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Postoperative locoregional recurrence pattern and treatment management of stage pT4 sigmoid colon cancer: a retrospective cohort study

Postoperative locoregional recurrence pattern and treatment management of stage pT4 sigmoid colon... Background: This study aimed to explore the pattern of locoregional recurrence after surgery in patients with non- metastatic stage pT4 sigmoid colon cancer and the role of adjuvant radiotherapy on survival. Methods: We retrospectively analyzed data from 208 patients who underwent surgery in our hospital. The patients were randomly divided into training and validation groups at a 1:1 ratio. Patients at high risk for locoregional recur- rence were screened using Cox regression analysis. Based on the data of 2,886 patients in the Surveillance, Epidemiol- ogy, and End Results (SEER) database, the effect of adjuvant radiotherapy on overall survival (OS) and cancer-specific survival (CSS) was evaluated by Kaplan–Meier curves. Results: Of the 208 patients, 57 (27.4%) presented with locoregional recurrences (14 anastomotic and 43 abdomi- nal or pelvic lymph node recurrences). Multivariate analysis showed that serum CEA, differentiation, lymph node dissection number, and N stage were independent predictors of locoregional recurrence-free survival (all p < 0.05). A risk-stratification model was constructed, and a total score of ≥ 6.5 points was considered the high-risk group for locoregional recurrence. Both the training and validation sets presented that the model had a good predictive abil- ity (area under the curve = 0.828 and 0.724, respectively). Analysis of SEER data revealed that adjuvant radiotherapy significantly prolonged OS and CSS in the high-risk population (all p < 0.05, vs. no radiotherapy). Conclusions: Patients with a total risk score of 6.5 or more had a high likelihood of locoregional recurrence, and perhaps adjuvant radiotherapy could improve their survival. Keywords: Sigmoid colon cancer, Recurrence, Survival, Surgery, Radiotherapy cancer, surgery alone or in combination with postopera- Background tive chemotherapy is the mainstay of treatment. However, Colon cancer is the most common malignant disease of the five-year overall survival (OS) rates of these patients the gastrointestinal tract, with more than 100,000 newly were only 52–64% [2]. In recent decades, with the devel- diagnosed cases each year [1]. For locally advanced colon opment of systemic therapies, the rate of distant metas- tasis in colon cancer has gradually decreased, and the Yaobin Lin and Shan Liu contributed equally. rate of postoperative locoregional recurrence (defined as *Correspondence: junxinwufj@aliyun.com tumor relapses at the anastomotic site or within regional lymph nodes of the sigmoid colon) is between 10–40% College of Clinical Medicine for Oncology, Fujian Medical University, 420 Fuma Rd, Jin’an District, Fuzhou 350014, Fujian, China [3–6]. Therefore, it is important to identify high-risk Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. Radiation Oncology (2022) 17:95 Page 2 of 12 groups for locoregional recurrence and formulate treat- were identified based on the third edition of the Inter - ment strategies. national Classification of Diseases for Oncology code, as The sigmoid colon, the last part of the colon, is espe - described in a previous article [17]. The screening process cially prone to cancer and accounts for approximately is illustrated in Additional file  1. Finally, 2886 patients 39.2% of all colon cancers [7]. For stage T4 sigmoid colon were included in the analysis. Both T stage and N stage cancer, it is sometimes difficult to perform radical resec - were redefined based on the American Joint Committee tion because of its anatomical characteristics [8–10]; On on Cancer TNM staging classification for colon cancer the other hand, it is often accompanied by invasion of 8th edition [18]. adjacent organs or structures, requiring multiple organ resection. It has been reported that the proportion of R1/ Treatments and follow‑up R2 resection (incomplete resection) is 15–35% [6, 11–13]. All patients in our hospital underwent colectomy with Radiotherapy (RT), another important local treatment en-bloc removal of the regional lymph nodes, of which method besides surgery, is not widely used in colon can- 20 (9.6%) underwent combined organ resection due to cer [12, 14]. The sigmoid colon is much lower and easier tumor invasion. Dissection of lymph nodes from para- to position on the RT target area delineation system than colic to the root of the inferior mesenteric artery, as well other parts of the colon, making adjuvant RT plausible as suspicious enlarged lymph nodes observed on pre- for sigmoid colon cancer [15, 16]. Our previous study operative imaging. Complete mesocolic excision was also found that adjuvant RT could prolong survival for performed, and surgical margins were negative in all stage pT4bN0-2M0 sigmoid colon cancer patients [17]. patients. One hundred fifty-five patients (74.5%) received The National Comprehensive Cancer Network guide - adjuvant chemotherapy. The three most common regi - line of colon cancer indicates that postoperative RT can mens were CAPEOX (capecitabine with oxaliplatin), be considered for stage T4 with penetration into a fixed FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin), structure. However, it does not provide a more detailed and capecitabine single-agent chemotherapy. Follow-up description of the target population. data, including locoregional recurrence and survival sta- This study first analyzed the clinicopathological data tus, were collected from medical records and telephone of 208 patients with non-metastatic pathologic stage T4 interviews. At the last follow-up, of the 208 patients, (pT4) sigmoid colon cancer in Fujian Cancer Hospital 98 were alive and 73 died. The remaining 37 patients and selected high-risk patients with locoregional recur- could not be contacted because their contact informa- rence after surgery using a risk-stratification model. tion was changed. The latest follow-up information for Then, in 2,886 patients from the Surveillance, Epidemi - these patients was recorded. Patients without postop- ology, and End Results (SEER) database, we preliminarily erative follow-up records were excluded from the study. demonstrated that postoperative RT has a positive prog- The median follow-up time was 61 months (interquartile nostic role in the population with high-risk of locore- range: 31–86 months). gional recurrence. All patients in the SEER database underwent sur- gery and divided into the surgery alone group (2,628 Methods cases, 91.1%) and the surgery followed by adjuvant RT Patients group (258 cases, 8.9%). Chemotherapy was not ana- The medical records of patients with stage pT4 sigmoid lyzed because the SEER database cannot distinguish colon cancer who received colectomy at our hospital which patients did not receive chemotherapy [19, 20]. from January 2010 to December 2016 were retrospec- All patients were actively followed-up. More detailed tively analyzed. A total of 208 patients were included follow-up information was not available from the SEER after excluding five patients who were lost to follow-up. database. Inclusion criteria were as follows: The patients (1) were diagnosed with sigmoid colon cancer by pathology, (2) Statistical analysis received sigmoid colon resection, (3) had a postoperative SPSS Statistics (version 26.0, IBM Corp) and GraphPad stage was pT4N0-2M0, (4) received no preoperative neo- Prism (version 5.0.1, GraphPad Software) were used for adjuvant therapy, (5) received no other anti-tumor ther- data analysis and plotting graphs. Statistical significance apy except chemotherapy after surgery, and (6) provided was set at P < 0.05. complete follow-up information. The 208 patients screened from our hospital were Clinicopathological data of stage pT4 sigmoid colon equally and randomly