Abstract
Background
Chemotherapy is regularly recommended for surgically rectal neuroendocrine carcinoma (NEC) patients. However, the additional benefit of perioperative radiotherapy for these patients is unclear to date. This study aims to evaluate the outcome of radiotherapy in rectal NECs who treated with surgery and chemotherapy.
Methods
This is a retrospective controlled study based on SEER database. Propensity score matching (PSM) was applied to reduce the baseline bias. Rectal NECs who underwent surgical resection plus chemotherapy with or without radiotherapy were extracted from SEER database. According to whether receiving radiotherapy, patients were divided into two cohorts: radiation treatment (RT) group and non-RT group. Overall survival (OS) was measured to assess the clinical benefits of RT. Kaplan–Meier survival analysis, univariable and multivariable regression analysis were applied.
Results
A total of 666 eligible patients were finally enrolled. The difference in OS remained significant both before and after PSM. Subgroup analyses revealed significantly better results for stage II, III and even IV patients who received radiotherapy whether before or after matching (all p < 0.05). The multivariable analysis showed that radiotherapy was associated with OS (HR 0.54; 95% CI 0.45 to 0.65; p < 0.001), together with distant metastasis. These results were consistent after matching (both p < 0.05).
Conclusions
Radiotherapy was an independent favorable prognostic factor for rectal NECs. The addition of radiotherapy to surgery plus chemotherapy might improve the clinical outcome. In the future, well-designed prospective studies are needed to assess the potential role of radiation in managing surgically resectable rectal NEC.
Keywords: Rectal malignancy, Neuroendocrine carcinoma, Surgery, Radiation therapy, Chemotherapy, Overall survival
Introduction
Over the past decades, the incidence rate of neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) are rising around the word [1–3]. Rectum is considered among the most frequent extra-pulmonary NECs [4]. Colorectal NEC accounts for less than 1% of all colorectal malignancies [5].
Radical surgery, mainly total mesorectal excision (TME), remains the mainstay of treatment for most localized rectal NECs, while adjuvant chemotherapy may reduce the risk of recurrence and is recommended in surgically resected patients [6, 7]. NECs are a highly aggressive cancer type associated with dismal prognosis and rapid disease progression [4, 8]. Local and distant relapse may both the major problem for rectal NECs [9].
Rectal NECs failed to benefit from research progress in the treatment of colorectal adenocarcinoma in the past decade [10]. Considering the high relapse rate observed following radical surgery, most clinicians would advocate platinum-based adjuvant therapy for digestive NECs [11]. In a real-world study, radiotherapy was used for digestive NECs including esophageal (74%), rectal (61%) and anal (83%) [12]. Another study showed that more than half of rectal NECs received chemoradiation before or after surgery [12]. For resectable rectal NECs, there is no standard adjuvant or neoadjuvant treatment modalities worldwide [13]. The European Neuroendocrine Tumor Society (ENETS) guideline recommended that adjuvant chemotherapy with 4–6 cycles of platinum/etoposide may be considered after surgery (grade 4B) [11]. Although radiotherapy plays an important role in improving local control alongside surgery for rectal adenocarcinoma [14], whether it might improve clinical outcome for rectal NECs, the evidence is still pending.
Given the importance of radiotherapy in rectal adenocarcinoma, we hypothesized that the clinical outcome would differ between individuals with and without radiotherapy for rectal NECs. To address this question, we compared the long-term survival between radiotherapy and non-radiotherapy for rectal NECs who were treated with surgical resection plus chemotherapy based on SEER database. Our study also included the subgroup analyses, including clinical stage and radiation timings, to explore the relationship between radiotherapy and clinical outcomes in different patient subsets.
