|Year : 2018 | Volume
| 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
Yi-Hung Kuo1, Cheng-Yi Huang2, Chih-Chien Chin1, Chih-Jung Chen2, Wen-Shih Huang1, Jeng-Fu You2, Yun-Ching Huang3
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 Submission||26-Mar-2017|
|Date of Decision||30-Jul-2017|
|Date of Acceptance||22-Oct-2017|
|Date of Web Publication||24-Apr-2018|
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
Source of Support: None, Conflict of Interest: None
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 May 25];51:41-9. Available from: http://www.e-fjs.org/text.asp?2018/51/2/41/231142
| Introduction|| |
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. 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. Previous studies and clinical trials have demonstrated that adjuvant chemotherapy can significantly benefit patients with stage III colon cancer.,, According to pooled analyses of stage II colon cancer, adjuvant chemotherapy generally results in more favorable outcomes.,
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. 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. 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., 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|| |
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.
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|| |
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).
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|
Click here to view
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|
Click here to view
|Table 4: Multivariate analysis for prognostic factors of 5-year disease-free survival in stage IIa and IIb|
Click here to view
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|
Click here to view
|Figure 2: Adjuvant chemotherapy was a possible risk factor for 5-year disease-free survival in patients with stage IIb colon cancer|
Click here to view
|Table 5: Independent risk factors between stage IIb patients with or without adjuvant chemotherapy|
Click here to view
|Table 6: Multivariate analysis for prognostic factors of 5-year disease-free survival in stage IIb with any risk|
Click here to view
|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|
Click here to view
|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|
Click here to view
| Discussion|| |
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. To our knowledge, the relationship between hypoalbuminemia and adverse outcomes of gastrointestinal surgery has been known for the last decade.,,, 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.).
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., The oncologic outcome is possibly linked to a detrimental immunological response after inflammation following postoperative complications.,, 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.
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. Hypoalbuminemia's unfavorable impact on oncologic survival was also noted in a later study. 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. 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. 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. 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.
Anemia has been known to occur with proximal colon cancer, delayed symptom duration, and higher cancer stage at diagnosis., For long-term cancer mortality, the correlation between anemia and mortality was investigated in a cohort study combining cases of colon and rectal cancer. 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). 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. 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, MOSAIC trial, and analysis of SEER that aimed to determine the efficacy of adjuvant chemotherapy, 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.,, 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. 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., 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.;,, 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. 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|| |
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.
Chia-Hao Chang supervised the statistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ju JH, Chang SC, Wang HS, Yang SH, Jiang JK, Chen WC, et al.
Changes in disease pattern and treatment outcome of colorectal cancer: A review of 5,474 cases in 20 years. Int J Colorectal Dis 2007;22:855-62.
O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96:1420-5.
O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, et al.
Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15:246-50.
Labianca R, Marsoni S, Pancera G, Torri V, Zaniboni A, Erlichman C, et al
. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: A randomised study. British Journal of Cancer 2007;97:1028-34.
André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al.
Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109-16.
Quasar Collaborative Group, Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, et al.
Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet 2007;370:2020-9.
Benson AB 3rd
, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, et al.
American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22:3408-19.
Lai CC, You JF, Yeh CY, Chen JS, Tang R, Wang JY, et al.
Low preoperative serum albumin in colon cancer: A risk factor for poor outcome. Int J Colorectal Dis 2011;26:473-81.
Zhen L, Zhe S, Zhenning W, Zhifeng M, Zhidong L, Xiaoxia L, et al.
Iron-deficiency anemia: A predictor of diminished disease-free survival of T3N0M0 stage colon cancer. J Surg Oncol 2012;105:371-5.
Francescutti V, Miller A, Satchidanand Y, Alvarez-Perez A, Dunn KB. Management of bowel obstruction in patients with stage IV cancer: Predictors of outcome after surgery. Ann Surg Oncol 2013;20:707-14.
Gibbs J, Cull W, Henderson W, Daley J, Hur K, Khuri SF, et al.
Preoperative serum albumin level as a predictor of operative mortality and morbidity: Results from the National VA Surgical Risk Study. Arch Surg 1999;134:36-42.
Buzby GP, Mullen JL, Matthews DC, Hobbs CL, Rosato EF. Prognostic nutritional index in gastrointestinal surgery. Am J Surg 1980;139:160-7.
Vincent JL, Dubois MJ, Navickis RJ, Wilkes MM. Hypoalbuminemia in acute illness: Is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg 2003;237:319-34.
Lohsiriwat V, Lohsiriwat D, Boonnuch W, Chinswangwatanakul V, Akaraviputh T, Lert-Akayamanee N, et al.
Pre-operative hypoalbuminemia is a major risk factor for postoperative complications following rectal cancer surgery. World J Gastroenterol 2008;14:1248-51.
