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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 51  |  Issue : 2  |  Page : 41-49

Differential impacts of clinical variables and 5-fluorouracil-based adjuvant chemotherapy on 5-year disease-free survival of patients with stage IIa and IIb colon cancer


1 Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
2 Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
3 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan; Department of Urology, Chang Gung Memorial Hospital, Chiayi, Taiwan

Date of Submission26-Mar-2017
Date of Decision30-Jul-2017
Date of Acceptance22-Oct-2017
Date of Web Publication24-Apr-2018

Correspondence Address:
Dr. Chih-Chien Chin
Department of Surgery, Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Chiayi Branch, No 6, Sec., West, Chia-Pu Road, Putz City, Chiayi 613
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_51_17

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  Abstract 

Background: The aim of this study was to evaluate practicable predictors of 5-year disease-free survival (DFS) and impact of 5-fluorouracil (5-FU)-based adjuvant chemotherapy in stage IIa and IIb colon cancer.
Materials and Methods: A total of 1474 patients with stage II colon cancer were enrolled in study. The independent predictors of 5-year DFS and the benefits of adjuvant chemotherapy were analyzed for patients with stage IIa (n = 771) and IIb (n = 703).
Results: The incidences of pretreatment anemia, hypoalbuminemia, emergent surgery, and lymphovascular invasion (LVI) corresponded significantly to an advanced T-stage in patients with stage II colon cancer. Although the incidence of surgical morbidity was not different between stage IIa and IIb, stage II patients with hypoalbuminemia had a higher incidence of surgical morbidity than did those with normal serum albumin (17.2% vs. 9.6%, P < 0.001). The co-independent survival predictors in patients with stage IIa and IIb colon cancer were carcinoembryonic antigen (CEA < 5 ng/mL, P = 0.007 and 0.043), serum albumin (≥3.5 g/dL, P < 0.001 and P = 0.025), and nonsurgical morbidity (P < 0.001, both). Suboptimal lymph node harvest (<12 examined nodes, P < 0.001) and no adjuvant chemotherapy (P = 0.008) were poor prognostic factors only in stage IIb colon cancer. LVI showed a trend to worse DFS (P = 0.059). A survival benefit from adjuvant chemotherapy analyzed in four subgroups stratified by stage IIa and IIb, with or without the present prognostic factors, was only observed in patients with stage IIb colon cancer with hypoalbuminemia, abnormal CEA, suboptimal lymph node harvest, and postoperative morbidity.
Conclusion: Different predictors of DFS were observed in stage IIa and IIb colon cancer; adjuvant chemotherapy could provide a survival benefit for patients with stage IIb colon cancer who have one of the four factors that were studied in our hospital-based analysis.

Keywords: Adjuvant chemotherapy, carcinoembryonic antigen, hypoalbuminemia, morbidity, survival of stage II colon cancer


How to cite this article:
Kuo YH, Huang CY, Chin CC, Chen CJ, Huang WS, You JF, Huang YC. Differential impacts of clinical variables and 5-fluorouracil-based adjuvant chemotherapy on 5-year disease-free survival of patients with stage IIa and IIb colon cancer. Formos J Surg 2018;51:41-9

How to cite this URL:
Kuo YH, Huang CY, Chin CC, Chen CJ, Huang WS, You JF, Huang YC. Differential impacts of clinical variables and 5-fluorouracil-based adjuvant chemotherapy on 5-year disease-free survival of patients with stage IIa and IIb colon cancer. Formos J Surg [serial online] 2018 [cited 2018 Oct 20];51:41-9. Available from: http://www.e-fjs.org/text.asp?2018/51/2/41/231142


  Introduction Top


Colorectal cancer is a common malignancy and the third leading cause of death in Taiwan. Stages II and III of this disease are the most common conditions at the time of diagnosis.[1] Even when patients with stage II and III colon cancer receive curative surgery, cancer relapse still occurs in approximately 15%–30% of stage II patients and 50%–60% of stage III patients.[2] Previous studies and clinical trials have demonstrated that adjuvant chemotherapy can significantly benefit patients with stage III colon cancer.[3],[4],[5] According to pooled analyses of stage II colon cancer, adjuvant chemotherapy generally results in more favorable outcomes.[6],[7]

