Adjuvant Chemotherapy and Tumor Sidedness in Stage II Colon Cancer: Analysis of the National Cancer Data Base

Background: Current guidelines recommend discussion of adjuvant chemotherapy (AC) for stage II colon cancer (CC) with high-risk features despite lacking conclusive randomized trial data. We examined AC administration in this population and its effect on overall survival (OS) for available patient, tumor, and treatment characteristics Methods: Using National Cancer Data Base, a cohort of 42,971 stage II CC patients diagnosed from 2004 to 2009, who underwent surgery with curative intent, was identified. Chi-square test and multivariate logistic regression were used to analyze baseline characteristics and to calculate odds of chemotherapy administration, respectively. Survival analysis was conducted using Kaplan Meier survival analysis with log-rank test and Cox proportional hazards regression modeling. Results: AC was administered to 26% patients. The use decreased with advancing age and elderly patients received more single-agent than multi-agent chemotherapy (3 vs. 2.4%, p < 0.0001). Major predictors of AC use included pT4 status, evaluation of <12 lymph nodes, high grade tumors, positive resection margins, age <65 years, left sided tumors, and low comorbidity score. AC was associated with improved OS regardless of high-risk features (pT4, undifferentiated histology, <12 lymph node evaluation, or positive resection margins), tumor location, age, gender, comorbidity index, chemotherapy regimen or type of colectomy (adjusted HR: single-agent 0.55, multi-agent 0.6; p < 0.0001). In subgroup analysis, AC use compensated for the survival differences otherwise seen between left and right sided tumors in the non-chemotherapy population. Conclusion: AC in stage II CC was associated with improved OS regardless of age, chemotherapy type or high-risk features. It improved 5-years OS irrespective of tumor location and seemed to compensate for the survival difference seen between right and left sided tumors noted in the non-chemotherapy group.


INTRODUCTION
Colorectal cancer is the third leading cause of cancer diagnosis in the United States (U.S.), both among men and women (1,2). It is also the second most common cause of cancer death when men and women are combined. As of January 2019, it was estimated that there were in excess of 1.5 million patients in the U.S. with a diagnosis of colorectal cancer (3). In 2020, it is estimated that an additional 147,950 new cases and 53,200 deaths will occur in the U.S (2). Surgical resection remains the mainstay of treatment for non-metastatic colon cancer, with adjuvant chemotherapy having demonstrated improved overall survival (OS) for stage III colon cancer patients (4)(5)(6)(7). In patients with stage II colon cancer, the role of adjuvant chemotherapy remains a point of debate (8)(9)(10)(11)(12)(13)(14)(15)(16). Since there are few definitive prospective clinical trials which have evaluated the use of adjuvant chemotherapy in stage II colon cancer, current clinical practice guidelines by the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend discussing chemotherapy in patients with tumors possessing high-risk features or microsatellite stability (MSS) and all T4 tumors (17)(18)(19)(20). Stage II microsatellite instability high (MSI-H) patients may have a good prognosis and do not benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy (21). In contrast, population-based studies have failed to demonstrate substantial OS benefit with the use of adjuvant chemotherapy for all patients with poor-prognostic or high-risk features (22,23).
Recently, a study looking at stage II colon cancer patients diagnosed from 1998 to 2006 using the National Cancer Data Base (NCDB) was able to demonstrate an OS benefit associated with adjuvant chemotherapy (24). Though the sample size in this study was large (N = 153,110), it included patients with other malignancies, thereby resulting in a competing mortality bias.
The primary objective of our study was to utilize data from the NCDB and assess for OS benefit of adjuvant chemotherapy in stage II colon cancer patients, with no other malignancies, diagnosed from 2004 to 2009. Since the US Food and Drug Administration (FDA) approved combination of 5-FU, leucovorin and oxaliplatin (FOLFOX) in 2004 (25), all patients receiving multi-agent chemotherapy in our study population were hypothesized to have received the FOLFOX regimen. The secondary objectives of our study were to assess the impact of tumor sidedness on OS with or without adjuvant chemotherapy, as well as to evaluate the association between adjuvant chemotherapy and the two major high-risk features of stage II colon cancer i.e., T4 tumors and inadequate lymph node evaluation (<12 lymph nodes). In addition, a multivariate analysis of determinant factors in utilization of chemotherapy from 2004 to 2009 was also performed.

Data Source
The NCDB is a joint quality improvement initiative of the American College of Surgeons' Commission on Cancer and the American Cancer Society. The NCDB contains 34 million patient records, and represents ∼70% of all newly diagnosed cases of cancer in the United States (26,27). Data access was approved by the NCDB after a thorough review of the study proposal. Participant User File (PUF), which included patients diagnosed with colon cancer from 2004 to 2014, was utilized to extract the study cohort.