assigned to training or valida- cancer patients diagnosed between 2004 and 2016 were tion groups using SPSS software (set seed = 2,000,000). screened from SEER database. Using SEER*Stat 8.3.8 Survival rates were calculated by Kaplan–Meier curves. (IMS, Inc. USA. https:// seer. cancer. gov/ seers tat/), cases Using Cox proportional risk regression, independent Lin  et al. Radiation Oncology (2022) 17:95 Page 3 of 12 predictors associated with locoregional recurrence-free (p = 0.001) were related to poorer LRRFS. Serum survival (LRRFS) were screened, and a model for pre- CA19-9 levels and vascular invasion were not inde- dicting postoperative locoregional recurrence was con- pendent factors for LRRFS (all p > 0.05). structed. The predictive power and optimal cutoff value of the model were assessed by receiver operating char- acteristic (ROC) curve and Youden index, respectively Establishment of the risk‑stratification model for LRRFS [21]. Data from the SEER database was analyzed to assess Based on the β regression coefficient and Exp (B) value, the effect of adjuvant RT on OS and cancer-specific sur - which were generated from the Cox regression analy- vival (CSS) in groups at different risk of locoregional sis, a risk scoring system was constructed (Table  3). The recurrence. scoring system aimed to integrate factors identified from multivariate analysis: serum CEA level, differentiation, lymph node dissection number, and N stage. We assigned Results 5 points for elevated serum CEA level, 3 points for poorly Patient characteristics for our institution differentiated or undifferentiated cells, 3 points for < 12 The general characteristics of 208 patients are presented lymph nodes dissected, and 5 points for the N2 stage. in Table 1. Patients aged 50–69 years accounted for 57.2% Zero points were assigned to normal serum CEA level, of the study population. The proportions of patients with well/moderate differentiation status, removal of fewer elevated serum carcinoembryonic antigen (CEA) levels than 12 lymph nodes, and the N0 and N1 stages. and ≥ 12 lymph node resections were 40.4% and 82.2%, Each patient in the training set was scored according respectively. The surgical margins were negative in all to the risk scoring system, and the total score was calcu- patients. Most patients had no vascular invasion (80.3%) lated. Figure  2 showed the area under the curve (AUC) or perineural invasion (81.7%). Finally, 74.5% of patients was 0.859 with an optimal cutoff value of 6.5 (sensitiv - received postoperative adjuvant chemotherapy. ity = 72.7%, specificity = 93.0%). Locoregional recurrence pattern of stage pT4 sigmoid colon cancer Valuation of the risk‑stratification model Locoregional recurrence occurred in 57 of 208 patients For training set, 75 (72.1%) patients were classified (27.4%). Fourteen patients (6.7%) had an anastomotic into the low locoregional recurrence risk group (total recurrence, and 43 (20.7%) had abdominal or pelvic score < 6.5), and 29 (27.9%) were classified into the high lymph node recurrence. The cumulative locoregional risk group (total score ≥ 6.5). The AUC of this risk -strat- recurrence rates in the first, second and third years after ification model is 0.828 (p < 0.001, Fig.  3A). Figure  3B surgery were 15.6, 23.6, and 26.5%, respectively (Fig. 1A). reveals that the high-risk group had worse LRRFS than Locoregional recurrence mainly occurred within three the low-risk group. Their 1-, 3-, and 5-year LRRFS rates years after surgery (96.5%, 55/57). The median locore - were 48.3% vs. 94.5%, 19.7% vs. 88.6%, and 13.1% vs. gional recurrence time was 11  months, and the inter- 86.7% (p < 0.001), respectively. In addition, OS was also quartile range was 8–18 months. worse in the high-risk group (p < 0.001, Fig. 3C). Once locoregional recurrence occurred, OS decreased The patients in the validation set were scored and significantly (p < 0.001, Fig.  1B). The 1-, 3-, and 5-year OS grouped according to the model. It also showed a good rates in the non-recurrence and recurrence groups were predictive power (AUC = 0.724, p < 0.001, Fig.  3D). Simi- 99.3% vs. 94.7%, 88.7% vs. 39.8%, and 82.6% vs. 26.4%, lar to the training set, the LRRFS and OS were worse respectively. in the high-risk group (all p < 0.001, vs. low-risk group, Fig. 3E, F). Prognostic factors affecting LRRFS Table  2 shows the results of the Cox regression analy- sis of independent predictors related to postopera- Patient characteristics for SEER database tive LRRFS of stage pT4 sigmoid colon cancer in the A total of 2,886 patients with non-metastatic stage pT4 training set. Univariate analysis revealed that serum sigmoid colon cancer were analyzed from the SEER CEA, serum carbohydrate antigen 19–9 (CA19-9), dif- database (Table  4). Most patients from the SEER data- ferentiation, vascular invasion, lymph node dissection base were also aged 50–69  years (47.7%). Patients with number, and N stage were associated with LRRFS (all elevated serum CEA levels, poor differentiation/undif - p < 0.05). Multivariate analysis showed that elevated ferentiated tumor status, < 12 lymph nodes removed, and serum CEA (p < 0.001), poor/undifferentiated differ - lymph node metastases were 52.2%, 21.8%, 19.3%, and entiation (p = 0.024), lymph node dissection number 56.9%, respectively. fewer than 12 (p = 0.029), and lymph node metastasis Lin et al. Radiation Oncology (2022) 17:95 Page 4 of 12 Table 1 Characteristics of patients with stage pT4 sigmoid colon cancer Character Training set (n = 104) Validation set (n = 104) Total (n = 208) N % N % N % Age (year) < 50 31 29.8 17 16.3 48 23.1 50–69 52 50.0 67 64.4 119 57.2 ≥ 70 21 20.2 20 19.2 41 19.7 Sex Male 66 63.5 62 59.6 128 61.5 Female 38 36.5 42 40.4 80 38.5 Serum CEA Normal 63 60.6 61 58.7 124 59.6 Elevated 41 39.4 43 41.3 84 40.4 Serum CA19-9 Normal 73 70.2 78 75.0 151 72.6 Elevated 31 29.8 26 25.0 57 27.4 Type of surgery Colon resection 94 90.4 94 90.4 188 90.4 Multiorgan resection 10 9.6 10 9.6 20 9.6 Differentiation Well/moderate 88 84.6 85 81.7 173 83.2 Poor/undifferentiated 16 15.4 19 18.3 35 16.8 Tumor size (cm) < 5 49 47.1 52 50.0 101 48.6 ≥ 5 55 52.9 52 50.0 107 51.4 Surgical margins Negative 104 100.0 104 100.0 208 100.0 Positive 0 0.0 0 0.0 0 0.0 Vascular invasion No 83 79.8 84 80.8 167 80.3 Yes 21 20.2 20 19.2 41 19.7 Perineural invasion No 82 78.8 88 84.6 170 81.7 Yes 22 21.2 16 15.4 38 18.3 Lymph node dissection number ≥ 12 88 84.6 83 79.8 171 82.2 < 12 16 15.4 21 20.2 37 17.8 T stage T4a 88 84.6 95 91.3 183 88.0 T4b 16 15.4 9 8.7 25 12.0 N stage N0 35 33.7 56 53.8 91 43.8 N1 46 44.2 29 27.9 75 36.1 N2 23 22.1 19 18.3 42 20.2 Adjuvant chemotherapy Yes 83 79.8 72 69.2 155 74.5 No 21 20.2 32 30.8 53 25.5 pT4 pathologic stage T4, N number, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9 Lin  et al. Radiation Oncology (2022) 17:95 Page 5 of 12 Fig. 1 The cumulative locoregional recurrence rates and OS rates for patients with stage pT4 sigmoid colon cancer. A The cumulative locoregional recurrence rates after surgery. B OS rates for patients with or without locoregional recurrence. OS overall survival Eec ff t of adjuvant radiotherapy on survival in different Locoregional recurrence or distant metastasis of colon locoregional recurrence risk groups cancer mainly occurs within 3  years after surgery [22], Based on the model, 1973 (68.4%) patients were assigned and Park et  al. [23] reported that patients who relapsed to the low-risk group and 913 (31.6%) patients to the within 3  years after surgery accounted for 95% of the high-risk group. The effect of adjuvant RT on OS are total population with recurrence. Similar results were presented in Fig.  4A–C. Adjuvant RT significantly pro - also found in this study; the cumulative locoregional longed OS in the entire population (Fig.  4A, p = 0.003). recurrence rate increased rapidly in the first 2 years, and For high-risk patients, adjuvant RT improved the OS, and patients who relapsed within 3 years accounted