061. (https://doi.org/10.1016/j.ctrv.2020.102061)
- 38↑
Wells JC, Sharma S, Del Paggio JC, Hopman WM, Gyawali B, Mukherji D, Hammad N, Pramesh CS, Aggarwal A & Sullivan R et al.An analysis of contemporary oncology randomized clinical trials from low/middle-income vs high-income countries. JAMA Oncology 2021 7 379–385. (https://doi.org/10.1001/jamaoncol.2020.7478)
