Small bowel adenocarcinoma (SBA) is an uncommon cancer of the gastrointestinal tract, which accounts for less than 5% of all gastrointestinal malignancies (1). SBA is generally defined as duodenal, jejunal, and ileal adenocarcinoma. Its mechanisms are poorly understood (2). Due to the lack of large-scale, multicenter, randomized controlled trials, the optimal therapeutics are controversial. The clinical practices on SBAs usually follow the guidelines of colorectal cancers (CRCs), in which surgery is the main strategy for early-stage disease and chemotherapy for advanced disease (3).

Radical resection is the standard treatment for stage II SBAs. However, the efficacy of adjuvant treatment for these patients is unclear. Previous studies reported that the number of lymph nodes (LNs) removed during surgery is an essential indicator for evaluating the severity and survival of patients (4). The National Comprehensive Cancer Network (NCCN) guideline of SBA (Version 2.2021) suggested that inadequate LNs examined (<5 for duodenal or <8 for jejunal/ileal primary tumor location) was one of the high-risk features for stage II SBA patients, for whom adjuvant chemotherapy was recommended. This consensus was drawn from two studies conducted by Thuy et al. and Overman et al., which analyzed SBA patients from the Surveillance, Epidemiology, and End Results Database (SEER) (5, 6). The former study included patients from 1988 to 2010 and the latter from 1988 to 2005.

Nevertheless, the treatment strategies for intestinal cancers have changed a lot based on findings of several large clinical trials in the past 20 years, which remarkably prolonged the survival time of patients. Before the 2000s, 5-fluorouracil (5-FU) monotherapy was the standard adjuvant chemotherapy choice for CRC and SBA patients (7). Combined regimens of oxaliplatin and 5-FU have emerged as a new standard of care since 2002 (8, 9). Targeted anticancer agents such as bevacizumab and cetuximab have been approved by the Food and Drug Administration (FDA) since 2004 (10, 11). The advances of these new drugs improved clinical survival outcomes significantly.

Another fact is that surgical modalities for SBA and CRC improved a lot in the past 20 years. By analyzing data from the SEER database, we found that the median number of total LNs removed during surgery increased from 6 in 2004 to 15 in 2018 in stage II SBA patients.

Thus, we speculate that, since LNs as an essential prognostic factor, the data before the 2000s may not exactly represent the current strategies for SBA treatment, especially for patients with stage II disease. In this study, we updated the LN number as a risk factor for stage II SBA patients with the latest data from the SEER database between 2004 and 2018 and indeed found that the cutoff value of LNs removed for jejunum and ileum should be changed.

SBA treatment is challenging, given its relative rarity and advanced stage of diagnosis. Due to the lack of large-scale, multicenter, randomized, controlled trials, the treatment strategies usually follow the consent of patients with CRCs. It is well accepted that patients with stage II CRC should be divided into a high-risk group and low-risk group according to several postoperative histology features, such as T4, grade 3 or 4, lymphovascular or perineural invasion, and <12 LNs examined (13). Patients with these high-risk features should receive adjuvant chemotherapy after the initial surgery (14). Similar evaluations had also been made for SBA. High-risk features for stage II SBA patients include T4 stage, close or positive surgical margins, few LNs examined (<5 for duodenal or <8 for jejunal/ileal primary tumor location), or tumor perforation according to NCCN guidelines. Our study focused on one of these features, LNs examined, and found that the optimal cut-off numbers for stage II SBA patients should be updated to 12 for jejunal/ileal primary tumor location, which was consistent with stage II CRC patients.

The recommendation of LN risks in the NCCN guideline (<5 for duodenal or <8 for jejunal/ileal primary tumor location) is drawn from patients in the SEER database from 1988 to 2010 and 1988 to 2005 (5, 6). However, the treatment strategies changed significantly in recent years. A recent study demonstrated that the LN numbers in NCCN guidelines (<5 for duodenal or <8 for jejunal/ileal primary tumor location) did not discriminate SBA patients from high and low risk (p = 0.166) (15). In Figure 5 , we can see that the median number of surgical removed LNs in stage II SBA patients is increasing, from 6 (95% CI, 6–8) in 2004 to 15 (95% CI, 8–17) in 2018. On the other hand, the addition of oxaliplatin to fluorouracil-based chemotherapy has become the standard treatment since 2002, which is more efficient than 5-FU monotherapy (9). Targeted anticancer agents such as bevacizumab and cetuximab have been developed since 2004. These strategies improved survival time significantly. Thus, the outcomes of SBA patients before 2004 may not represent a true picture of current treatments.

Our study updated the survival data using the latest SEER database in patients with stage II SBA diagnosed between 2004 and 2018. We demonstrated that patients with stage II SBA and total examined LNs <5 for duodenal tumors or <12 for jejunal/ileal primary tumors were at high risk. These patients may benefit from adjuvant chemotherapy. We also established a nomogram to predict the 5- and 10-year survival rates of SBA patients, which was more accurate than the AJCC staging system.

Several limitations exist in our analysis. There is a lack of treatment information in the SEER database, such as surgical margins, tumor perforation, chemotherapy regimen, recurrence, and molecular features. We cannot compare the survival outcome directly between patients with and without adjuvant chemotherapy. SEER database is retrospective, and we excluded patients with incomplete information, which may lead to selection bias. Though 935 patients were finally included in our study, large multicenter, randomized clinical trials are strongly needed to further confirm the conclusion. The BALLAD trial (NCT02502370) is ongoing, which is the first prospective trial designed to recruit 100 participants and to assess the benefit of adjuvant chemotherapy versus observation alone in patients with stage I–III SBA. Primary outcomes are 3-year disease-free survival and overall survival (OS), with expected results in 2023.

The total number of LNs harvested is an important prognostic factor of survival in stage II SBA. Patients with total examined LNs <5 for duodenal or <12 for jejunal/ileal primary tumor are at high risk. Sufficient LN dissection is recommended for stage II SBA patients.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

ZL, SZ, and JS designed the study. ZL, KL, JG, CJ, and YM collected and analyzed the data. ZL and KL organized the manuscript. All authors have read and approved the final manuscript.

This work is supported by grants from the National Natural Science Foundation of China (81602635), Zhejiang Provincial Natural Science Foundation (LY21H160042), and Zhejiang Medical and Health Project (2017205840, 2018274816, 2019334185).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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