for 96.5% the median OS was prolonged by 64  months (Fig.  4C, of the recurrence population. Even if the surgical margins p = 0.001). While for patients with low risk of locore- of the patients were all negative, 6.7% of patients had an gional recurrence, the effect of adjuvant RT on OS was anastomotic recurrence. However, the factors affecting not significant (Fig. 4B, p = 0.329). locoregional recurrence have not been determined, and The effect of adjuvant RT on CSS are presented in the results of different studies have been slightly differ - Fig.  4D–F. Similar to OS, adjuvant RT extended CSS in ent. Wang et  al. [24] focused on the tumor site, T stage, the entire population (Fig.  4D, p = 0.020) and high-risk and serum CEA level. Vergara-Fernandez et al. [25] sug- group (Fig.  4F, p = 0.008). For patients with low locore- gested that the number of lymph nodes removed and gional recurrence risk, treatment with or without adju- nerve invasion are important elements affecting the vant RT had no significant impact on CSS (Fig.  4E, locoregional recurrence of colorectal cancer. Analysis p = 0.598). of sex, age, and family history of cancer showed no cor- relation with postoperative recurrence or metastasis of colon cancer [26]. It demonstrated that colon cancer Discussion locoregional recurrence may be affected by many com - In this study, a risk-stratification model was established to plex factors. This study also confirmed that serum CEA screen the high-risk population of postoperative locore- level (p < 0.001) and the lymph node dissection number gional recurrence. The model integrated four param - (p = 0.029) were independent factors affecting locore - eters: serum CEA level, differentiation status, number gional recurrence. For differentiation and N stage, they of lymph nodes dissected, and N stage. Compared with were also the independent predictors (p = 0.024 and the low-risk group, high-risk patients (total score ≥ 6.5) p = 0.001, respectively). Adjuvant chemotherapy was were more likely to have a locoregional recurrence and ineffective at local tumor control (p = 0.134), requiring worser LRRFS and OS (all p < 0.001). In addition, this additional postoperative treatments such as RT. study confirmed that adjuvant RT could improve OS and Serum CEA is a routinely-used marker for diagnos- CSS in patients with high locoregional recurrence risk ing and monitoring colorectal cancer [27, 28]. However, (all p < 0.05, vs. no RT). The model we developed may different researchers hold different views on the role of have implications for the postoperative management of serum CEA for prognosis [19, 24, 29]. In our current some patients, such as providing local interventions and research, elevated serum CEA was found to be an inde- strengthening follow-up monitoring. pendent predictor of locoregional recurrence (p < 0.001), Lin et al. Radiation Oncology (2022) 17:95 Page 6 of 12 Table 2 Variables associated with LRRFS for stage pT4 sigmoid colon cancer in the training set Variable Univariable analysis Multivariable analysis Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Age (year) 0.077 < 50 Reference – 50–69 0.744 (0.364–1.520) 0.417 ≥ 70 0.180 (0.040–0.797) 0.024 Sex Male Reference – Female 0.781 (0.379–1.611) 0.504 Serum CEA Normal Reference – Reference – Elevated 4.765 (2.258–10.056) < 0.001 4.844 (2.137–10.979) < 0.001 Serum CA19-9 Normal Reference – Reference – Elevated 2.806 (1.414–5.567) 0.003 1.575 (0.762–3.256) 0.221 Type of surgery Colon resection Reference – Multiorgan resection 1.216(0.427–3.458) 0.714 Differentiation Well/moderate Reference – Reference – Poor/undifferentiated 3.256 (1.541–6.878) 0.002 2.630 (1.139–6.074) 0.024 Tumor size (cm) < 5 Reference – ≥ 5 1.382 (0.687–2.779) 0.365 Vascular invasion No Reference – Reference – Yes 2.311 (1.094–4.878) 0.028 1.326 (0.576–3.050) 0.507 Perineural invasion No Reference – Yes 1.220 (0.550–2.710) 0.624 Lymph node dissection number ≥ 12 Reference – Reference – < 12 3.332 (1.580–7.026) 0.002 2.789 (1.112–6.994) 0.029 T stage T4a Reference – T4b 0.964 (0.372–2.499) 0.940 N stage < 0.001 0.001 N0 Reference – Reference – N1 2.089 (0.735–5.936) 0.167 1.039 (0.320–3.378) 0.949 N2 8.138 (2.962–22.358) < 0.001 4.741 (1.591–14.125) 0.005 Adjuvant chemotherapy Yes Reference – No 0.449 (0.158–1.280) 0.134 pT4 pathologic stage T4, CI confidence interval, LRRFS locoregional recurrence-free survival, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9 with a score of 5 in the risk stratification model. There - a determinant of postoperative treatment [2, 30, 31]. fore, regular monitoring of changes in serum CEA levels As confirmed in this study, the N stage was associated after surgery is still recommended. with postoperative locoregional recurrence (p = 0.001), Another key factor affecting the survival of colon and the risk in stage N2 patients was 4.741 times than cancer patients is lymph node metastasis, which is also that in stage N0 patients (95% confidence interval [CI]: Lin  et al. Radiation Oncology (2022) 17:95 Page 7 of 12 Table 3 Risk scoring system Risk variable B value Exp (B) Risk coefficient Risk score Serum CEA Normal 0.000 1.000 1.000 0 Elevated 1.578 4.844 4.844 5 Differentiation Well/moderate 0.000 1.000 1.000 0 Poor/undifferentiated 0.967 2.630 2.630 3 Lymph node dissection number ≥ 12 0.000 1.000 1.000 0 < 12 1.026 2.789 2.789 3 N stage N0 0.000 1.000 1.000 0 N1 0.039 1.039 1.039 0 N2 1.556 4.741 4.741 5 CEA carcinoembryonic antigen lymph nodes, as required by clinical guidelines, to achieve a more accurate N stage and reduce the risk of postoperative locoregional recurrence. Perineural invasion is a feature of aggressiveness for colon cancer [24, 32]. It is reported that invasion of peripheral nerves means worse five-year survival [33]. This conclusion has also been confirmed by other studies [25, 34–36]. However, recent studies have reached con- tradictory conclusions, finding that perineural infiltration is unrelated to locoregional recurrence or poor prognosis of colon cancer [4, 24]. In our study, on the premise that surgical margins were negative, it was also found that perineural invasion was not affecting the locoregional recurrence (p = 0.624). RT is one of the most important local interventions; however, for colon cancer, postoperative RT is rarely performed. Preliminary studies conducted in the 1990s revealed that adjuvant RT could improve local control and disease-free survival (DFS) of colon cancer [13, 37, Fig. 2 ROC curve of risk scores. The optimal cutoff value was 38]. Since 2000, interest in RT has diminished [39]. This assessed for the event of locoregional recurrence. ROC receiver may be related to the lack of prospective clinical studies operating characteristic; AUC area under the curve that clearly support the role of RT in colon cancer. The only phase III randomized controlled trial had shown 1.591–14.125, p = 0.005). However, the risk of locore- similar survival rates for postoperative chemoradio- gional recurrence in stage N1 patients was similar to the therapy and chemotherapy in colon cancer (5-year OS: stage N0 patients (p = 0.949). Therefore, patients with 58% vs. 62%, p > 0.05; 5-year DFS: 51% vs. 51%, p > 0.05) stage N2 disease should be vigilant about locoregional [14]. At the same time, the trial had several limitations, recurrence after surgery so that it can be treated as soon such as the inclusion of T3 patients (18.7%, 35/187) and as possible. In addition to the N stage, we found that the insufficient enrollment (the original plan was to enroll lymph nodes dissected number was related to locore- 700 cases, and enrollment was stopped after 222 cases). gional recurrence. The risk of locoregional recurrence Another shortcoming was that only 48% of patients was 2.789-fold higher in patients with fewer than 12 underwent preoperative imaging, and 19% of patients lymph node dissection (95% CI: 1.112–6.994, p = 0.029). had clips placed during the operation, making the