Methods and materials
Cohort selection
Using data from SEER *-Stat 8.4.2 software [15], we extracted the clinical data of patients diagnosed with rectal NECs (AYA site recode 2020 revision code: 9.3.5.1.2) between 1990 and 2020. We developed a merged meta-dataset from eight independent SEER registry database [16–23]. Patients who had undergone surgical resection (site-specific surgery codes 10–80) plus chemotherapy and with sufficient demographic, clinical stage, treatment and follow-up information were included. These variables included year of diagnosis, age at diagnosis, sex, race, surgery type, tumor primary site, pathological subtypes, treatment types, survival time, vital status, treatment sequence with surgery and AJCC clinical stage. We adopted the survival months flag variable to exclude the incomplete or missing survival data. In addition, we removed the duplicate cases by checking patients ID in the cohort. The patients who had conflicting data or whose diagnosis time were ahead of year 1990 were also excluded. Based on whether they received external beam radiotherapy, patients were allocated into the radiation treatment (RT) group and non-radiation treatment (non-RT) group. The inclusion criteria and screening diagram was shown in Fig. 1.
Fig. 1.
The inclusion criteria and screening diagram
According to AJCC/UICC/WHO staging systems, rectal NECs are staged as for rectal adenocarcinomas [24]. The 7th edition of AJCC rectal cancer was released in 2009, so the cases diagnosed between 1990 and 2009 were staged with 6th editions, while the cases after 2010 were staged with 7nd editions. We integrated these staging groups and divided these patients into stage I, II, III and IV.
Moreover, the subjects enrolled in this study covered not only NECs but also G3 NETs. This is due to the changes of pathological diagnosis criteria for NECs. In the WHO classification of 2010, NEC was initially defined as poorly differentiated (G3) neuroendocrine tumor (NET) with Ki-67 > 20%. From the year 2019, the well-differentiated G3 NETs was separated from the NEC. In SEER database, the diagnosis time for NEC however was ahead of that changing time point.
Propensity score matching
Propensity score matching (PSM) [25] was used to balance the baseline covariates, including gender, sex, age, stage, pathological subtypes and treatment sequences. The matched samples were obtained by performing nearest-neighbor matching in a 1:1 ratio. The factors applied for PSM analysis based on significant p values from the univariable analysis. The optimal caliper value was determined by starting with a relatively large value then gradually decrease it, until the covariable across groups was statistically balanced after matching. Besides, to allow replicable analysis, random number seed was set when performing PSM.
Survival and subgroup survival analyses
In our study, overall survival (OS) was set as the primary outcome and defined as the time from diagnosis of rectal NEC to death due to any cause. We assess the radiation efficacy in the two groups for rectal NECs who both received surgery and chemotherapy before and after PSM. In addition, we conducted subgroup analyses in patients at different stages. Considering radiotherapy sequence with surgery might affect the outcome of cancer treatment, we compared pre-operative radiotherapy with post-operative radiotherapy on OS within RT group.
Univariable and multivariable Cox regression model
The potential risk factors of OS were estimated by the univariable and multivariable Cox proportional hazards model. The variables found significant in univariable analysis for OS were incorporated into multivariable COX regression model. The hazard ratios (HR) were estimated with 95% confidence intervals (CI).
Statistical methods
All the data was collected in Microsoft Excel. The baseline differences between the two groups were assessed by the χ2 test. Statistical analyses were performed with SPSS 26 and GraphPad Prism 8 software. The Reverse Kaplan-Meier approach was used to estimate the median follow-up time. The proportional hazard assumption was tested in Cox models. A p-value ≤ 0.05 was defined as the statistically significant. All Kaplan-Meier curves were generated by GraphPad Prism.
Results
Patient characteristics
A total of 666 eligible patients with rectal NECs who underwent both surgery and chemotherapy in the SEER database were selected for this study. Of them, there were 354 cases (53.2%) in RT group and 312 cases (46.8%) in non-RT group.
The patient characteristics were summarized in Table 1. Before matching, 45.5% (303 cases) were female. The age ranged from 24 to 86 years and the median age was 59.0 years (IQR 50.0–69.0 years) among these patients. Of them, 27.2% of the patients had metastatic disease at the time of diagnosis. Regarding the pathological type, the small-cell morphology (26.3%) was more frequent than the large-cell morphology (10.7%).
Table 1.
