Population-based analysis provide a fighting chance to improve our interpretations of this kind of rare malignancy due to the lack of prospective study in CRNECs. Using the SEER cancer registry, a total of 251 patients met the inclusion criteria, of which, 152 patients (60.56%) received AC. With propensity score-matched techniques, the analysis gave a robust conclusion by reducing the selection bias and improving the validity. We demonstrated that AC was invalid for improved CSS in patients with nonmetastatic CRNECs regardless of tumor stages. To the best of our knowledge, it is the first study with more than 250 patients to provide evidence to reject AC for patients with resectable CRNECs. Of interest, patients with left-sided CRNECs may had a poorer prognosis compared to those with right-sided disease, although it failed to reach a statistic significance (HR, 1.614; 95% CI, 0.992–2.235; P = 0.054). In addition, our findings demonstrated that current N classification was not a significant predictor of patient survival. Multivariate analyses explored the revised Nr classification, based on LNR of 0.30 and 0.75 as cutoff value (Nr0: LNR≤0.30; Nr1: 0.3 < LNR≤0.75; Nr2: LNR > 0.75), as an independent prognostic factor. With the foundation of revised Nr classification, a revised TNrM was proposed for nonmetastatic CRNEC: stage I (T1–2Nr0), stage II (T1-2Nr1 or T3Nr0–1 or T4Nr0), and stage III (TxNr2 or T4Nr1). TNrM stage had better stratification according to Kaplan-Meier survival curves (P < 0.001).
In the present study, we found that the age of 60 (P = 0.848) and number of 12 of resected regional lymph nodes (P = 0.082) acted as an optimal cutoff value in terms of survival, failing to reach a statistic significance. It is well known that resection of more than 12 lymph nodes is associated with better prognosis in common colorectal carcinoma besides its pivotal role in accurate staging[11, 12], however it failed to reach a significance in CRNECs, which consisted of small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. As an important indicator of treatment quality and therapeutic implications in early-stage patients, total LN yield in colon cancer resection specimens is influenced critically by extent of surgical resection and the following pathological evaluation, and a low LN yield in a resection specimen may indicate an inadequate surgical resection or unsatisfactory pathological examination[12, 13]. Better survival may be achieved even in patients with positive LN in case of a higher number of recovered nodes. Alternatively, a low LN yield may also be a reflection of a unique biological characteristics of the tumors such as the MSI phenotype, instead of the situation mentioned above. Despite of the lack of a statistic significance, number of more than 12 of resected regional LN was associated with a better survival, showing in Fig. 3A, and further validation should be organized in the future in a larger sample of patients.
Incidence of NECs is rare, with a poor prognosis and commonly arising in the esophagus and large bowel, approximately 1000 cases annually. As the most common site of extrapulmonary NECs with an increasing incidence, gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs) represents less than 1% of all GI malignancies[1, 9, 16], with about 7% in the pancreas, and about to 40% in the colon[1, 8, 17]. Poorly differentiated neuroendocrine carcinomas, reflected by the number of mitoses or the Ki-67–positive fraction of > 20%, are distinguished into large or small cells in 2010 WHO classification[3, 4]. High-grade neuroendocrine carcinomas (HGNECs) are characterized by a high mitotic rate and a worse prognosis than common neuroendocrine tumors, and show neuro-endocrine marker expression, such as synaptophysin or chromogranin A. Despite of an increase in the incidence over recent years, CRNECs is still a rare and aggressive type of malignancy of dismal prognosis[2, 8, 17], less than 1% of colorectal carcinomas[2, 7]. Many studies illustrated a poorer prognosis of colorectal compared to pancreatic NEC, despite of the similar response to chemotherapy[22, 23]. Still, many HGNECs patients were present with advanced- or late-stage disease, approximately 50% of the NEC patients with synchronous metastatic disease[5, 24], due to the lack of early symptoms, and there is a lack of the optimal treatment HGNECs of the colon and rectum.