Alves A, Panis Y, Mathieu P, Mantion G, Kwiatkowski F, Slim K, et al.
Postoperative mortality and morbidity in French patients undergoing colorectal surgery: Results of a prospective multicenter study. Arch Surg 2005;140:278-83.
Wortel CH, van Deventer SJ, Aarden LA, Lygidakis NJ, Büller HR, Hoek FJ, et al.
Interleukin-6 mediates host defense responses induced by abdominal surgery. Surgery 1993;114:564-70.
Lundy J, Ford CM. Surgery, trauma and immune suppression. Evolving the mechanism. Ann Surg 1983;197:434-8.
Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet 2001;357:539-45.
Kooby DA, Stockman J, Ben-Porat L, Gonen M, Jarnagin WR, Dematteo RP, et al.
Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 2003;237:860-9.
Lerut T, Moons J, Coosemans W, Van Raemdonck D, De Leyn P, Decaluwé H, et al.
Postoperative complications after transthoracic esophagectomy for cancer of the esophagus and gastroesophageal junction are correlated with early cancer recurrence: Role of systematic grading of complications using the modified Clavien classification. Ann Surg 2009;250:798-807.
Mavros MN, de Jong M, Dogeas E, Hyder O, Pawlik TM. Impact of complications on long-term survival after resection of colorectal liver metastases. Br J Surg 2013;100:711-8.
Heys SD, Walker LG, Deehan DJ, Eremin OE. Serum albumin: A prognostic indicator in patients with colorectal cancer. J R Coll Surg Edinb 1998;43:163-8.
Cengiz O, Kocer B, Sürmeli S, Santicky MJ, Soran A. Are pretreatment serum albumin and cholesterol levels prognostic tools in patients with colorectal carcinoma? Med Sci Monit 2006;12:CR240-7.
Boonpipattanapong T, Chewatanakornkul S. Preoperative carcinoembryonic antigen and albumin in predicting survival in patients with colon and rectal carcinomas. J Clin Gastroenterol 2006;40:592-5.
Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on cancer prognostic factors consensus conference: Colorectal working group. Cancer 2000;88:1739-57.
Thirunavukarasu P, Talati C, Munjal S, Attwood K, Edge SB, Francescutti V, et al.
Effect of incorporation of pretreatment serum carcinoembryonic antigen levels into AJCC staging for colon cancer on 5-year survival. JAMA Surg 2015;150:747-55.
Gonzalez-Hermoso F, Perez-Palma J, Marchena-Gomez J, Lorenzo-Rocha N, Medina-Arana V. Can early diagnosis of symptomatic colorectal cancer improve the prognosis? World J Surg 2004;28:716-20.
Dunne JR, Gannon CJ, Osborn TM, Taylor MD, Malone DL, Napolitano LM, et al.
Preoperative anemia in colon cancer: Assessment of risk factors. Am Surg 2002;68:582-7.
Stapley S, Peters TJ, Sharp D, Hamilton W. The mortality of colorectal cancer in relation to the initial symptom at presentation to primary care and to the duration of symptoms: A cohort study using medical records. Br J Cancer 2006;95:1321-5.
Hari DM, Leung AM, Lee JH, Sim MS, Vuong B, Chiu CG, et al.
AJCC cancer staging manual 7th
edition criteria for colon cancer: Do the complex modifications improve prognostic assessment? J Am Coll Surg 2013;217:181-90.
Gill S, Loprinzi CL, Sargent DJ, Thomé SD, Alberts SR, Haller DG, et al.
Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J Clin Oncol 2004;22:1797-806.
O'Connor ES, Greenblatt DY, LoConte NK, Gangnon RE, Liou JI, Heise CP, et al.
Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. J Clin Oncol 2011;29:3381-8.
Lin HH, Chang YY, Lin JK, Jiang JK, Lin CC, Lan YT, et al.
The role of adjuvant chemotherapy in stage II colorectal cancer patients. Int J Colorectal Dis 2014;29:1237-43.
Kumar A, Kennecke HF, Renouf DJ, Lim HJ, Gill S, Woods R, et al.
Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer. Cancer 2015;121:527-34.
Quah HM, Chou JF, Gonen M, Shia J, Schrag D, Landmann RG, et al.
Identification of patients with high-risk stage II colon cancer for adjuvant therapy. Dis Colon Rectum 2008;51:503-7.
Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993;363:558-61.
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260:816-9.
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al.
Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N
Engl J Med 2003;349:247-57.
Hemminki A, Mecklin JP, Järvinen H, Aaltonen LA, Joensuu H. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 2000;119:921-8.
Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B, et al.
Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:1745-50.
Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al.
Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010;28:3219-26.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]