Despite the lack of absolute data and conclusions, postoperative adjuvant chemotherapy is only recommended for high-risk stage II colon cancer, which includes stage IIb, obstruction, perforation, poor-grade tumors, and suboptimal lymph node harvest (<12) according to the guidelines from American Society of Clinical Oncology.[7] Lymphovascular invasion (LVI) or perineural invasion and unclear resection margin have also been considered risk factors and are recommended for adjuvant chemotherapy in the National Comprehensive Cancer Network Guidelines.[8] In addition to these factors, Lai et al. and Zhen et al. defined hypoalbuminemia and iron-deficiency anemia as poor prognostic factors of overall and disease-free survival (DFS) in patients with nonstage IV colon cancer.[9],[10] Although numerous factors have been reported to influence the survival of stage II colon cancer patients, these clinicopathologic factors do not reliably predict the efficacy of adjuvant chemotherapy.

Generally, stage II colon cancer patients have excellent oncologic outcomes, and the benefit of adjuvant chemotherapy is still not strongly evident for all cases of stage II colon cancer. Selecting patients who may most benefit from adjuvant chemotherapy has become a crucial task in treating stage II colon cancer. The present study aimed to identify the common clinical predictors of DFS and to evaluate the impact of 5-fluorouracil (5-FU)-based adjuvant chemotherapy on patients with stage IIa (T3) and IIb (T4) colon cancer. We hypothesized that different benefit of DFS from adjuvant chemotherapy would be evident among patients with or without risk factors in the guidelines from American Society of Clinical Oncology.


  Materials and Methods Top


Study population

From January 1995 to July 2003, 1474 stage II colon cancer patients were enrolled in this study. All of them had received radical resection for colon cancer. The included patients underwent regular postoperative surveillance and a prospective data collection until December 2009 or death. The appropriate approval from the Institutional Review Board (IRB, 104–6053B) of Chang Gung Memorial Hospital was obtained.

The clinicopathologic and demographic data included age, sex, tumor locations, radical cancer resection, surgical timing (elective or emergent surgery), preoperative laboratory data (serum albumin, carcinoembryonic antigen [CEA], and hemoglobin), colon cancer stage (as defined according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system, sixth edition), tumor grade (good, moderate, and poor differentiation), histology (adenocarcinoma, mucinous adenocarcinoma), postoperative adjuvant chemotherapy, and postoperative morbidity. We defined anemia according to the World Health Organization criteria: hemoglobin <12 g/dL in premenopausal women and <13 g/dL in men and postmenopausal women. We considered CEA levels ≥5 ng/mL as abnormal data. Hypoalbuminemia was defined as a serum albumin level <3.5 g/dL. The postoperative surveillance included CEA being followed every 3 months and a yearly computed tomography (CT) of the chest, abdomen, and pelvis for up to 5 years. Cancer relapse was identified in the follow-up according to rising CEA and lesions in a whole-body CT. The primary endpoint of this study was to evaluate the possible benefit of 5-year DFS in patients with stage IIa and IIb colon cancer who received adjuvant chemotherapy or received observation after cancer surgery.

Statistical analysis

In this study, Fisher's exact test was used to compare patients' categorical variables between stage IIa and IIb. The 5-year DFS was calculated as the number of months from primary cancer resection to first cancer relapse or death. The survival difference was estimated using the Kaplan–Meier method, and a comparison was performed using the log-rank test. A Cox proportional hazards regression model was employed for multivariate analyses to identify the independent prognostic factors for DFS. All statistical analyses were performed using SPSS version 17.0 software (SPSS, Inc., Chicago, IL, USA). All P values were two-tailed and were considered statistically significant if they were <0.05.


