Postoperative Adjuvant Chemotherapy Improves Survival in Stage II Colon Cancer ? A Propensity Score Matching Analysis

Objective: The use of postoperative adjuvant chemotherapy (POAC) after surgery for patients with stage II colon cancer remains controversial. The current study was conducted to investigate the effectiveness of POAC using propensity score (PS) matching analysis based on prognostic factors. Materials: Two hundred and nineteen patients with stage II colon cancer who underwent surgery with curative intent between 1995 and 2005 were enrolled. Methods: PS matching analysis was used to adjust for differences in clinicopathological severity between the patients with and without POAC. Results: Before PS matching analysis significant survival benefits from POAC were not recognized for recurrence-free survival (Hazard ratio=0.76, 95%CI; 0.40-1.45, p=0.41) or cancer-specific survival (Hazard ratio=0.52, 95%CI; 0.22-1.19, p=0.12). After PS matching analysis significant survival benefits from POAC were not recognized for recurrence-free survival (Hazard ratio=0.55, 95%CI; 0.23-1.23, p=0.15) or cancer-specific survival (Hazard ratio=0.46, 95%CI; 0.16-1.18, p=0.11). Conclusion: The one-to-one pair PS matching successfully balanced the clinicopathological factors between the patients with and without POAC. The PS matching analysis demonstrated no significant difference in survival in the patients with stage II colon cancer.


Introduction
Colorectal cancer is one of the most common causes of cancer death all over the world, and its incidence in Japan is increasing rapidly 1) 2) .Overall, 25-40% of patients diagnosed with adenocarcinoma of the colon will have stage II disease, which portends a relatively good prognosis, with 5-year overall survival rates ranging from 72 to 85% 3) , compared with stage III disease 4) -6) .Therefore, the possible benefit of postoperative adjuvant chemo-therapy (POAC) is small.However, patients with high-risk features have been traditionally considered more likely to benefit from POAC 7) .National Comprehensive Cancer Network (NCCN) guidelines do not recommend routine administration of adjuvant chemotherapy for stage II patients, except for those with high risk features, such as poorlydifferentiated tumors, T4 disease, perforated tumors and those with inadequate lymph node sampling (http://www.nccn.org).Similarly, in the European Society for Medical Oncology (ESMO) clinical practice guideline and Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines, POAC should not be routinely recommended except for in high-risk patients 8) 9) .However, the use of this treatment after surgery for patients with stage II disease remains controversial 10) .Thus, the current study was conducted to investigate the effectiveness of POAC using propensity score (PS) matching analysis based on these prognostic factors.

Patient selection
Two hundred and nineteen patients with stage II colon cancer (TNM classification 7th edition 11) ) who underwent surgery with curative intent at our department between 1995 and 2005 were enrolled in the present study.We retrospectively reviewed the database and medical records.The median observation period was 73.4 months (range: 2.2-184.2months).

Postoperative adjuvant chemotherapy (POAC)
We decided whether or not the patients received POAC based on clinicopathological factors (i.e., preoperative CEA, differentiation, invasion depth, lymphatic invasion, venous invasion, the number of dissected lymph nodes and preoperative ileus and perforation) and general status (age).During the present study period, we did not consider the location of the primary tumor when deciding the indication for POAC.Ultimately, the decision regarding the use of POAC was made for each case based on individual patient/physician discussions.All of the eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 6) .All patients were required to provide informed consent 6) .During the present study period, patients received 5-FU drugs orally, starting 4-8 weeks after surgery 6) .We did not perform preoperative adjuvant chemotherapy at our department because preoperative adjuvant chemotherapy was not widely accepted during the present study period 6) .

Pathological examination
All specimens were investigated in the following manner 12) : After resection of the primary tumor, the excised specimen was opened on the antimesenteric side by the surgeon.After fixation in formalin, the specimen and lymph nodes were also examined by the pathologist 5) .

Follow-up program
During the first 3 years, patients were followed with clinical assessment and measurement of serum CEA every 3 months, and with chest X-ray or computed tomography and abdominal ultrasonography or computed tomography every 3-6 months 5) .For the remaining 2 years, all tests were performed every 6 months 5) .Colonoscopy was performed 1 year after the operation and every 2 years, thereafter, for the next 4 years 5) .