imple- Surgeons should try their best to remove 12 or more mentation of postoperative RT more difficult. Lin et al. Radiation Oncology (2022) 17:95 Page 8 of 12 Fig. 3 Valuation of the risk-stratifications model in training and validation set. A ROC curve of risk stratifications in the training set. B LRRFS rates of different risk stratifications in the training set. C OS rates of different risk stratifications in the training set. D ROC curve of risk stratifications in the validation set. E LRRFS rates of different risk stratifications in the validation set. F OS rates of different risk stratifications in the validation set. ROC receiver operating characteristic; AUC area under the curve; LRRFS locoregional recurrence-free survival; OS overall survival As targeted therapy and immunotherapy are more 44]. Previously, we also found that some sigmoid colon widely adopted, the pattern of treatment failure has cancer patients may benefit from postoperative RT [17], changed [40], and the distant failure rate has decreased. and this study once again demonstrated the positive With further exploration of the efficacy and safety of effect of adjuvant RT on survival from the perspective of chemoradiotherapy for colon cancer, the role of radiation locoregional recurrence. is being reconsidered [41–43]. A single-center retrospec- Adjuvant RT has several advantages for sigmoid colon tive study reported in 2016 that adjuvant RT can enhance cancer compared to other parts of the colon. First, the the local control rate and prolong DFS, particularly in sigmoid colon extends from the left iliac crest to the patients with stage T4b or residual tumors [6]. These third sacral plane and continues with the rectum, which findings have also been confirmed by other studies [12, can be readily positioned and targeted for precise local Lin  et al. Radiation Oncology (2022) 17:95 Page 9 of 12 Table 4 Characteristics of patients with stage pT4 sigmoid colon cancer from SEER database Variable With adjuvant radiation (n = 258) Without adjuvant radiation Total (n = 2886) (n = 2628) N % N % N % Insurance Insured 185 71.7 2003 76.2 2188 75.8 Uninsured 18 7.0 106 4.0 124 4.3 Unknown 55 21.3 519 19.7 574 19.9 Age (year) <50 57 22.1 468 17.8 525 18.2 50–69 144 55.8 1233 46.9 1377 47.7 ≥ 70 57 22.1 927 35.3 984 34.1 Sex Male 129 50.0 1360 51.8 1489 51.6 Female 129 50.0 1268 48.2 1397 48.4 Race White 196 76.0 1984 75.5 2180 75.5 Black 22 8.5 289 11.0 311 10.8 Others 39 15.1 343 13.1 382 13.2 Unknown 1 0.4 12 0.5 13 0.5 Marital status Married 140 54.3 1348 51.3 1488 51.6 Others 107 41.5 1175 44.7 1282 44.4 Unknown 11 4.3 105 4.0 116 4.0 Differentiation Well/moderate 211 81.8 2046 77.9 2257 78.2 Poor/undifferentiated 47 18.2 582 22.1 629 21.8 Tumor size (cm) < 5 66 25.6 1096 41.7 1162 40.3 ≥ 5 183 70.9 1462 55.6 1645 57.0 Unknown 9 3.5 70 2.7 79 2.7 Serum CEA Normal 119 46.1 1261 48.0 1380 47.8 Elevated 139 53.9 1367 52.0 1506 52.2 Perineural Invasion Yes 33 12.8 379 14.4 412 14.3 No 108 41.9 1154 43.9 1262 43.7 Unknown 117 45.3 1095 41.7 1212 42.0 Lymph node dissection number ≥ 12 212 82.2 2116 80.5 2328 80.7 < 12 46 17.8 512 19.5 558 19.3 T stage T4a 83 32.2 1653 62.9 1736 60.2 T4b 175 67.8 975 37.1 1150 39.8 N stage N0 148 57.4 1095 41.7 1243 43.1 N1 66 25.6 850 32.3 916 31.7 N2 44 17.1 683 26.0 727 25.2 N = number; CEA = carcinoembryonic antigen; SEER = the Surveillance, Epidemiology, and End Results Lin et al. Radiation Oncology (2022) 17:95 Page 10 of 12 Fig. 4 The effect of adjuvant radiotherapy on OS and CSS. OS rates of all patients (A), low-risk group (B), and high-risk group (C). CSS rates of all patients (D), low-risk group (E), and high-risk group (F). OS overall survival; CSS cancer-specific survival irradiation [15, 16]. In other parts of the colon, it is dif- development of motion management technology also ficult to delineate the postoperative target area under provides technical support for RT in colon cancer [45]. the condition of organ movement without the placement This study had some limitations. First, the cases used of silver clips [4, 42, 45]. Second, the types of organs at to construct the risk stratification model were all nega - risk for sigmoid colon cancer are relatively fixed, which tive for the surgical margins. Therefore, this model is not facilitates quality control of RT. Third, RT in the surgi - suitable for predicting the risk of locoregional recurrence cal area of sigmoid colon cancer has a smaller irradia- in patients with positive resection margins; however, tion volume and a lower cumulative radiation dose to therapeutic intervention should be actively administered. the small intestine, which may reduce the occurrence Second, the selection method of variables included in of radiation enteritis. In addition, adjuvant RT for colon the multivariate analysis has limitations. Factors with p cancer was previously performed using two-dimensional values greater than 0.05 in the univariate analysis were total abdominal irradiation [46–48], while the applica- not included in the multivariate analysis, but these fac- tion of three-dimensional conformal RT and intensity- tors may also be associated with locoregional recur- modulated RT techniques has reduced radiation toxicity rence. Third, the number of patients with colon cancer in normal tissues such as the small bowel [15, 16]. The who received postoperative RT in our institution was not Lin  et al. Radiation Oncology (2022) 17:95 Page 11 of 12 design, data collection and analysis, data interpretation, or preparation of the enough for statistical analysis, and there was no locore- manuscript. gional recurrence-related information in the SEER data- base [49]. Therefore, this study used the data from our Availability of data and materials The dataset analyzed in this study from SEER database can be obtained from: center to analyze postoperative locoregional recurrence https:// seer. cancer. gov/ data/. Other data used and/or analyzed during the and then analyzed the effect of adjuvant RT on OS and current study are available from the corresponding author on reasonable CSS using the SEER database. It is necessary to conduct request. new studies to evaluate the value of postoperative RT from the perspective of LRRFS. In addition, the SEER Declarations database does not record details on RT, such as the range Ethics approval and consent to participate of irradiation target, prescribed dose, and radiation- This study was approved by the ethics committee of Fujian Cancer Hospital related toxicity [20, 50]. Therefore, the details of the RT (No. K2022–005–01). This study was a retrospective analysis of medical records, and informed consent of patients was not required. plan need to be explored further. Finally, it is difficult to avoid selection bias in retrospective analyses, which must Consent for publication be verified and further developed in prospective studies. Not applicable. Competing interests The authors declare that they have no competing interests. Conclusions Author details In this study, a risk-stratification model was established College of Clinical Medicine for Oncology, Fujian Medical University, for predicting postoperative locoregional recurrence in 420 Fuma Rd, Jin’an District, Fuzhou 350014, Fujian, China. Depar tment pT4 sigmoid colon cancer. This model has the advantages of Hematology-Oncology, Fujian Children’s Hospital, Fuzhou 350014, Fujian, China. Department of Radiation Oncology, Fujian Medical University Cancer of few indices, easy accessibility, and simple operation. In Hospital, Fujian Cancer Hospital, Fuzhou 350014, Fujian, China. this model, patients with a total score of 6.5 or more have a high probability of locoregional recurrence and poor Received: 13 March 2022 Accepted: 28 April 2022 survival. Local interventions, such as postoperative RT, should be supplemented for the high-risk population. References Abbreviations 1. 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Postoperative locoregional recurrence pattern and treatment management of stage pT4 sigmoid colon cancer: a retrospective cohort study