  Results Top


Patient's characteristics

The clinicopathological characteristics of the 1474 patients in this study are summarized in [Table 1]. The cohort, which included 709 (48.1%) women and 765 (51.9%) men, was further stratified by TNM T-stage into stage IIa (T3N0M0, 771 patients) and stage IIb (T4N0M0, 703 patients). The mean age was 63.9 ± 13.2 years (range 22–91 years; median, 66 years) in the IIa group and 61.6 ± 13.5 years (range 25–93 years; median, 63 years) in the IIb group. Anemia, hypoalbuminemia, emergent surgery, percentage of optimal lymph node harvest, histology type and grade, and postoperative adjuvant chemotherapy with 5-FU infusion differed significantly between the patients in the stage IIa and IIb groups. The presence of anemia, hypoalbuminemia, LVI, and emergent surgery for the patients with colon cancer corresponded significantly with an advanced T-stage (P< 0.001). In the entire stage II group, the patients with proximal colon cancer suffered anemia more frequently than did those with distal colon cancer (78.1% vs. 55.6%, P < 0.001). There were more of patients with stage IIb receiving adjuvant chemotherapy for their cancer treatment (P< 0.001).
Table 1: Characteristic of 1474 patients with stage II colon cancer

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Postoperative morbidity did not differ between the patients with stage IIa and IIb colon cancer in [Table 1]. Regarding surgical timing, compared with elective colon cancer surgery, emergent surgery was correlated with higher incidences of postoperative morbidity in patients with stage IIa (17.2% vs. 9.9%, P = 0.077, data not shown) and stage IIb colon cancer (17.9% vs. 11.1%, P = 0.045, data not shown). Furthermore, stage II patients with hypoalbuminemia suffered a higher incidence of surgical morbidity than did those with normal serum albumin (17.2% vs. 9.6%, respectively; P < 0.001). Hypoalbuminemia was significantly correlated with the performance of emergent colon cancer surgery in stage IIa and IIb patients [Table 2].
Table 2: Relationship between hypoalbuminemia and surgical timing in stage IIa and IIb colon cancer

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Outcome of cancer treatment

Cancer relapse was observed in 183 patients, namely, 57 (7.4%) and 126 (17.9%) stage IIa and IIb patients, respectively, at a median follow-up time of 61 months (range 2–150 months). The 5-year DFS rate was 82.4% and 73.8% in patients with stage IIa and stage IIb colon cancer, respectively. According to univariate analysis, abnormal CEA (≥5 ng/mL), hypoalbuminemia (<3.5 g/dL), emergent surgery for colon cancer, and postoperative morbidity were significant risk factors influencing 5-year DFS in stage IIa and IIb patients. The cancer distal to the splenic flexure of the colon (P = 0.022), cancer with circumferential involvement (P = 0.012), suboptimal lymph node examination (P = 0.041), and no adjuvant chemotherapy (P = 0.005) were the risk factors of DFS for stage IIb patients [Table 3]. In multivariate Cox regression model, the statistically significant factors which were further selected to analyze their independence from previous univariate analysis were abnormal CEA, hypoalbuminemia, and postoperative morbidity influencing patients' 5-year DFS in stage IIa or IIb. The presence of LVI showed a trend toward poor DFS in stage IIb colon cancer (P = 0.059). Suboptimal lymph node examination (P< 0.001) and no adjuvant chemotherapy (P = 0.008) were independent risk factors only for patients with stage IIb colon cancer [Table 4].
Table 3: Univariate analysis for prognostic factors of 5-year disease-free survival in stage IIa and IIb

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Table 4: Multivariate analysis for prognostic factors of 5-year disease-free survival in stage IIa and IIb

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Adjuvant chemotherapy was not an independent prognostic factor for 5-year DFS in patients with stage IIa colon cancer [Table 4] and [Figure 1]. In contrast, it was an independent factor for DFS in stage IIb colon cancer [Table 4] and [Figure 2]. Except LVI, none of the independent prognostic factors, including abnormal CEA, hypoalbuminemia, postoperative morbidity, and suboptimal lymph node examination, displayed variation with or without adjuvant chemotherapy [Table 5]. Therefore, we further stratified the stage IIb patients into two subgroups according to the presence or absence of risk factors to evaluate the benefit of adjuvant chemotherapy. A total of 302 stage IIb patients had no risk factors and 401 stage IIb patients had one or more risk factors which were analyzed in above section. The relationship between the benefit of adjuvant chemotherapy (5-FU-based treatment) and prognostic factors in patients with stage IIb colon cancer was further analyzed independently using Cox regression [Table 6]. Adjuvant chemotherapy remained one of the independent prognostic factors for 5-year DFS. In patients with stage IIb colon cancer and risk factors, including abnormal CEA, hypoalbuminemia, suboptimal lymph node examination, and postoperative morbidity, the 5-year DFS differed significantly between those receiving adjuvant chemotherapy and those receiving observation [Figure 3]. In contrast, patients would not benefit from adjuvant chemotherapy if they had stage IIb colon cancer without any independent factors [Figure 4].
Figure 1: Adjuvant chemotherapy was not a risk factor for 5-year disease-free survival in patients with stage IIa colon cancer

