GEP-NEC is a distinctive part of neuroendocrine neoplasm and has prognosis different from gastrointestinal neuroendocrine tumor and other cancer. Because of the rarity of GEP-NEC, there are few data on the clinicopathological characteristics and prognosis of GEP-NEC. It is still an unsolved challenge for clinicians to make prognostic stratifications and predict the survival outcome of GEP-NEC. As far as we know, nomogram models have been applied to predict the survival status of various tumors and show better predictive value compared with other traditional staging systems. However, there are no nomograms that quantify and visualize risk by various prognostic factors to predict the prognosis of GEP-NEC.
In our study, a total of 887 GEP-NEC patients from the SEER database were analyzed. Age, sex, N stage, tumor size, primary tumor resection, radiotherapy and chemotherapy were independent prognostic factors of OS in GEP-NEC patients. The nomogram was built based on these prognostic factors and was used to predict the 1-year and 2-year survival rates in GEP-NEC patients. The nomogram showed better predictive performance than the TNM staging system for OS both in the training and validation cohorts.
Patients with GEP-NEC had a poor prognosis with a median OS of 10 months. 1- and 2-year survival rates were 43.9% and 27.1%, respectively. Even for patients with localized disease treated with surgery, long-term survival was short, at 22 months, suggesting that micrometastases may have been present at diagnosis. According to our nomogram, patients with the higher age or larger tumor size would likely have poorer prognosis. Sex was associated with survival as a prognostic factor. The nomogram also illustrates that patients with lymph node metastases are more likely to die than N0 stage patients. N stage contributed significantly to the prognosis prediction of GEP-NEC patients which may have the potential to help identify high-risk individuals for treatment enhancement. That was generally consistent with what Erstad et al found, that a high positive lymph node ratio (LNR) was described as a prognostic marker associated with an increased risk of death in rectal NEC[5]. Taken together, some of these variables have been reported as predictive factors for gastric NEC patients in previous studies[6, 7]. Interestingly, the traditional T stage and M stage failed to show independent prognostic significance.
Whether patients can benefit from surgery was still controversial and patients needed to be carefully evaluated[8]. The European Neuroendocrine Tumor Society (ENETS) consensus published in 2023 and National Comprehensive Cancer Network (NCCN) guidelines (version 2.2022) both assumed that curative surgery is usually recommended in localized diseases and surgical resection of metastases is not recommended in advanced metastatic disease[9, 10]. On the contrary, the European Society for Medical Oncology (ESMO) and the North American Neuroendocrine Tumor Society (NANETS) consensus published in 2020 both suggested that patients with poorly differentiated NEC should not undergo resection because of the extremely poor prognosis that does not seem to be affected by surgical resection[11, 12]. A study that included poorly differentiated colorectal NEC found that primary tumor resection was not associated with survival in localized or metastatic disease[13]. A study that included 49 pancreatic NEC patients observed that patients who underwent surgery had longer OS than those who did not (16 months vs. 9.6 months), but the difference was not significant[14]. In our study, the nomogram suggested primary tumor resection as a protective factor for patients with GEP-NEC. In subgroup analysis, median OS was observed for up to 22 months in patients with localized disease who underwent surgery. In the entire GEP-NEC cohort, primary tumor resection significantly prolonged OS, although the median OS was short with only 14 months and 7 months for patients who received surgery and patients who didn’t (P < 0.001). This was generally consistent with the results of a retrospective study that included 1,861 gastrointestinal NEC patients, which reported a median OS of 13.3 months for patients who underwent surgery[15]. A recent study based on the SEER database also showed that primary tumor resection may prolong survival in patients with gastrointestinal NEC with bone metastases[16]. Although this study may include NET G3 patients. As increased molecular pathology information becomes available, it is necessary to manage NEC patients as distinct patient groups and assess the benefits of surgery.
Chemotherapy is the mainstay of treatment for localized NEC and advanced disease. Clinically, platinum-based chemotherapy is the main treatment option. First-line chemotherapy regimens include platinum/etoposide or cisplatin/etoposide regimens[17, 18]. Our nomogram showed a significant impact of chemotherapy in the prediction of survival outcomes. For patients after radical surgery, adjuvant therapy is still recommended due to the high recurrence rate after radical surgery[3]. Our subgroup analysis showed that in postoperative patients, median OS was prolonged by 8 months in patients who received adjuvant chemotherapy compared to patients who did not (16 months vs. 8 months). In addition, for patients with advanced disease, previous studies found that palliative chemotherapy significantly prolongs survival in GEP-NEC patients with median OS of approximately 11–12 months[15, 19–23]; however, some of the studies do not distinguish between NEC and NET G3. As was shown in our study, the median OS in GEP-NEC patients receiving and not receiving palliative chemotherapy was 9 months and 2 months, respectively.