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Abstract

Background: This study aimed to explore the pattern of locoregional recurrence after surgery in patients with non- metastatic stage pT4 sigmoid colon cancer and the role of adjuvant radiotherapy on survival. Methods: We retrospectively analyzed data from 208 patients who underwent surgery in our hospital. The patients were randomly divided into training and validation groups at a 1:1 ratio. Patients at high risk for locoregional recur- rence were screened using Cox regression analysis. Based on the data of 2,886 patients in the Surveillance, Epidemiol- ogy, and End Results (SEER) database, the effect of adjuvant radiotherapy on overall survival (OS) and cancer-specific survival (CSS) was evaluated by Kaplan–Meier curves. Results: Of the 208 patients, 57 (27.4%) presented with locoregional recurrences (14 anastomotic and 43 abdomi- nal or pelvic lymph node recurrences). Multivariate analysis showed that serum CEA, differentiation, lymph node dissection number, and N stage were independent predictors of locoregional recurrence-free survival (all p < 0.05). A risk-stratification model was constructed, and a total score of ≥ 6.5 points was considered the high-risk group for locoregional recurrence. Both the training and validation sets presented that the model had a good predictive abil- ity (area under the curve = 0.828 and 0.724, respectively). Analysis of SEER data revealed that adjuvant radiotherapy significantly prolonged OS and CSS in the high-risk population (all p < 0.05, vs. no radiotherapy). Conclusions: Patients with a total risk score of 6.5 or more had a high likelihood of locoregional recurrence, and perhaps adjuvant radiotherapy could improve their survival. Keywords: Sigmoid colon cancer, Recurrence, Survival, Surgery, Radiotherapy cancer, surgery alone or in combination with postopera- Background tive chemotherapy is the mainstay of treatment. However, Colon cancer is the most common malignant disease of the five-year overall survival (OS) rates of these patients the gastrointestinal tract, with more than 100,000 newly were only 52–64% [2]. In recent decades, with the devel- diagnosed cases each year [1]. For locally advanced colon opment of systemic therapies, the rate of distant metas- tasis in colon cancer has gradually decreased, and the Yaobin Lin and Shan Liu contributed equally. rate of postoperative locoregional recurrence (defined as *Correspondence: junxinwufj@aliyun.com tumor relapses at the anastomotic site or within regional lymph nodes of the sigmoid colon) is between 10–40% College of Clinical Medicine for Oncology, Fujian Medical University, 420 Fuma Rd, Jin’an District, Fuzhou 350014, Fujian, China [3–6]. Therefore, it is important to identify high-risk Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. Radiation Oncology (2022) 17:95 Page 2 of 12 groups for locoregional recurrence and formulate treat- were identified based on the third edition of the Inter - ment strategies. national Classification of Diseases for Oncology code, as The sigmoid colon, the last part of the colon, is espe - described in a previous article [17]. The screening process cially prone to cancer and accounts for approximately is illustrated in Additional file  1. Finally, 2886 patients 39.2% of all colon cancers [7]. For stage T4 sigmoid colon were included in the analysis. Both T stage and N stage cancer, it is sometimes difficult to perform radical resec - were redefined based on the American Joint Committee tion because of its anatomical characteristics [8–10]; On on Cancer TNM staging classification for colon cancer the other hand, it is often accompanied by invasion of 8th edition [18]. adjacent organs or structures, requiring multiple organ resection. It has been reported that the proportion of R1/ Treatments and follow‑up R2 resection (incomplete resection) is 15–35% [6, 11–13]. All patients in our hospital underwent colectomy with Radiotherapy (RT), another important local treatment en-bloc removal of the regional lymph nodes, of which method besides surgery, is not widely used in colon can- 20 (9.6%) underwent combined organ resection due to cer [12, 14]. The sigmoid colon is much lower and easier tumor invasion. Dissection of lymph nodes from para- to position on the RT target area delineation system than colic to the root of the inferior mesenteric artery, as well other parts of the colon, making adjuvant RT plausible as suspicious enlarged lymph nodes observed on pre- for sigmoid colon cancer [15, 16]. Our previous study operative imaging. Complete mesocolic excision was also found that adjuvant RT could prolong survival for performed, and surgical margins were negative in all stage pT4bN0-2M0 sigmoid colon cancer patients [17]. patients. One hundred fifty-five patients (74.5%) received The National Comprehensive Cancer Network guide - adjuvant chemotherapy. The three most common regi - line of colon cancer indicates that postoperative RT can mens were CAPEOX (capecitabine with oxaliplatin), be considered for stage T4 with penetration into a fixed FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin), structure. However, it does not provide a more detailed and capecitabine single-agent chemotherapy. Follow-up description of the target population. data, including locoregional recurrence and survival sta- This study first analyzed the clinicopathological data tus, were collected from medical records and telephone of 208 patients with non-metastatic pathologic stage T4 interviews. At the last follow-up, of the 208 patients, (pT4) sigmoid colon cancer in Fujian Cancer Hospital 98 were alive and 73 died. The remaining 37 patients and selected high-risk patients with locoregional recur- could not be contacted because their contact informa- rence after surgery using a risk-stratification model. tion was changed. The latest follow-up information for Then, in 2,886 patients from the Surveillance, Epidemi - these patients was recorded. Patients without postop- ology, and End Results (SEER) database, we preliminarily erative follow-up records were excluded from the study. demonstrated that postoperative RT has a positive prog- The median follow-up time was 61 months (interquartile nostic role in the population with high-risk of locore- range: 31–86 months). gional recurrence. All patients in the SEER database underwent sur- gery and divided into the surgery alone group (2,628 Methods cases, 91.1%) and the surgery followed by adjuvant RT Patients group (258 cases, 8.9%). Chemotherapy was not ana- The medical records of patients with stage pT4 sigmoid lyzed because the SEER database cannot distinguish colon cancer who received colectomy at our hospital which patients did not receive chemotherapy [19, 20]. from January 2010 to December 2016 were retrospec- All patients were actively followed-up. More detailed tively analyzed. A total of 208 patients were included follow-up information was not available from the SEER after excluding five patients who were lost to follow-up. database. Inclusion criteria were as follows: The patients (1) were diagnosed with sigmoid colon cancer by pathology, (2) Statistical analysis received sigmoid colon resection, (3) had a postoperative SPSS Statistics (version 26.0, IBM Corp) and GraphPad stage was pT4N0-2M0, (4) received no preoperative neo- Prism (version 5.0.1, GraphPad Software) were used for adjuvant therapy, (5) received no other anti-tumor ther- data analysis and plotting graphs. Statistical significance apy except chemotherapy after surgery, and (6) provided was set at P < 0.05. complete follow-up information. The 208 patients screened from our hospital were Clinicopathological data of stage pT4 sigmoid colon equally and randomly assigned to training or valida- cancer patients diagnosed between 2004 and 2016 were tion groups using SPSS software (set seed = 