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Figure 2: Adjuvant chemotherapy was a possible risk factor for 5-year disease-free survival in patients with stage IIb colon cancer

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Table 5: Independent risk factors between stage IIb patients with or without adjuvant chemotherapy

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Table 6: Multivariate analysis for prognostic factors of 5-year disease-free survival in stage IIb with any risk

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Figure 3: Adjuvant chemotherapy improved the 5-year disease-free survival in patients with stage IIb colon cancer with any risk factors, including pretreatment hypoalbuminemia, abnormal pretreatment carcinoembryonic antigen, surgical morbidity, and suboptimal lymph node count

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Figure 4: No other significant benefit of adjuvant chemotherapy was found for 5-year disease-free survival in patients with stage IIb colon cancer without the presenting risk factors

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  Discussion Top


Relationship between pretreatment hypoalbuminemia, surgical morbidity, and oncologic outcome

Hypoalbuminemia has been widely considered an indicator of malnutrition. It occurs in surgical patients not only because of catabolic problems from surgical stress but is also associated with numerous preoperative conditions or characteristics of patients with colon cancer, such as cancer obstruction, perforation, and cachexia. The relationship between hypoalbuminemia, surgical timing, and postoperative morbidity was noted in the present results. For conditions of colon cancer perforation or obstruction that might cause hypoalbuminemia, regardless of whether patients have stage IIa or IIb colon cancer, patients have a greater chance of receiving emergent surgery than elective surgery [Table 2]. Emergent compared with elective colon cancer surgery was correlated with higher incidence of postoperative morbidity in patients with stage IIa (17.2% vs. 9.9%, P = 0.077, data not shown) and stage IIb (17.9% vs. 11.1%, P = 0.045, data not shown) colon cancer. The incidence of surgical morbidity in all the patients with stage II colon cancer also corresponded to patients' pretreatment hypoalbuminemia (16.0% vs. 10.0%, P = 0.003, data not shown). Lower serum albumin has been considered with the short-term outcome, including morbidity, after management for bowel obstruction management.[11] To our knowledge, the relationship between hypoalbuminemia and adverse outcomes of gastrointestinal surgery has been known for the last decade.[12],[13],[14],[15] In a large multicenter study for colorectal surgery for conditions including colorectal cancer and diverticulitis, hypoalbuminemia was the most significant factor among six independent factorsfor postoperative morbidity (age >70 years, neurologic comorbidity, hypoalbuminemia, cardiorespiratory comorbidity, long operative duration, and peritoneal contamination.).[16]

A systemic inflammatory response might be induced by inflammatory cytokines, such as interleukin 6, after major surgery. In such cases, postoperative morbidity can induce a persistent inflammatory status and maintain immunosuppression.[17],[18] The oncologic outcome is possibly linked to a detrimental immunological response after inflammation following postoperative complications.[19],[20],[21] In our study, the presence of surgical morbidity and hypoalbuminemia acted as independent factors for 5-year DFS for patients with stage IIa or stage IIb colon cancer. The impact of surgical morbidity was not just evident in our patients with stage II colon cancer, but a shorter relapse-free survival after metastasectomy for colon cancer with liver metastasis was also independently predicted in another observational study. The severity of morbidities also corresponded to the relapse-free and overall survival.[22]