NECs is quite another malignancy, and it did not benefit from improvement achieved in colorectal carcinoma over the past decade[20, 24]. The majority of published data regarding chemotherapy for NECs is derived from patients with advanced disease. Evidence to support clinical managements for CRNEC is scarce. Due to the rarity of CRNEC and the resulting difficulty to accumulate a large cohort for evaluation, there are few retrospective studies and almost no prospective studies to evaluate its prognostic value of AC, resulting in the fact that, due to the histological and clinical resemblance, treatment is more likely in analogy to the much more common SCLC[1, 20], with platinum-based chemotherapy as a cornerstone. In clinical practice, relevant features addressing the optimal management strategy of NECs consists of clinical behavior, mitoses, Ki-67 expression, morphology and so on. Bearing the high relapse rate following radical surgery in mind, platinum-based AC in this setting would be advocated, although it was not supported by sufficient evidence, with no randomized studies ever addressing the effect. The 5-year overall survival (OS) rate varied from 50.1–54.5% for patients with localized disease, compared to 20.0–29.2% for patients with regional disease, and the best treatment strategy for patients with nonmetastatic CRNECs remains controversial. Many CRNEC patients recurred rapidly after surgery, implying a role for adjuvant chemotherapy[8, 20]. One retrospective study including 132 patients with nonmetastatic CRNECs received operation treatment from the SEER database that has compared AC versus observation for CRNECs, demonstrated that no significant improvement in survival achieved for patients receiving AC compared with those with observation, despite of the different regimens selected for chemotherapy. Although it was in correspondence with our findings, this conclusion may be limited due to the small sample of patients, so we enrolled more patients to further confirm it. The present study demonstrated that AC was invalid for improved CSS in patients with nonmetastatic CRNECs regardless of tumor stages. Furthermore, it was notable that the 5-year survival (37%) for patients undergoing both radical surgery and adjuvant chemotherapy remains low, similar to that for the same cohort undergoing surgery alone, at 32%, implying the limited benefit of adjuvant chemotherapy. Differentiation and Ki-67 is able to determine prognostic groups[1, 26]. A multicenter, retrospective study identified higher objective response but poorer survival associated with higher Ki-67 index whose cut-off was 55% (P < 0.001) [5, 23, 27], coming to the conclusion that NEC with Ki-67 > 55% may benefit from combination therapies. There are no studies with satisfactory inclusion evaluating the efficacy of adjuvant chemotherapy in patients with CRNECs. Notably, we first assessed the efficacy of AC in nonmetastatic CRNEC of large, small cell patients and precisely diagnosed CRNECs. In our study, only 152 patients (60.56%) received AC, suggesting a poor compliance with the guidelines, one major reason for which is probably attributed to a lack of consensus regarding the role of adjuvant therapy, as no evidence supporting the efficacy of AC existed.
Our study went further to validate the prognostic effects of current T and N classification to advocate a more tailored TNM staging system. With the population-based analysis, our result surprisingly demonstrated that both the current N classification and the T classification failed to precisely predict the CSS, which was in correspondence with the conclusion from study of Wu Z et al. We suggest that the LNR-based Nr classification is more useful in the CRNECs staging system than the current N classification system consulted to that of common colorectal carcinoma. LNR-based classification has been proved to be helpful in terms of the breast, stomach, colorectum and so on. Based on the number of positive LNs, the classic N classification can be affected by the LNs yield, which may be influenced by the extent of surgical resection, the following pathological evaluation as well as the characteristics of the tumor. To the best of our knowledge, this is the first study to investigate the role of LNR and the corresponding TNM stage on CSS of CRNEC, and further successfully to advocate the LNR-based classification (Nr) as a better predictor of the CSS. Based on the new advocated Nr classification, a refined TNrM stage was proposed.
By using the PSM method, which has a number of potential advantages over more common matching techniques such as retaining all the samples, the analysis gave a robust conclusion by reducing the estimation bias and improving validity. Despite of the inherit defects, our study has several strengths. With a total of 251 patients who were identified as nonmetastatic CRNEC of large, small cell patients and precisely diagnosed CRNECs, this is the largest study to date that evaluates patients with CRNECs and their treatment outcomes. With these data, we are able to show that AC are not associated with survival in a large, national cohort.
However, our analysis is subject to limitations related to the nature of registry-derived data and the inherent selection bias given by the retrospective study when interpreting the findings. Unmeasured confounders still exist, despite of the effort that a PS-matched technique and a competing-risks model were used to minimize the bias. However, to the best of our knowledge, no randomized study is recruiting for this purpose which the effect of AC in patients with CRNECs is explored. Second, poorly differentiated NECs are characterized by a Ki-67 index > 50–60%. However, the grading of NECs in the SEER database is mainly evaluated by tumor differentiation instead of on Ki-67 index which could not be identified. Third, there is no coding for recurrence as well as the types of chemotherapy in the SEER database, and the effect of AC may be influenced bearing it in mind that chemotherapy was classified even if it was interrupted before completion. So, it is unknown whether shortened or prolonged therapy may affect survival. Forth, there was a significant number of patients had < 12 lymph nodes examined in our cohort and SEER only collects data for overall survival (OS) rather than disease-specific survival (DFS).
In summary, by using the SEER dataset, our study revises survival based on the LNR and subsequently propose a new evidence-based stage grouping for CRNECs. The new TNrM stage more accurately predict survival of patients with CRNECs than the current AJCC N classification. Furthermore, the present study argues that AC was invalid for improving the survival of patients with nonmetastatic CRNECs following resection. Nevertheless, future work is still needed to externally verify the validation of the revised TNrM stage and the certain role of AC.