2,000,000). screened from SEER database. Using SEER*Stat 8.3.8 Survival rates were calculated by Kaplan–Meier curves. (IMS, Inc. USA. https:// seer. cancer. gov/ seers tat/), cases Using Cox proportional risk regression, independent Lin  et al. Radiation Oncology (2022) 17:95 Page 3 of 12 predictors associated with locoregional recurrence-free (p = 0.001) were related to poorer LRRFS. Serum survival (LRRFS) were screened, and a model for pre- CA19-9 levels and vascular invasion were not inde- dicting postoperative locoregional recurrence was con- pendent factors for LRRFS (all p > 0.05). structed. The predictive power and optimal cutoff value of the model were assessed by receiver operating char- acteristic (ROC) curve and Youden index, respectively Establishment of the risk‑stratification model for LRRFS [21]. Data from the SEER database was analyzed to assess Based on the β regression coefficient and Exp (B) value, the effect of adjuvant RT on OS and cancer-specific sur - which were generated from the Cox regression analy- vival (CSS) in groups at different risk of locoregional sis, a risk scoring system was constructed (Table  3). The recurrence. scoring system aimed to integrate factors identified from multivariate analysis: serum CEA level, differentiation, lymph node dissection number, and N stage. We assigned Results 5 points for elevated serum CEA level, 3 points for poorly Patient characteristics for our institution differentiated or undifferentiated cells, 3 points for < 12 The general characteristics of 208 patients are presented lymph nodes dissected, and 5 points for the N2 stage. in Table 1. Patients aged 50–69 years accounted for 57.2% Zero points were assigned to normal serum CEA level, of the study population. The proportions of patients with well/moderate differentiation status, removal of fewer elevated serum carcinoembryonic antigen (CEA) levels than 12 lymph nodes, and the N0 and N1 stages. and ≥ 12 lymph node resections were 40.4% and 82.2%, Each patient in the training set was scored according respectively. The surgical margins were negative in all to the risk scoring system, and the total score was calcu- patients. Most patients had no vascular invasion (80.3%) lated. Figure  2 showed the area under the curve (AUC) or perineural invasion (81.7%). Finally, 74.5% of patients was 0.859 with an optimal cutoff value of 6.5 (sensitiv - received postoperative adjuvant chemotherapy. ity = 72.7%, specificity = 93.0%). Locoregional recurrence pattern of stage pT4 sigmoid colon cancer Valuation of the risk‑stratification model Locoregional recurrence occurred in 57 of 208 patients For training set, 75 (72.1%) patients were classified (27.4%). Fourteen patients (6.7%) had an anastomotic into the low locoregional recurrence risk group (total recurrence, and 43 (20.7%) had abdominal or pelvic score < 6.5), and 29 (27.9%) were classified into the high lymph node recurrence. The cumulative locoregional risk group (total score ≥ 6.5). The AUC of this risk -strat- recurrence rates in the first, second and third years after ification model is 0.828 (p < 0.001, Fig.  3A). Figure  3B surgery were 15.6, 23.6, and 26.5%, respectively (Fig. 1A). reveals that the high-risk group had worse LRRFS than Locoregional recurrence mainly occurred within three the low-risk group. Their 1-, 3-, and 5-year LRRFS rates years after surgery (96.5%, 55/57). The median locore - were 48.3% vs. 94.5%, 19.7% vs. 88.6%, and 13.1% vs. gional recurrence time was 11  months, and the inter- 86.7% (p < 0.001), respectively. In addition, OS was also quartile range was 8–18 months. worse in the high-risk group (p < 0.001, Fig. 3C). Once locoregional recurrence occurred, OS decreased The patients in the validation set were scored and significantly (p < 0.001, Fig.  1B). The 1-, 3-, and 5-year OS grouped according to the model. It also showed a good rates in the non-recurrence and recurrence groups were predictive power (AUC = 0.724, p < 0.001, Fig.  3D). Simi- 99.3% vs. 94.7%, 88.7% vs. 39.8%, and 82.6% vs. 26.4%, lar to the training set, the LRRFS and OS were worse respectively. in the high-risk group (all p < 0.001, vs. low-risk group, Fig. 3E, F). Prognostic factors affecting LRRFS Table  2 shows the results of the Cox regression analy- sis of independent predictors related to postopera- Patient characteristics for SEER database tive LRRFS of stage pT4 sigmoid colon cancer in the A total of 2,886 patients with non-metastatic stage pT4 training set. Univariate analysis revealed that serum sigmoid colon cancer were analyzed from the SEER CEA, serum carbohydrate antigen 19–9 (CA19-9), dif- database (Table  4). Most patients from the SEER data- ferentiation, vascular invasion, lymph node dissection base were also aged 50–69  years (47.7%). Patients with number, and N stage were associated with LRRFS (all elevated serum CEA levels, poor differentiation/undif - p < 0.05). Multivariate analysis showed that elevated ferentiated tumor status, < 12 lymph nodes removed, and serum CEA (p < 0.001), poor/undifferentiated differ - lymph node metastases were 52.2%, 21.8%, 19.3%, and entiation (p = 0.024), lymph node dissection number 56.9%, respectively. fewer than 12 (p = 0.029), and lymph node metastasis Lin et al. Radiation Oncology (2022) 17:95 Page 4 of 12 Table 1 Characteristics of patients with stage pT4 sigmoid colon cancer Character Training set (n = 104) Validation set (n = 104) Total (n = 208) N % N % N % Age (year) < 50 31 29.8 17 16.3 48 23.1 50–69 52 50.0 67 64.4 119 57.2 ≥ 70 21 20.2 20 19.2 41 19.7 Sex Male 66 63.5 62 59.6 128 61.5 Female 38 36.5 42 40.4 80 38.5 Serum CEA Normal 63 60.6 61 58.7 124 59.6 Elevated 41 39.4 43 41.3 84 40.4 Serum CA19-9 Normal 73 70.2 78 75.0 151 72.6 Elevated 31 29.8 26 25.0 57 27.4 Type of surgery Colon resection 94 90.4 94 90.4 188 90.4 Multiorgan resection 10 9.6 10 9.6 20 9.6 Differentiation Well/moderate 88 84.6 85 81.7 173 83.2 Poor/undifferentiated 16 15.4 19 18.3 35 16.8 Tumor size (cm) < 5 49 47.1 52 50.0 101 48.6 ≥ 5 55 52.9 52 50.0 107 51.4 Surgical margins Negative 104 100.0 104 100.0 208 100.0 Positive 0 0.0 0 0.0 0 0.0 Vascular invasion No 83 79.8 84 80.8 167 80.3 Yes 21 20.2 20 19.2 41 19.7 Perineural invasion No 82 78.8 88 84.6 170 81.7 Yes 22 21.2 16 15.4 38 18.3 Lymph node dissection number ≥ 12 88 84.6 83 79.8 171 82.2 < 12 16 15.4 21 20.2 37 17.8 T stage T4a 88 84.6 95 91.3 183 88.0 T4b 16 15.4 9 8.7 25 12.0 N stage N0 35 33.7 56 53.8 91 43.8 N1 46 44.2 29 27.9 75 36.1 N2 23 22.1 19 18.3 42 20.2 Adjuvant chemotherapy Yes 83 79.8 72 69.2 155 74.5 No 21 20.2 32 30.8 53 25.5 pT4 pathologic stage T4, N number, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9 Lin  et al. Radiation Oncology (2022) 17:95 Page 5 of 12 Fig. 1 The cumulative locoregional recurrence rates and OS rates for patients with stage pT4 sigmoid colon cancer. A The cumulative locoregional recurrence rates after surgery. B OS rates for patients with or without locoregional recurrence. OS overall survival Eec ff t of adjuvant radiotherapy on survival in different Locoregional recurrence or distant metastasis of colon locoregional recurrence risk groups cancer mainly occurs within 3  years after surgery [22], Based on the model, 1973 (68.4%) patients were assigned and Park et  al. [23] reported that patients who relapsed to the low-risk group and 913 (31.6%) patients to the within 3  years after surgery accounted for 95% of the high-risk group. The effect of adjuvant RT on OS are total population with recurrence. Similar results were presented in Fig.  4A–C. Adjuvant RT significantly pro - also found in this study; the cumulative locoregional longed OS in the entire population (Fig.  4A, p = 0.003). recurrence rate increased rapidly in the first 2 years, and For high-risk patients, adjuvant RT improved the OS, and patients who relapsed within 3 years accounted for 96.5% the median OS was prolonged by 64  months (Fig.  4C, of the recurrence population. Even if the surgical margins