Although our present results revealed that hypoalbuminemia was an independent prognostic factor for 5-year DFS, whether hypoalbuminemia influences the oncologic outcome of colon cancer remains controversial. In 1998, hypoalbuminemia was documented as a prognostic factor for the survival of patients with curable colon cancer.[23] Hypoalbuminemia's unfavorable impact on oncologic survival was also noted in a later study.[24] From another viewpoint, hypoalbuminemia was not considered a prognostic factor for the survival of patients with colon cancer; however, when it occurred in conjunction with another factor, such as CEA, it became a predictor of oncologic outcome.[25] The results of survival studies for hypoalbuminemia might vary depending on different endpoints and definitions of survival, including overall survival, DFS, or cancer-specific survival. We considered that low DFS in stage II colon cancer patients with hypoalbuminemia might be caused by higher incidence of surgical morbidity or other known negative characteristics of colon cancer, including obstruction or perforation.

Abnormal pretreatment carcinoembryonic antigen

Several studies have provided evidence that abnormal CEA (≥5 ng/mL) can be a stage-independent factor for predicting oncologic outcome. The AJCC proposed the inclusion of pretreatment CEA to complement the TNM staging of colon cancer as early as 2000.[26] In 2015, Thirunavukarasu et al. using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database analyzed the impact of CEA on the overall TNM staging of colon cancer.[27] An abnormal pretreatment CEA level (≥5 ng/mL) was a stage-independent poor prognostic factor associated with increasing overall cancer mortality (hazard ratio [HR] 1.59; 95% confidence interval [CI], 1.49–1.69, P < 0.001). In their study, patients with stage IIIa colon cancer and without abnormal CEA had higher overall survival than did those with stage I or IIa colon cancer and abnormal CEA (P< 0.001). A similar independent effect of abnormal CEA on the 5-year DFS of patients with stage II colon cancer was also noted in our study. However, the major disagreement between the studies by Thirunavukarasu et al. and our study was in the information on and influence of adjuvant chemotherapy, especially for patients with stage III colon cancer. The effect of adjuvant chemotherapy was not analyzed in their study, and there was a possibility of inappropriate estimation of risk according to abnormal pretreatment CEA for different stages of colon cancer in their study. In our study, multivariate analysis was performed for available clinical factors in patients with stage IIa and IIb colon cancer, and we found that patients with stage IIb colon cancer and any independent risk factors received a greater survival benefit from adjuvant chemotherapy.

Pretreatment anemia

Anemia has been known to occur with proximal colon cancer, delayed symptom duration, and higher cancer stage at diagnosis.[28],[29] For long-term cancer mortality, the correlation between anemia and mortality was investigated in a cohort study combining cases of colon and rectal cancer.[30] Although anemia was correlated with mortality, its prognostic role might be counterintuitive and influenced by various TNM stages. In our observation, stage IIb colon cancer with preoperative anemia showed an unfavorable DFS only in univariate analysis [Cox regression, P = 0.022, [Table 3].

For patients with stage II colon cancer, we reached a different conclusion from that of Zhen et al., who determined that anemia is an independent predictor of long-term outcome in patients with stage IIa colon cancer (Cox regression, P = 0.009).[10] Because our raw data were categorized according to the AJCC TNM staging system, sixth edition, the pathologists of our institution did not stratify the stage IIb set into groups with adjacent organ invasion or perforation of the visceral peritoneum. The presence of stage IIb colon cancer with direct invasion to adjacent organs (stage IIc colon cancer, AJCC TNM staging system, seventh edition) actually predicts a much worse long-term outcome.[31] This might be due to influence the different result between our observations of patients with stage IIb colon cancer and those of Zhen et al.

Impact of adjuvant chemotherapy on subgrouping patients

In the previous studies that were based on a pooled analysis,[32] MOSAIC trial,[5] and analysis of SEER that aimed to determine the efficacy of adjuvant chemotherapy,[33] different results, including a significant survival benefit from 5-FU-based treatment, a trend toward improved DFS from oxaliplatin treatment, and a lack of a survival benefit from unclear regimens of adjuvant therapy were observed in patients with high-risk stage II colon cancer. In these studies, patients with stage II colon cancer were evaluated collectively or stratified according to individual risk factors.