The general characteristics of rectal NECs
| Items | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Non-RT group (n = 312), n (%) |
RT group (n = 354), n (%) | P value | Non-RT (n = 291), n (%) | RT group (n = 291), n (%) | Chi-square test P value | |
| Year of diagnosis | 0.258 | 0.514 | ||||
| After 2009 | 168(53.8) | 194(54.8) | 158(54.3) | 166(57.0) | ||
| 2003–2008 | 89(28.5) | 113 (31.9) | 83(28.5) | 85(29.2) | ||
| Before 2002 | 55(17.6) | 47(13.3) | 50(17.2) | 40(13.7) | ||
| Gender | 0.646 | 0.617 | ||||
| Male | 173(55.4) | 190(53.7) | 157(54.0) | 163(56.0) | ||
| Female | 139(44.6) | 164 (44.3) | 134(46.0) | 128 (44.0) | ||
| Age at diagnosis | 0.408 | 0.219 | ||||
| <=45 | 52(16.7) | 46(13.0) | 51(17.5) | 40(13.1) | ||
| 46–60 | 112(35.9) | 134(37.9) | 97(33.3) | 115(39.5) | ||
| >=61 | 148(47.4) | 174(49.2) | 143(49.1) | 136(46.7) | ||
| Race | 0.497 | 0.267 | ||||
| White | 249(79.8) | 269(76.0) | 234(80.4) | 221(75.9) | ||
| Black | 32(10.3) | 43(12.1) | 26(8.9) | 38(13.1) | ||
| Other | 31(9.9) | 42(11.9) | 31(10.7) | 32(11.0) | ||
| Clinical stage | 0.018 | 1.000 | ||||
| I | 34(10.9) | 54(15.3) | 34(11.7) | 34(11.7) | ||
| II | 35(11.2) | 59(16.7) | 35(12.0) | 35(12.0) | ||
| III | 142(45.5) | 161(45.5) | 142(48.8) | 142(48.8) | ||
| IV | 101(32.4) | 80(22.6) | 80(27.5) | 80(27.5) | ||
| T stage | 0.110 | 0.117 | ||||
| T1/2 | 92(29.5) | 85 (24.0) | 90(30.9) | 73(25.1) | ||
| T3/4 | 220(70.5) | 269(76.0) | 201(69.1) | 218(74.9) | ||
| N stage | 0.678 | 0.854 | ||||
| N0 | 108(34.6) | 128(36.2) | 82(36.1) | 84(28.9) | ||
| N1/2 | 204(65.4) | 226(63.8) | 209(63.9) | 207(71.1) | ||
| M stage | 0.016 | 1.000 | ||||
| M0 | 211(67.6) | 274(77.4) | 211(72.5) | 211(72.5) | ||
| M1 | 101(32.4) | 80(22.6) | 80(27.5) | 80(27.5) | ||
| Tumor site | 0.058 | 0.197 | ||||
| Rectum | 235(75.3) | 288(81.4) | 219(75.3) | 232(83.2) | ||
| Rectosigmoid junction | 77(24.7) | 66 (18.6) | 72(24.7) | 59(16.8) | ||
| Histologic type | 0.211 | 0.168 | ||||
| Small cell | 91(29.2) | 84 (23.7) | 82(28.2) | 68 (23.4) | ||
| Large cell | 29(9.3) | 42(11.9) | 26(8.9) | 38(13.1) | ||
| NOS | 192(61.5) | 228(64.4) | 183(62.9) | 185(63.6) | ||
| Chemotherapy sequence | 0.420 | 0.711 | ||||
| After surgery | 193(61.9) | 202(57.1) | 177(60.8) | 168(58.1) | ||
| Before surgery | 94(30.1) | 123 (34.7) | 90(29.2) | 99 (34.0) | ||
| Both before and after surgery | 25(8.0) | 29(8.2) | 24(8.2) | 23(7.9) | ||
| Type of surgery | 0.491 | 0.411 | ||||
| Local resection | 81(26.0) | 85(24.0) | 74(25.4) | 72(24.7) | ||
| Radical resection | 219(70.2) | 238(67.2) | 206(70.8) | 201(69.1) | ||
| Extensional resection | 12(3.8) | 20(5.6) | 11(3.8) | 18(6.2) | ||
NEC neuroendocrine carcinoma, RT radiation therapy
At baseline, the M stage and clinical stage were found to be significantly different across groups (both p < 0.05)). Patients in the non-RT group presented a higher proportion of clinical stage M1. Then 1:1 PSM with a caliper of 0.1 was performed. After matching, 582 cases were finally included in the analysis, with 291 cases equally in each group. There was no significant difference any more after matching in general clinical characteristics between the two groups (all p > 0.05).
