Adjuvant chemotherapy does not provide survival benefits to elderly patients with stage II colon cancer

To date, the effect of adjuvant chemotherapy after curative resection in patients with stage II colon cancer remains controversial. Still, little is known about the effects of adjuvant chemotherapy in patients with stage II colon cancer who are older than 70 years, as most studies did not focus on this population. This study aimed to investigate the oncologic outcomes of elderly patients with stage II colon cancer who underwent curative resection with or without postoperative adjuvant chemotherapy. We retrospectively reviewed medical records of patients older than 70 years who underwent curative resection of stage II primary colon cancer during 2002–2015. Patients were classified into surgery alone (SA) and adjuvant chemotherapy (AC) groups and propensity score-matched at a 1:1 ratio using a logistic regression. The end points were recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Of the 623 patients who met the criteria, 145 were assigned to each arm after propensity score matching. The mean ages of the SA and AC groups were 74.3 and 74.0 years, respectively. A log-rank test revealed no significant inter-group differences in RFS (p = 0.202), CSS (p = 0.486) or OS (p = 0.299). In a Cox regression analysis, adjuvant chemotherapy was not found to be an independent factor affecting RFS (p = 0.206), CSS (p = 0.487) or OS (p = 0.301). Adjuvant chemotherapy does not appear to yield survival benefits in elderly patients with stage II colon cancer.

Statistical analysis. SPSS version 25.0 for Windows (IBM Corp, Armonk, NY, USA) was used for the statistical analysis. A p value < 0.05 was considered statistically significant. Categorical baseline characteristics were analyzed using the χ 2 -test or linear-by-linear association, and continuous variables were analyzed using Student's t-test. The two groups of patients were balanced using propensity score matching, which included a logistic regression with 1:1 nearest neighbor matching and a caliper of 0.2. The following covariables included: age, sex,

Results
A total of 623 patients underwent curative resection at our institution between 2002 and 2015. Of these, 63 patients and 34 patients were excluded because of a history of other malignancy and missing data, respectively. Finally, 526 patients were included in our analysis (Fig. 1). Their baseline characteristics are presented in Table 1. Briefly, the overall mean age was 75.7 years (range: 70-93 years), and there was a slight male predominance (300/526, 57%).
In an initial group comparison, patients in the SA group were older and had a lower BMI, higher ASA classification, larger tumor size and more frequent venous invasion, compared to the AC group. After propensity score matching to balance the pre-existing and pathologic variables, 145 patients were assigned to each arm. The mean ages of the matched SA and AC groups were 74.3 and 74.0 years, respectively ( Table 2). In the AC group, after propensity score matching, the regimens followed were: 5-FU (n = 61), capecitabine (n = 40), capecitabine and oxaliplatin (n = 1), uracil/tegafur (UFT; n = 18), folinic acid-FU-oxaliplatin (FOLFOX; n = 21), and unknown (as the patients received chemotherapy at other hospitals; n = 4).