In our multivariate analysis of stage IIb colon cancer patients with these factors, five factors independently influenced 5-year DFS [Table 6]. Stage IIb patients with risk factors receiving 5-FU-based adjuvant chemotherapy had significantly superior 5-year DFS. Our findings suggest that stage IIa or stage IIb patients without any of our risk factors might receive less benefit from adjuvant chemotherapy. From our observations, we could not explain why the adjuvant chemotherapy did not benefit the subgroup of stage IIb patients without risk factors [Figure 4]. This result might have occurred because of the small number of case in the subgroup and the absence of further stratification of stage IIb colon cancer into T4a and T4b categories according to the AJCC TNM staging system, seventh edition. Our findings were similar to those of several reports that have suggested that the benefit of adjuvant chemotherapy might be limited to a high-risk group.[34],[35],[36] Kumar et al. mentioned that the purpose of adjuvant chemotherapy is to prevent cancer relapse for cancer patients with high risk; the DFS was one of the most sensitive measures of the intended effect of adjuvant chemotherapy.[35] They also recommended using adjuvant chemotherapy in patients with high risk to improve DFS, cancer-specific survival, and overall survival.

In addition to above information, we should consider the possible role of microsatellite instability (MSI) on the efficacy of chemotherapy if we had this molecular information in our database. The majority of colorectal cancers develop via chromosome instability and mutation; approximately 15% have defective DNA mismatch repair (dMMR) which has frequently been measured by the presence of MSI.[37],[38] In addition to the improved stage-dependent survival in colorectal cancer with dMMR, different treatment benefit of 5-FU-based therapy has been observed in some clinical trials.;[39],[40],[41] however, different results of these studies did not draw the equal conclusion. New data presented by Sargent et al. in 2010 supported MMR status as a clinically useful marker in patients being considered for5-FU-based adjuvant chemotherapy.[42] Patients with dMMR tumors receiving 5-FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42–2.91; P = 0.85). The lack of benefit from 5-FU-based chemotherapy in patients with dMMR tumors indicates that such patients should not receive 5-FU-based adjuvant chemotherapy. In contrast, adjuvant therapy significantly improved DFS (HR, 0.67; 95% CI, 0.48–0.93; P = 0.02) in patients without dMMR tumors.

The present study had several limitations. First, it was a retrospective study for observing the 5-year DFS of patients with stage II colon cancer. In our experience, over the past two decades, whether to use adjuvant chemotherapy after curative surgery for stage II colon cancer has always been subject to the attending physician's clinical discretion. No data on the dose intensity and adverse effects during the use of adjuvant chemotherapy were available. Second, we hypothesized that hypoalbuminemia is an indicator of patients' colon cancer characteristics, such as cancer obstruction, perforation, and cachexia. However, in this study, hypoalbuminemia is equivalent to known risk factors, such as cancer obstruction or perforation. Third, an inaccurate observation of complications was possible because this study was retrospective. In addition, we did not further subgroup the different surgical morbidity types because of the low number of cases with surgical morbidity. The lack of data on the severity of complications and the low-performance rate of adjuvant chemotherapy after surgical morbidity were sources of possible bias.


  Conclusion Top


Different survival predictors could exist for various T-stages of stage II colon cancer. Simple pretreatment clinical factors, such as hypoalbuminemia, abnormal CEA, and surgical morbidity, could effectively predict prognosis for stage II colon cancer; hypoalbuminemia was associated with emergent surgery and surgical morbidity according to our observation. The lymph node count ≥12 also remained valuable for long-term oncologic outcome prediction in patients with stage IIb colon cancer. Because of the limited number of cases, we could not strongly document the benefit of adjuvant chemotherapy for patients with stage IIb colon cancer without risk factors (hypoalbuminemia, surgical morbidity, abnormal CEA, and suboptimal lymph node count). However, we suggested that stage IIb patients with these risk factors could obtain improved oncologic outcomes with the use of 5-FU-based adjuvant chemotherapy. A prospective study is mandatory to confirm the survival benefit of adjuvant chemotherapy among this subgroup of patients.

Acknowledgment

Chia-Hao Chang supervised the statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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