p = 0.001). While for patients with low risk of locore- of the patients were all negative, 6.7% of patients had an gional recurrence, the effect of adjuvant RT on OS was anastomotic recurrence. However, the factors affecting not significant (Fig. 4B, p = 0.329). locoregional recurrence have not been determined, and The effect of adjuvant RT on CSS are presented in the results of different studies have been slightly differ - Fig.  4D–F. Similar to OS, adjuvant RT extended CSS in ent. Wang et  al. [24] focused on the tumor site, T stage, the entire population (Fig.  4D, p = 0.020) and high-risk and serum CEA level. Vergara-Fernandez et al. [25] sug- group (Fig.  4F, p = 0.008). For patients with low locore- gested that the number of lymph nodes removed and gional recurrence risk, treatment with or without adju- nerve invasion are important elements affecting the vant RT had no significant impact on CSS (Fig.  4E, locoregional recurrence of colorectal cancer. Analysis p = 0.598). of sex, age, and family history of cancer showed no cor- relation with postoperative recurrence or metastasis of colon cancer [26]. It demonstrated that colon cancer Discussion locoregional recurrence may be affected by many com - In this study, a risk-stratification model was established to plex factors. This study also confirmed that serum CEA screen the high-risk population of postoperative locore- level (p < 0.001) and the lymph node dissection number gional recurrence. The model integrated four param - (p = 0.029) were independent factors affecting locore - eters: serum CEA level, differentiation status, number gional recurrence. For differentiation and N stage, they of lymph nodes dissected, and N stage. Compared with were also the independent predictors (p = 0.024 and the low-risk group, high-risk patients (total score ≥ 6.5) p = 0.001, respectively). Adjuvant chemotherapy was were more likely to have a locoregional recurrence and ineffective at local tumor control (p = 0.134), requiring worser LRRFS and OS (all p < 0.001). In addition, this additional postoperative treatments such as RT. study confirmed that adjuvant RT could improve OS and Serum CEA is a routinely-used marker for diagnos- CSS in patients with high locoregional recurrence risk ing and monitoring colorectal cancer [27, 28]. However, (all p < 0.05, vs. no RT). The model we developed may different researchers hold different views on the role of have implications for the postoperative management of serum CEA for prognosis [19, 24, 29]. In our current some patients, such as providing local interventions and research, elevated serum CEA was found to be an inde- strengthening follow-up monitoring. pendent predictor of locoregional recurrence (p < 0.001), Lin et al. Radiation Oncology (2022) 17:95 Page 6 of 12 Table 2 Variables associated with LRRFS for stage pT4 sigmoid colon cancer in the training set Variable Univariable analysis Multivariable analysis Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Age (year) 0.077 < 50 Reference – 50–69 0.744 (0.364–1.520) 0.417 ≥ 70 0.180 (0.040–0.797) 0.024 Sex Male Reference – Female 0.781 (0.379–1.611) 0.504 Serum CEA Normal Reference – Reference – Elevated 4.765 (2.258–10.056) < 0.001 4.844 (2.137–10.979) < 0.001 Serum CA19-9 Normal Reference – Reference – Elevated 2.806 (1.414–5.567) 0.003 1.575 (0.762–3.256) 0.221 Type of surgery Colon resection Reference – Multiorgan resection 1.216(0.427–3.458) 0.714 Differentiation Well/moderate Reference – Reference – Poor/undifferentiated 3.256 (1.541–6.878) 0.002 2.630 (1.139–6.074) 0.024 Tumor size (cm) < 5 Reference – ≥ 5 1.382 (0.687–2.779) 0.365 Vascular invasion No Reference – Reference – Yes 2.311 (1.094–4.878) 0.028 1.326 (0.576–3.050) 0.507 Perineural invasion No Reference – Yes 1.220 (0.550–2.710) 0.624 Lymph node dissection number ≥ 12 Reference – Reference – < 12 3.332 (1.580–7.026) 0.002 2.789 (1.112–6.994) 0.029 T stage T4a Reference – T4b 0.964 (0.372–2.499) 0.940 N stage < 0.001 0.001 N0 Reference – Reference – N1 2.089 (0.735–5.936) 0.167 1.039 (0.320–3.378) 0.949 N2 8.138 (2.962–22.358) < 0.001 4.741 (1.591–14.125) 0.005 Adjuvant chemotherapy Yes Reference – No 0.449 (0.158–1.280) 0.134 pT4 pathologic stage T4, CI confidence interval, LRRFS locoregional recurrence-free survival, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9 with a score of 5 in the risk stratification model. There - a determinant of postoperative treatment [2, 30, 31]. fore, regular monitoring of changes in serum CEA levels As confirmed in this study, the N stage was associated after surgery is still recommended. with postoperative locoregional recurrence (p = 0.001), Another key factor affecting the survival of colon and the risk in stage N2 patients was 4.741 times than cancer patients is lymph node metastasis, which is also that in stage N0 patients (95% confidence interval [CI]: Lin  et al. Radiation Oncology (2022) 17:95 Page 7 of 12 Table 3 Risk scoring system Risk variable B value Exp (B) Risk coefficient Risk score Serum CEA Normal 0.000 1.000 1.000 0 Elevated 1.578 4.844 4.844 5 Differentiation Well/moderate 0.000 1.000 1.000 0 Poor/undifferentiated 0.967 2.630 2.630 3 Lymph node dissection number ≥ 12 0.000 1.000 1.000 0 < 12 1.026 2.789 2.789 3 N stage N0 0.000 1.000 1.000 0 N1 0.039 1.039 1.039 0 N2 1.556 4.741 4.741 5 CEA carcinoembryonic antigen lymph nodes, as required by clinical guidelines, to achieve a more accurate N stage and reduce the risk of postoperative locoregional recurrence. Perineural invasion is a feature of aggressiveness for colon cancer [24, 32]. It is reported that invasion of peripheral nerves means worse five-year survival [33]. This conclusion has also been confirmed by other studies [25, 34–36]. However, recent studies have reached con- tradictory conclusions, finding that perineural infiltration is unrelated to locoregional recurrence or poor prognosis of colon cancer [4, 24]. In our study, on the premise that surgical margins were negative, it was also found that perineural invasion was not affecting the locoregional recurrence (p = 0.624). RT is one of the most important local interventions; however, for colon cancer, postoperative RT is rarely performed. Preliminary studies conducted in the 1990s revealed that adjuvant RT could improve local control and disease-free survival (DFS) of colon cancer [13, 37, Fig. 2 ROC curve of risk scores. The optimal cutoff value was 38]. Since 2000, interest in RT has diminished [39]. This assessed for the event of locoregional recurrence. ROC receiver may be related to the lack of prospective clinical studies operating characteristic; AUC area under the curve that clearly support the role of RT in colon cancer. The only phase III randomized controlled trial had shown 1.591–14.125, p = 0.005). However, the risk of locore- similar survival rates for postoperative chemoradio- gional recurrence in stage N1 patients was similar to the therapy and chemotherapy in colon cancer (5-year OS: stage N0 patients (p = 0.949). Therefore, patients with 58% vs. 62%, p > 0.05; 5-year DFS: 51% vs. 51%, p > 0.05) stage N2 disease should be vigilant about locoregional [14]. At the same time, the trial had several limitations, recurrence after surgery so that it can be treated as soon such as the inclusion of T3 patients (18.7%, 35/187) and as possible. In addition to the N stage, we found that the insufficient enrollment (the original plan was to enroll lymph nodes dissected number was related to locore- 700 cases, and enrollment was stopped after 222 cases). gional recurrence. The risk of locoregional recurrence Another shortcoming was that only 48% of patients was 2.789-fold higher in patients with fewer than 12 underwent preoperative imaging, and 19% of patients lymph node dissection (95% CI: 1.112–6.994, p = 0.029). had clips placed during the operation, making the imple- Surgeons should try their best to remove 12 or more mentation of postoperative RT more difficult. Lin et al. Radiation