Survival analyses
Before matching, the median follow-up for OS was 98.0 months (95% CI 85.5–110.5) in overall cohorts. Totally 266 deaths had observed in the two groups, respectively. The median OS of the RT group and non-RT group were 22.0 and 13.0 months (HR 0.61, 95% CI 0.51–0.73, p < 0.001), respectively (Fig. 2).
Fig. 2.
Overall survival analysis for two groups. A Before matching. B After matching
After matching, the median follow-up for OS was 105.0 months (95% CI 86.4–121.6). Totally 245 deaths had occurred in RT and non-RT group, respectively. The median OS of the two group were 18.0 and 14.0 months (HR 0.71, 95% CI 0.59–0.86, p < 0.001), respectively (Figs. 2 and 3).
Fig. 3.
Subgroup survival analyses of the rectal NECs by clinical stage before matching. A OS of Stage (I) B OS of Stage (II) C OS of Stage (III) D OS of Stage IV
Multivariable analyses before and after matching
The variables found significant in univariable analysis for OS were further incorporated into multivariable COX regression model, including T stage, N stage, M stage and radiation therapy. Before matching, the multivariable analysis showed that independent prognostic factors for OS included M stage (M0 versus M1) and radiation therapy. The multivariable COX regression analysis indicated that radiotherapy significantly improved OS (HR 0.54, 95% CI 0.45–0.65, p = 0.005), compared with no radiotherapy in pre-matched dataset. The univariable analysis revealed that these variables did not affect the OS, including pathological type (small cell versus large cell), surgery type (local resection versus radical resection versus extensional resection), tumor site (rectum versus rectosigmoid junction) and chemotherapy timing with surgery (pre-operative versus post-operative) (all p > 0.05) (Table 2).
Table 2.
Univariable and multivariable COX regression analyses of rectal NECs for OS
| Characteristics | Before matching | After matching | ||||||
|---|---|---|---|---|---|---|---|---|
| Univariable | Multivariable | Univariable | Multivariable | |||||
| HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P | |
| Year of diagnosis | N/A | |||||||
| After 2009 | 1 | 1 | ||||||
| 2003–2008 | 1.09(0.84–1.43) | 0.518 | 1.11(0.85–1.47) | 0.533 | ||||
| Before 2002 | 1.87(1.35–2.58) | 0.371 | 1.96(1.44–2.72) | 0.302 | ||||
| Sex | N/A | N/A | ||||||
| Male | 1 | 1 | ||||||
| Female | 0.856(0.72–1.02) | 0.079 | 0.88(0.74–1.06) | 0.183 | ||||
| Age | N/A | N/A | ||||||
| ≤ 45 | 1 | 1 | ||||||
| 46–60 | 0.86(0.66–1.12) | 0.256 | 0.84(0.63-1.00) | 0.202 | ||||
| > 61 | 1.02(0.79–1.31) | 0.892 | 1.11(0.85–1.44) | 0.442 | ||||
| Race | 0.495 | N/A | N/A | |||||
| White | 1 | 1 | ||||||
| Black | 1.09(0.84–1.43) | 0.514 | 0.83(0.61–1.13) | 0.241 | ||||
| Others | 0.88(0.66–1.17) | 0.369 | 1.24(0.87–1.77) | 0.227 | ||||
| T stage | ||||||||
| T1/2 | 1 | 1 | 1 | 1 | ||||
| T3/4 | 1.34(1.06–1.70) | 0.016 | 1.23(0.93–1.64) | 0.429 | 1.67(1.34–2.09) | < 0.001 | 1.26(0.94–1.70) | 0.127 |
| N stage | 0.345 | |||||||
| N0 | 1 | 1 | 1 | 1 | ||||
| N1/2 | 1.35(1.12–1.63) | 0.011 | 1.32(1.06–1.70) | 0.375 | 1.16(0.95–1.41) | 0.158 | 1.50(1.00-2.25) | 0.048 |
| M stage | 0.84(0.57–1.23) | < 0.001 | ||||||
| M0 | 1 | 1 | 1 | 1 | ||||
| M1 | 3.14(2.60–3.79) | < 0.001 | 3.01(2.48–3.64) | < 0.001 | 2.84(2.328–3.46) | < 0.001 | 3.86(2.45–6.07) | < 0.001 |