Propensity score (PS) matching Analysis
PS matching analysis was used to adjust for differences in clinicopathological severity between the patients with and without POAC.First, the PS was estimated.The log odds of the probability that a patient received POAC was modeled for potential confounders: age, preoperative CEA, differentiation, invasion depth, lymphatic invasion, venous invasion, the number of dissected lymph nodes and the presence of preoperative ileus or perforation.The reason we chose these clinicopathological factors as confounders for PS matching analysis was because we had decided whether or not we should recommend POAC to the patients based primarily on these factors.The discrimination of the propensity model was assessed with calculation of the c-statistic.One-to-one pair matching was done without replacement, and PS were matched with calipers<0.1.PS matching analysis was performed using SPSS Statistics version 22 (IBM Corporation, Somers, NY, USA).

Statistical analysis
Recurrence-free and cancer-specific survival were calculated using the Kaplan-Meier method and univariate analyses were performed using the log-rank test.Discrete variables were compared using Fisherʼs exact probability test and continuous variables were compared using the Mann-Whitney U-test.The Cox proportional-hazard model was used to determine Hazard ratios and 95% confidence intervals.Data were analyzed statistically using JMP 9.0.2 software (SAS Institute Inc., Cary, NC, USA).Differences were considered statistically significant at p<0.05.Values are expressed as median (min.-max.).

Details of the regimens and doses of POAC
One hundred and nineteen patients (54.3%) underwent POAC.The details of the regimens and doses of POAC are shown in Table -1.The most frequently encountered regimen was tegafur-uracil combination in 58 patients (48.7%) followed by fluorouracil in 55 patients (46.2%).The durations of POAC ranged from six months to one year in 21 patients (17.6%), from one to two years in 70 patients (58.8%) and more than two years in 27 patients (22.7%).Only one patient (0.8%) discontinued POAC within less than six months because of recurrence.The mean duration of POAC was 25.9 months.

Comparisons of recurrence-free and cancer-
specific survival according to the clinicopathological factors in the entire cohort Significant differences in recurrence-free survival were recognized in venous invasion (p = 0.007) (Table -2).There was a trend towards worse recurrence-free survival in patients with proximal colon (p = 0.06), invasion depth of T4 (p = 0.06) and moderate-severe lymphatic invasion (p = 0.07).There were no significant differences with respect to the other clinicopathological factors.Next, significant differences in cancer-specific survival were recognized with respect to location (p = 0.01), differentiation (p = 0.005), invasion depth (p=

Comparisons of the clinicopathological factors between patients with and without POAC
In univariate analysis, there were significant differences in age, invasion depth, lymphatic invasion and venous invasion between the patients with and without POAC.Specifically, patients who received POAC were more likely to be younger (p<0.0001), to have an invasion depth of T4 (p = 0.04), a moderate-severe lymphatic invasion (p = 0.002) and/or a moderate-severe venous invasion (p<0.0001)(Table-3).There were no significant differences between the two groups with respect to the other clinicopathological factors.Recurrence-free survival b) Cancer-specific survival c) Cecum or ascending colon or transverse colon d) Descending colon or sigmoid colon or rectosigmoid colon e) CEA<3.1 ng/ml f) CEA ≥3.1 ng/ml g) Well-and moderately-differentiated adenocarcinoma h) Poorly-differentiated or mucinous adenocarcinoma or signet ring cell carcinoma

Comparisons of recurrence-free and cancerspecific survival according to the clinicopathological factors in the propensity matched cohort
The median propensity score was 0.37 (0.07-0.97) in the patients without POAC and 0.69 (0.20-0.98) in the patients with POAC (p<0.0001).The c-statistic was 0.79, indicating satisfactory discrimination.After PS matching analysis, in univariate analysis, there were no significant differences with respect to the clinicopathological factors between the patients with and without POAC (