Discussion
Our study shows that postoperative adjuvant chemotherapy confers no major survival benefit in patients older than 70 years with stage II colon cancer, even after propensity score matching. Additionally, adjuvant chemotherapy did not affect the RFS, CSS, or OS outcomes even in patients with high-risk features. These findings may have a positive impact on many patients, especially those at an advanced age, who can avoid the problems associated with chemotherapy.
As noted previously, no consensus has been reached regarding the effect of adjuvant chemotherapy for stage II colon cancer. The QUASAR trial reported improved survival outcomes in patients with stage II colon cancer who received chemotherapy comprising FU and folinic acid 9   However, there are authors who have shown positive effects of chemotherapy on elderly patients. Fata et al. reported that elderly patients with stage II/III colon cancer benefit from 5-FU-based adjuvant therapy, without a significant increase in toxicity compared to that in their younger counterparts 18 . There is even an article about the benefit of adjuvant therapy after curative resection in stage IV colon cancer. Rahbari et al. analysed a total of 297 patients with curative resection of colorectal cancer liver metastasis. According to their results, adjuvant chemotherapy was associated with improved survival in the entire cohort (HR 0.69; 95% CI 0.69-0.98) 19 .
Some studies have evaluated the efficacy of adjuvant chemotherapy, particularly in patients older than 70 years with stage II colon cancer. For example, Tsai et al. reported no significant difference in OS between patients who received adjuvant chemotherapy and those without adjuvant chemotherapy 6 . However, that study compared two groups, adjuvant chemotherapy vs. no adjuvant chemotherapy, that were unbalanced in terms of baseline characteristics such that the former group had a worse pathologic grade and larger proportion of pT4 stage disease. In a large Korean database study 20 , Kim et al. performed a subgroup analysis of patients older than 70 years with stage II colon cancer and concluded that adjuvant chemotherapy yielded an OS benefit. However, Kim and colleagues also reported that their two groups were unbalanced in terms of baseline characteristics, and limitations of their dataset precluded analyses of RFS and CSS. By contrast, we performed propensity score matching to balance the study groups and conducted analyses of both RFS and CSS. These represent strengths of our study.
In our multivariable analysis of patients who received adjuvant chemotherapy, we identified perineural invasion, a well-known prognostic factor for stage II colon cancer 13 , as a statistically independent factor affecting RFS and CSS. Furthermore, CEA and tumour size also affected CSS and OS in multivariable analysis. A higher pretreatment CEA level has been identified as a predictor of RFS and OS [21][22][23] . In particular, an elevated CEA level preoperatively in early stage colon cancer has been associated with a poor prognosis compared with normal CEA levels in a node-positive tumour 24 . Tumour size is also a factor associated with a poor oncologic prognosis 25,26 .
We further identified obstruction and postoperative complications as significant factors affecting CSS and OS and confirmed a lack of covariance between these factors (χ 2 -test, p > 0.999. We note that patients with obstruction had a lower BMI, compared to those without obstruction (21.6 vs. 23.1 kg/m 2 , p = 0.004), which indicates the need for careful attention to avoid postoperative complications during chemotherapy in fragile patients. Furthermore, a lower BMI is always associated with a worse condition. We recommend further study of cancer-related mortality after chemotherapy.
To our best knowledge, our study is first study of its type to apply propensity score matching to balance patient groups even with respect to co-morbidity. Our findings were consistent with other recent studies that found no difference in the oncologic outcomes of patients with stage II colon cancer who did and did not receive adjuvant chemotherapy. Taken together, these findings underscore the need to discuss guidelines for the management of geriatric patients with stage II colon cancer.
Limitations. This study had some potential limitations. First, the retrospective design might have led to selection bias. Second, we were unable to obtain information about patients who received chemotherapy at a reduced dose or cycle number. Third, we included a relatively small number of patients, compared to other studies based on national databases. However, the total number of initially included patients was not small, and the 290 patients remaining after propensity score matching was sufficient for a statistical analysis. Fourth, we lacked data regarding why chemotherapy was not given to some patients, even in the high-risk subgroup. Although we were limited by an inability to confirm the Eastern Cooperative Oncology Group performance status, we attempted to eliminate differences in confirmed comorbidities between the two groups as much as possible. Fifth, in the medical records, there was no information about resection margin status, such as intermediate or close margin, according to the National Comprehensive Cancer Network guideline 13 , although information about other high-risk features was present. Our study only included patients who underwent curative resection (R0). For this reason, there were no patients with a positive margin.

conclusion
Adjuvant chemotherapy did not appear to confer RFS, CSS, or OS benefits in patients older than 70 years with stage II colon cancer. However, our finding that obstructive colon cancer and postoperative complications were associated with poorer survival outcomes suggests that patients meeting these criteria should be followed cautiously during chemotherapy. Our findings underscore the need to revise guidelines for the treatment of stage II colon cancer. As our study population is not representative of all patients with stage II disease, we believe that a well-balanced, large population-based study is warranted.