| Tumor location | N/A | N/A | ||||||
| Rectum | 1 | 1 | ||||||
| Rectosigmoid junction | 1.03(0.82–1.28) | 0.828 | 1.03(0.821–1.28) | 0.828 | ||||
| Histologic type | N/A | N/A | ||||||
| Large cells | 1 | 1 | ||||||
| Small cells | 1.02(0.75–1.40) | 0.897 | 1.01(0.73–1.41) | 0.937 | ||||
| NOS | 0.82(0.613–1.09) | 0.174 | 0.78(0.58–1.06) | 0.106 | ||||
| Chemotherapy sequence | N/A | N/A | ||||||
| After surgery | 1 | 1 | ||||||
| Before surgery | 1.21(1.00-1.46) | 0.099 | 1.21(0.98–1.48) | 0.071 | ||||
| Both before and after surgery | 1.24 (0.89–1.72) | 0.051 | 0.97 (0.68–1.38) | 0.868 | ||||
| Surgery type | N/A | N/A | ||||||
| Local resection | 1 | 1 | ||||||
| Radical resection | 0.81(0.67–0.98) | 0.33 | 0.85(0.69–1.04) | 0.121 | ||||
| Extensional resection | 0.94(0.62–1.44) | 0.780 | 0.85(0.52–1.39) | 0.522 | ||||
| Radiation | ||||||||
| No | 1 | 1 | 1 | 1 | ||||
| Yes | 0.50(0.45–0.65) | < 0.001 | 0.54(0.45–0.65) | < 0.001 | 0.69(0.58–0.83) | < 0.001 | 0.55(0.45–0.67) | < 0.001 |
N/A not applicable, CI confidence interval, HR hazard ratio, NEC neuroendocrine carcinoma, OS overall survival
We also performed the univariable and multivariable analyses on the post-matching dataset. The independent prognostic factors OS were consistent with the variables found in the pre-PSM dataset (Table 2).
Subgroup survival analyses
To assess the efficacy of radiation in patients at different stages, patients were assigned into stages I, II, III, and IV. In stage I patients, no differences were found between RT and non-RT group for OS before matching (both p > 0.05). In stage II, III and IV patients, radiotherapy was associated with reduced risk of mortality for OS before matching (all p < 0.05) The similar results were observed for OS in post-matching dataset (all p < 0.05) (Fig. 4; Table 3).
Fig. 4.
Subgroup survival analyses of the rectal NECs by clinical stage after matching. A OS of Stage (I) B OS of Stage (II) C OS of Stage (III) D OS of Stage IV
Table 3.
Subgroup OS analyses of rectal NECs by clinical stages
| Before matching | |||||
|---|---|---|---|---|---|
| No. | non-RT group | RT group | HR (95%CI) | P | |
| I | 88 | 88.0 | 171.0 | 1.08(0.60–1.97) | 0.4161 |
| II | 94 | 10.0 | 36.0 | 0.29(0.16–0.52) | < 0.001 |
| III | 303 | 12.0 | 23.0 | 0.73(0.56–0.95) | 0.0160 |
| IV | 181 | 8.0 | 7.0 | 0.63(0.47–0.85) | 0.0010 |
| After matching | |||||
|---|---|---|---|---|---|
| No. | non-RT group | RT group | HR (95%CI) | P | |
| I | 68 | 88.0 | 171.0 | 1.00(0.51–1.96) | 0.6679 |
| II | 70 | 10.0 | 24.0 | 0.36(0.21–0.63) | < 0.001 |
| III | 284 | 18.0 | 22.0 | 0.75(0.57–0.98) | 0.0315 |
| IV | 160 | 8.0 | 7.0 | 0.69(0.50–0.95) | 0.0118 |
CI confidence interval, HR hazard ratio, NEC neuroendocrine carcinoma, OS overall survival, RT radiation therapy
The optimal sequences of RT with surgery are unclear for operable rectal NECs. We compared the survival time between pre-operative and post-operative radiotherapy within the RT group. Of them, 181 cases received radiotherapy at post-operative stage, while 141 cases at pre-operative stage. In pre-matching dataset, the median OS in post-operative RT and pre-operative patients were both 22.0 months (p = 0.5730). Similar results were obtained in post-matching dataset (Fig. 5; Table 4).