Discussion
For the 25% of patients with stage II colon cancer who will have future recurrence, it is generally believed that there were residual undetectable micrometastases at the time of primary resection.If POAC will decrease this risk of recurrence, the identification of the candidates who will benefit from POAC is crucial 13) .In order to better identify and treat stage II cancer patients with a risk of recurrence, dozens of investigations have been published over the decades.However, finding reliable prognostic factors has proven elusive 7) .This makes risk stratification difficult, leaving physicians to individualize treatment for stage II patients, which can result in widespread variations in practice 14) .To date, this issue has been addressed in several clinical trials and practice-based studies.However, controversy remains over the role of POAC.Some groups have reported that stage II patients derived a statistically significant survival benefit from POAC 15) 16) .On the other hand, other large subsequent studies have not shown statistical significance in survival 17)-19) .
In Japan, POAC after curative surgery was developed primarily using oral fluoropyrimidine, such as oral 5-FU 20) 21) .Consequently, the background of the regimen in POAC is different from the above-mentioned studies that were conducted in western countries.Therefore, the benefit of oral adjuvant chemotherapy in stage II patients must be established.In the current study, PS matching analysis was performed to examine the benefit of oral POAC.
The PS is the probability of treatment assignment conditional on measured baseline covariates 22) .PS methods are increasingly being used to reduce or minimize the confounding that is seen frequently in observational studies of the effect of treatment on outcomes 23) .In clinical practice, significant differences exist between patients who are and are not treated with POAC, particularly with regard to age, clinicopathological factors, and patient/physician preferences.Therefore, in the current study we used PS matching analysis techniques to address selection bias due to nonrandom treatment assignment.As a result, although the analysis of baseline clinicopathological factors in the entire cohort indicated more active utilization of POAC among the patients with more severe clinicopathological factors, the one-to-one pair PS matching successfully balanced the clinicopathological factors between the patients with and without POAC.To our knowledge, to date there have been three reports regarding the efficacy of POAC in stage II colon cancer using the PS matching analysis.Kim KY and colleagues 24) used the PS matching analysis for reliable evaluation of treatment efficacy.They reported that there was no significant efficacy of POAC in the risk of death for the propensity matched patients with stage II colon cancer.This result is similar to that of the current study.Oʼ Connor and colleagues 25) also concluded that POAC did not improve overall survival in the patients with stage II colon cancer, either with or without poor prognostic features.Weiss and colleagues 26) divided patients with stage II colon cancer patients into two groups, right-sided and left-sided, and examined the efficacy of POAC in each group.They also reported that POAC did not improve overall survival for either right-or left-sided colon cancers.While the results may vary depending upon the confounders that are used in the PS matching analysis, these reports and our study were consistent with the previous studies 17) -19) which demonstrated no significant difference in survival.
Finally, several limitations in the current study that are inherent to retrospective studies and the non-randomized design should be considered.First, this data was collected and examined at one single institute, and only a small number of patients were enrolled in the current study.Second, regimens of oral POAC were not fixed throughout.Third, since we used only oral 5-FU drugs during the present study period, we were not able to investigate the effectiveness of the modern chemotherapy such as oxaliplatin-based regimen.However, in the subgroup analyses with the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin Adjuvant Treatment of Colon Cancer (MOSAIC) trial 27) , the addition of oxaliplatin to fluoropyrimidine didnʼ t demonstrate statistically significant benefit in overall survival and disease-free survival either in the entire stage II patients or in the high-risk patients.Therefore, the effectiveness of the addition of oxaliplatin to fluoropyrimidine seems to be inconclusive.Fourth, the results in the PS matching analysis depends on a way to divide the clinicopathological factors as confounders into two groups.In this paper, we followed the Japanese Classification of Colorectal Carcinoma.Second English Edition 12) .Finally, microsatellite instability (MSI) data was not available in the current study.MSI status impacts the benefit from POAC in colon cancer 28) .Future efforts to personalize treatment of colon cancers will likely involve direct gene expression testing of each patient 26) 29) .
A multicenter prospective randomized phase III study (SACURA trial; ClinicalTrials.gov NCT00392899), the primary end point of which is disease-free survival, is currently under way in Japan 30) .In this study, biomolecular profiles, such as microsatellite instability (MSI) and chromosomal instability, as well as histopathological factors are being assessed to evaluate any correlation with recurrence and survival as an additional translational study.Similarly, a multicenter prospective nonrandomized controlled study (JMFC46-1201) is also currently under way 31) .The aim of this study is to evaluate the usefulness of POAC with the same high risk features as the current study (i.e., poorly-differentiated or mucinous adenocarcinoma, invasion depth of T4, inadequate lymph node sampling, preoperative ileus or perforation).Furthermore, the effect on positivity for CEA mRNA will be assessed as a secondary end point.The results of these studies will provide important information about POAC using oral 5-FU agent for stage II colon cancer.

Conclusions
The one-to-one pair PS matching successfully balanced the clinicopathological factors between the patients with and without POAC.The PS matching analysis demonstrated no significant difference in survival in the patients with stage II colon cancer.

Table - 2
Comparisons of recurrence-free and cancer-specific survival according to the clinicopathological factors in the entire cohort Table-4).Comparisons of recurrence-free and cancer-