Collectively, our nomogram suggested that both surgery and chemotherapy were protective prognostic factors. As a recent database-based study of rectal NEC found, the combination of radical surgery and chemotherapy was associated with a higher survival rate compared to surgery or chemotherapy alone[5]. Therefore, surgery plus chemotherapy may be the preferred approach for early-stage patients, and patients should be carefully selected.
ENETS consensus also indicated that course of radiation and chemotherapy is a reasonable treatment strategy for patients with specific comorbidities or specific tumor anatomical sites where surgery is not advisable (i.e., esophagus)[3]. That suggestion was consistent in our study that our nomogram indicated that survival rate of GEP-NEC patients who received radiotherapy was higher than that of patients who didn’t. It was interesting to note that we did not find neoadjuvant chemotherapy was an significant independent prognostic variable in GEP-NEC cohort, although the small sample size was insufficiently powered. This was consistent with the results of a recent retrospective study of rectal NEC[5]. While Ma et al. found that gastric NEC/ mixed adeneuroendocrine carcinoma (MANEC) patients treated with neoadjuvant chemotherapy had better survival than patients who had surgery first (3-year OS rate 68.8% vs. 43.8%, 5-year OS rate 57.4% vs. 28.5%, respectively). Multivariate analyses also showed that neoadjuvant chemotherapy was an independent factor affecting OS[24]. Another study found a better OS in patients who received neoadjuvant therapy and this gastrointestinal NEC cohort had a high proportion of margin-positive resection, thus suggesting that neoadjuvant therapy may have a stage-reducing effect[15]. It would be worthwhile to increase the sample size to further explore the prognostic impact of neoadjuvant chemotherapy in GEP-NEC patients.
Although tumor site was not an independent predictor in our model, Kaplan-Meier survival curves illustrated that prognosis tended to differ by primary tumor site. Patients with colon, esophageal and rectal primaries had worse survival compared to other primaries. That is generally consistent with the results of some large European series[19]. In addition, histology (large cell NEC vs. small cell NEC) appears to be a prognostic factor in some studies. Previous studies reported that the median survival and 5-year survival rate with large cell NEC were better than that of the patients with small cell NEC (16 months vs. 6 months, 32% vs. 6%), but the statistical significance of the differences remains controversial[1, 25]. In our data, specific histological classifications were mostly missing and therefore insufficient to explore their prognostic impact. The future development of genetic molecular markers with prognostic implications in the field of NEC would be promising[26].
We used C-index, ROC, calibration plots, DCA and IDI for internal validation and model comparison. For NEC, the TNM staging system of adenocarcinoma is now commonly applied[11]. The model validation showed that the nomogram exhibited better survival predictive ability than that of the TNM staging system. The nomogram proved to have an excellent ability of discrimination with higher C-index and AUC of ROC curve in nomogram than TNM staging system. The calibration plots of the nomogram demonstrated a strong agreement between the predicted survival probability and the actual survival rate. Furthermore, the nomogram was demonstrated to be clinically useful compared with the TNM staging system through DCA. IDI indicated a significant overall improvement of the nomogram compared with the TNM staging system.
There are several limitations to this study. Firstly, gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) has undergone many changes in terminology and classification over the past decade, and high-quality data on GEP-NEC are often not available in registries. In this regard, we excluded the NET data and our nomogram was able to specifically predict the prognosis of the poorly-differentiated GEP-NEC population. Secondly, the study is lacking some important information to support the analysis of the impact of the variables, such as Ki-67, carcinoembryonic antigen (CEA), lactate dehydrogenase, thrombocyte level and neutrophil-to-lymphocyte ratio, which were considered to be predictive factors for NEC patients[27]. Additional variables associated with the prognosis of GEP-NEC need to be included to further improve the predictive value of the model. Thirdly, detailed information about systemic therapy was not provided in the SEER database, for example, chemotherapy regimens were unknown. Results from the recent TOPIC-NEC phase 3 randomized clinical trial showed no statistically significant differences in OS between the etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) groups in advanced high grade NEN of the digestive system. Notably, subgroup analysis showed that EP produced a more favorable OS in patients with pancreatic primary[22]. A previous phase 2 clinical trial also confirmed similar efficacy for EP and IP regimens. In addition, the study found that IP was slightly more effective than EP in patients with non-small cell NEC[23]. The prognostic impact of systemic treatment options including immunotherapy and whether to divide GEP-NEC into different entities are the next important clinical issues. Despite such limitations, our prognostic nomogram model proved to be an instructive and practical model to accurately predict individual outcomes in GEP-NEC patients.