Fig. 5.
Subgroup survival analyses of the rectal NECs by radiotherapy sequences. A Radiotherapy sequences based on pre-matching. B: Radiotherapy sequences based on post-matching
Table 4.
Subgroup OS analyses of rectal NECs by radiotherapy and surgery sequences
| No. | Pre-operative RT | Post-operative RT | HR (95%CI) | P | |
|---|---|---|---|---|---|
| Before matching | 354 | 22.0 | 22.0 | 0.93(0.72–1.2) | 0.5730 |
| After matching | 291 | 18.0 | 21.0 | 0.98(0.75–1.30) | 0.9123 |
CI confidence interval, HR hazard ratio, NEC neuroendocrine carcinoma, OS overall survival, RT radiation therapy
Discussion
There was a lack of consensus regarding chemoradiation in the neoadjuvant and adjuvant setting for rectal NECs. Our current study indicated that radiotherapy had remarkably better survival for these patients. Matched population analysis further confirmed that patients could derive significant benefits from radiation treatment. In addition, the conclusions of our current study can be applied in both rectal NEC and G3 NETs due to the latest diagnostic criteria. In subset analyses, the significant survival advantage effect of radiotherapy on survival was observed in stage II and III patients. Unexpectedly, the stage IV rectal NECs that had been treated with radiation therapy also exhibited slight improvements in their OS outcomes. We speculated that radiotherapy may probably be performed towards the local lesions and the distant metastases therefore lead to survival benefits in these patients. Indeed, an addition of radiotherapy could improve survival for patients with oligometastatic cancer. In rectal adenocarcinoma, pre-operation radiotherapy improved local control as compared with post-operation radiotherapy [26]. In the subset analysis of this study, radiotherapy timings with surgery did not affect the survival outcome. As COX regression analysis shown, cellular subtype (small cellular and large cellular subtype carcinoma) also had no association with survival for rectal NECs. We plan to explore the answer in the future real-world evidence research.
Currently, surgical resection remains the mainstay of treatment for most localized rectal NECs. Recent data suggest that lateral pelvic lymph node dissection may be helpful to avoid the local recurrence for this disease [27]. Although surgery and (chemo) radio therapy has been widely used clinically, standard treatment of neoadjuvant or adjuvant setting remains to be established. In a recent US study, up to 61% of rectal NECs underwent chemoradiation following surgery [12]. A retrospective study found that radiotherapy and chemotherapy were associated with improved outcomes over surgical resection and chemotherapy for patients with localized esophageal NECs. Thus, chemoradiotherapy should be considered as a primary strategy for these patients. In another study of 806 cases, adjuvant chemotherapy with EP regimen prolonged the survival in patients with locoregional colorectal NECs following surgical resection [28]. A retrospective study with 71 cases found that radiation therapy was the only significant factor for OS among surgery, radiotherapy, sex and age at diagnosis [29]. The ongoing NEONEC study will evaluate the outcome of the neoadjuvant and adjuvant chemotherapy in patients with localized GI NEC including rectal primary. In this study, radiotherapy is proposed specifically for anorectal NEC patients (Clinical Trial NCT04268121).
The strength of the current study is the strict screening protocol and the large sample size to create a well-balanced patient cohort and statistically stable results. Our study included more than 600 patients with rectal NECs and analyzed them properly to prove the hypothesis. PSM performed in this study is a valuable method to reduce the baseline bias and achieve pseudo-randomization in retrospective observation studies. In this study, clinical staging was the key baseline confounder and required to balance. The survival results showed good repeatability before and after PSM processing.