Oncology (2022) 17:95 Page 8 of 12 Fig. 3 Valuation of the risk-stratifications model in training and validation set. A ROC curve of risk stratifications in the training set. B LRRFS rates of different risk stratifications in the training set. C OS rates of different risk stratifications in the training set. D ROC curve of risk stratifications in the validation set. E LRRFS rates of different risk stratifications in the validation set. F OS rates of different risk stratifications in the validation set. ROC receiver operating characteristic; AUC area under the curve; LRRFS locoregional recurrence-free survival; OS overall survival As targeted therapy and immunotherapy are more 44]. Previously, we also found that some sigmoid colon widely adopted, the pattern of treatment failure has cancer patients may benefit from postoperative RT [17], changed [40], and the distant failure rate has decreased. and this study once again demonstrated the positive With further exploration of the efficacy and safety of effect of adjuvant RT on survival from the perspective of chemoradiotherapy for colon cancer, the role of radiation locoregional recurrence. is being reconsidered [41–43]. A single-center retrospec- Adjuvant RT has several advantages for sigmoid colon tive study reported in 2016 that adjuvant RT can enhance cancer compared to other parts of the colon. First, the the local control rate and prolong DFS, particularly in sigmoid colon extends from the left iliac crest to the patients with stage T4b or residual tumors [6]. These third sacral plane and continues with the rectum, which findings have also been confirmed by other studies [12, can be readily positioned and targeted for precise local Lin  et al. Radiation Oncology (2022) 17:95 Page 9 of 12 Table 4 Characteristics of patients with stage pT4 sigmoid colon cancer from SEER database Variable With adjuvant radiation (n = 258) Without adjuvant radiation Total (n = 2886) (n = 2628) N % N % N % Insurance Insured 185 71.7 2003 76.2 2188 75.8 Uninsured 18 7.0 106 4.0 124 4.3 Unknown 55 21.3 519 19.7 574 19.9 Age (year) <50 57 22.1 468 17.8 525 18.2 50–69 144 55.8 1233 46.9 1377 47.7 ≥ 70 57 22.1 927 35.3 984 34.1 Sex Male 129 50.0 1360 51.8 1489 51.6 Female 129 50.0 1268 48.2 1397 48.4 Race White 196 76.0 1984 75.5 2180 75.5 Black 22 8.5 289 11.0 311 10.8 Others 39 15.1 343 13.1 382 13.2 Unknown 1 0.4 12 0.5 13 0.5 Marital status Married 140 54.3 1348 51.3 1488 51.6 Others 107 41.5 1175 44.7 1282 44.4 Unknown 11 4.3 105 4.0 116 4.0 Differentiation Well/moderate 211 81.8 2046 77.9 2257 78.2 Poor/undifferentiated 47 18.2 582 22.1 629 21.8 Tumor size (cm) < 5 66 25.6 1096 41.7 1162 40.3 ≥ 5 183 70.9 1462 55.6 1645 57.0 Unknown 9 3.5 70 2.7 79 2.7 Serum CEA Normal 119 46.1 1261 48.0 1380 47.8 Elevated 139 53.9 1367 52.0 1506 52.2 Perineural Invasion Yes 33 12.8 379 14.4 412 14.3 No 108 41.9 1154 43.9 1262 43.7 Unknown 117 45.3 1095 41.7 1212 42.0 Lymph node dissection number ≥ 12 212 82.2 2116 80.5 2328 80.7 < 12 46 17.8 512 19.5 558 19.3 T stage T4a 83 32.2 1653 62.9 1736 60.2 T4b 175 67.8 975 37.1 1150 39.8 N stage N0 148 57.4 1095 41.7 1243 43.1 N1 66 25.6 850 32.3 916 31.7 N2 44 17.1 683 26.0 727 25.2 N = number; CEA = carcinoembryonic antigen; SEER = the Surveillance, Epidemiology, and End Results Lin et al. Radiation Oncology (2022) 17:95 Page 10 of 12 Fig. 4 The effect of adjuvant radiotherapy on OS and CSS. OS rates of all patients (A), low-risk group (B), and high-risk group (C). CSS rates of all patients (D), low-risk group (E), and high-risk group (F). OS overall survival; CSS cancer-specific survival irradiation [15, 16]. In other parts of the colon, it is dif- development of motion management technology also ficult to delineate the postoperative target area under provides technical support for RT in colon cancer [45]. the condition of organ movement without the placement This study had some limitations. First, the cases used of silver clips [4, 42, 45]. Second, the types of organs at to construct the risk stratification model were all nega - risk for sigmoid colon cancer are relatively fixed, which tive for the surgical margins. Therefore, this model is not facilitates quality control of RT. Third, RT in the surgi - suitable for predicting the risk of locoregional recurrence cal area of sigmoid colon cancer has a smaller irradia- in patients with positive resection margins; however, tion volume and a lower cumulative radiation dose to therapeutic intervention should be actively administered. the small intestine, which may reduce the occurrence Second, the selection method of variables included in of radiation enteritis. In addition, adjuvant RT for colon the multivariate analysis has limitations. Factors with p cancer was previously performed using two-dimensional values greater than 0.05 in the univariate analysis were total abdominal irradiation [46–48], while the applica- not included in the multivariate analysis, but these fac- tion of three-dimensional conformal RT and intensity- tors may also be associated with locoregional recur- modulated RT techniques has reduced radiation toxicity rence. Third, the number of patients with colon cancer in normal tissues such as the small bowel [15, 16]. The who received postoperative RT in our institution was not Lin  et al. Radiation Oncology (2022) 17:95 Page 11 of 12 design, data collection and analysis, data interpretation, or preparation of the enough for statistical analysis, and there was no locore- manuscript. gional recurrence-related information in the SEER data- base [49]. Therefore, this study used the data from our Availability of data and materials The dataset analyzed in this study from SEER database can be obtained from: center to analyze postoperative locoregional recurrence https:// seer. cancer. gov/ data/. Other data used and/or analyzed during the and then analyzed the effect of adjuvant RT on OS and current study are available from the corresponding author on reasonable CSS using the SEER database. It is necessary to conduct request. new studies to evaluate the value of postoperative RT from the perspective of LRRFS. In addition, the SEER Declarations database does not record details on RT, such as the range Ethics approval and consent to participate of irradiation target, prescribed dose, and radiation- This study was approved by the ethics committee of Fujian Cancer Hospital related toxicity [20, 50]. Therefore, the details of the RT (No. K2022–005–01). This study was a retrospective analysis of medical records, and informed consent of patients was not required. plan need to be explored further. Finally, it is difficult to avoid selection bias in retrospective analyses, which must Consent for publication be verified and further developed in prospective studies. Not applicable. Competing interests The authors declare that they have no competing interests. Conclusions Author details In this study, a risk-stratification model was established College of Clinical Medicine for Oncology, Fujian Medical University, for predicting postoperative locoregional recurrence in 420 Fuma Rd, Jin’an District, Fuzhou 350014, Fujian, China. Depar tment pT4 sigmoid colon cancer. This model has the advantages of Hematology-Oncology, Fujian Children’s Hospital, Fuzhou 350014, Fujian, China. Department of Radiation Oncology, Fujian Medical University Cancer of few indices, easy accessibility, and simple operation. In Hospital, Fujian Cancer Hospital, Fuzhou 350014, Fujian, China. this model, patients with a total score of 6.5 or more have a high probability of locoregional recurrence and poor Received: 13 March 2022 Accepted: 28 April 2022 survival. Local interventions, such as postoperative RT, should be supplemented for the high-risk population. References Abbreviations 1. 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Journal

Radiation OncologySpringer Journals

Published: May 13, 2022

Keywords: Sigmoid colon cancer; Recurrence; Survival; Surgery; Radiotherapy

References