Our current study has several limitations, especially the retrospective nature of the study design. As a result, the efficacy of treatment outcomes results needs to be proved by a well-designed prospective design. In addition, the SEER database lacks radiation information, including radiation dose and target area, which might influence the clinical efficacy of rectal NECs. From a gene profiling viewpoint, NECs are often characterized by genomic aberrations in RB1 and P53. Otherwise, ki-67 is used to differentiate the Grades of neuroendocrine neoplasm (NEN) and always overexpress in high grade NET and NEC. Unfortunately, these molecules are not available for analysis in the SEER Research data. In addition, other variables were not available in SEER database, including local recurrence, circumferential resection margin by MRI and chemotherapy regimen types. In addition, MRI is the most accurate tool for the local staging and circumferential resection margin evaluation and a useful modality to select the appropriate treatment for rectal NECs. Although the clinical stage information is available, the detailed MRI scan results are absent in current SEER database.
Despite these limitations, our study has important implications. Insights from this study indicated an association between radiotherapy and prolonged survival for individual patients. Although surgical treatment is now accepted as a standard treatment modality for patients with local advanced rectal NEC, there is a high risk of local relapse after surgery [4, 9, 30]. Local recurrence negatively affects both long-term survival and quality of life for rectal carcinoma [31]. Our study indicated that radiotherapy was an independent favorable prognostic factor for rectal NECs. Otherwise, the radiotherapy timing and pathological typing has no impact on the patient’s outcome. Radiation treatment should be considered either before or after surgical resection. It is commonly believed that adjuvant radiotherapy after operation may decrease local recurrence risk, and yet maintain the benefits from surgical excision. On the other hand, neoadjuvant radiotherapy before surgery may reduce tumor burden, increase anus retention rate and lower the local relapse rate for these patients. We think the improved local control contributes to prolonged long-term survival by radiotherapy for local advanced rectal NEC. NEC are a heterogenous group of malignancies with varied gene signatures [32], novel molecular genetic study might be helpful to better guide the precision treatment for individual patients. Based on the transcriptional factors analyses, NECs were categorized into five molecular subtypes each with distinct molecular and clinical features [33]. Among them, the HNF4A subtype exhibited gastrointestinal-like signature and proficient RB function [33]. Peptide receptor radionuclide therapy (PRRT) has recently been developed for the treatment of NEN. A study showed encouraging results using Lutetium-177 in patients with G3 NETs [34]. For refractory NEC, PRRT should probably only be considered following chemotherapy in selected patients with a high uptake on somatostatin receptor imaging [35]. Interestingly, A portion of G1-2 NETs may undergo transformation to NEC following PRRT treatment [36].
In conclusion, this was a retrospective analysis of patients with rectal NECs treated with multimodal therapy between 1990 and 2020 from the SEER registry database. Our study indicated that radiotherapy was an independent favorable prognostic factor for rectal NECs. The addition of radiotherapy to surgery plus chemotherapy might improve the clinical outcome for these patients. Otherwise, the radiotherapy timing and pathological typing has no impact on the patient’s outcome. Our study indicated an association between radiotherapy and prolonged survival. In the future, well-designed prospective studies are required to assess the potential role of radiation in managing surgically resectable rectal NEC.
Acknowledgements
The authors thank the Surveillance, Epidemiology, and End Results (SEER) database which provided data for our research.
Author contributions
Xiaojun Liu: MD, lxjmail2008@126.com, ideas; formulation, methodology, software, responsible for statistical analyses; Jiaying Li, MM, software, validation, writing-original draft; Farooq Benish, MD, software, validation, writing-original draft, language polishing; Shuping Li, MD, document retrieval, visualization; Weisheng Zhang, professor, the corresponding author, project administration, conceptualization, supervision.
Funding
This study was supported by the Joint Research Fund General Support Project of Gansu Province (24JRRA891) and the Institution Research Fund Project of Gansu Provincial Hospital (21GSSYA-2).
Data availability
The SEER database provides publicly available data for this study, which means that obtaining informed consent from participants or ethical approval from an institutional review board is not necessary. We obtained access to SEER Research Data File by signing a Data-Use Agreement that outlines the terms and conditions for access. We confirm that all research was performed in accordance with relevant guidelines/regulations. Our study was carried out following the Helsinki Declaration contents.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The SEER database provides publicly available data for this study, which means that obtaining informed consent from participants or ethical approval from an institutional review board is not necessary. We obtained access to SEER Research Data File by signing a Data-Use Agreement that outlines the terms and conditions for access. We confirm that all research was performed in accordance with relevant guidelines/regulations. Our study was carried out following the Helsinki Declaration contents.