Study Population
The American Joint Committee on Cancer (AJCC) sixth edition was used for staging purposes and site-specific information was defined according to the AJCC's Collaborative Stage Data Collection System (CCS). Using CCS we excluded patients with appendiceal adenocarcinoma along with exclusion of those who underwent surgical procedures spanning less than a partial colectomy. Only patients with a pathologically confirmed diagnosis were included for analysis. Patients lacking documentation about the variables of interest were also excluded. A final cohort of 42,971 patients diagnosed with stage II colon cancer from 2004 to 2009 was identified using an agemandated eligibility criteria (18 years and above), along with above mentioned inclusion and exclusion criteria (Figure 1). The year 2009 was chosen as a cut-off to enable a minimum followup of 5 years for all patients while maintaining a uniform cancer staging system (AJCC, 6th edition).

Measured Outcomes and Variables
The primary endpoint of this study was the 5-years OS. In patients who were alive at the last follow-up, OS was censored at 60 months. Age was analyzed as an ordinal variable after being grouped into 18-64 years, 65-74 years and above. Patients were categorized into four ethnic groups; Caucasians, African-Americans, Hispanics, and others. Patient performance status was analyzed using the Charlson/Deyo comorbidity index and the primary site of colon cancer was recoded into left, right, or transverse part of the colon. Other variables analyzed included gender, institution (academic vs. non-academic), insurance status, average neighborhood income level, year of diagnosis, geographic location of treating institution, histologic grade, involvement of margins, adequacy of lymph nodes evaluated during surgery, pathologic primary tumor characteristics (pT), type of colectomy, and adjuvant chemotherapy.

Statistical Analysis
Descriptive analysis of patient's demographic and clinical information according to receipt of adjuvant chemotherapy was performed using the Pearson chi-square test. Multivariate logistic regression model was used to calculate the odds ratio (OR) of chemotherapy administration based on several determinant factors including age, race, baseline comorbidity index, institution, geographic location, year of diagnosis, tumor laterality, grade, adequate lymph node evaluation, pT, surgery, and margins. Kaplan Meier survival curves and Cox proportional hazards model were utilized to perform survival analysis. Kaplan Meier survival curves were adjusted and tested with the log-rank test. A Cox proportional hazards model was constructed using age, average neighborhood income level and Charlson/Deyo comorbidity index as ordinal variables. Other variables including gender, race, institution, insurance status, year of diagnosis, location of primary tumor, histologic grade, adequacy of lymph node evaluation, pT, margins, type of surgery and adjuvant chemotherapy were analyzed as categorical variables in this  model. Hazards ratios (HR) and 95% confidence intervals (CI) were generated with HR <1.0 indicating survival benefit. The p < 0.05 was considered statistically significant and Statistical Analysis Software (SAS version 9.4; SAS Institute, Cary, NC) was used for all analyses.

Patient Characteristics
We identified 42,971 patients from NCDB who were diagnosed with stage II colon cancer between 2004 and 2009. Patient and tumor characteristics are shown in Table 1, stratified according to receipt of adjuvant chemotherapy. The overall frequency of adjuvant chemotherapy administration was 26% and did not differ significantly by the academic level of treating institution, median family income level or adequacy of lymph node evaluation.
Very elderly patients (age ≥ 75 years) received significantly less chemotherapy as compared to the elderly (65-74 years)  Patients with tumors located on the left side of colon more often received adjuvant chemotherapy (25.6%) compared to those with tumors of the right (17.9%) or transverse colon (20.4%), which was significantly different as depicted by p < 0.0001. Furthermore, patients with high-risk features including pT4 (43.5%), positive margins (37.2%), and high grade tumors (24.8%) more often received adjuvant chemotherapy as compared to other respective risk groups (p < 0.0001). Majority of the patients underwent subtotal colectomy (data not shown) and were least likely to receive adjuvant chemotherapy (19.9%) as compared to those who underwent partial (22.5%) or total (24.6%) colectomy. Table 2 demonstrates differences of chemotherapy administration among various age groups stratified according to the type of chemotherapy. Young patients more often received

Determinant Factors for Adjuvant Chemotherapy Administration
In multivariate logistic regression analysis, patients with highrisk features were more likely to receive adjuvant chemotherapy (  academic level of treating institution, geographic location and year of diagnosis.

Independent Predictors of Overall Survival
The crude 5-years OS rate for all patients receiving any kind of adjuvant chemotherapy was 73.5% as compared to 54.3% among those not receiving chemotherapy (  Figure 2 demonstrates the association between adjuvant chemotherapy and improved OS. This further reflects the similar survivals associated with single-and multi-agent chemotherapy regimens in adjuvant setting. Patients with right sided tumors had better OS compared to left sided tumors (adjusted HR 0.93, 95% CI 0.9-0.97). Figure 3 demonstrates the association between tumor sidedness and improved OS. Among the four high-risk features evaluated in the study, including pT, grade, adequacy of lymph node evaluation and margins, improved OS was associated with pT3 lesions (adjusted HR 0.59, 95% CI 0.57-0.62, compared to pT4), low grade tumors (adjusted HR 0.88, 95% CI 0.82-0.93, compared to high grade tumors), adequate lymph node evaluation (adjusted HR 0.74, 95% CI 0.71-0.76, compared to inadequate lymph node assessment) and negative margins at surgery (adjusted HR 0.64, 95% CI 0.59-0.68, as compared to positive margins).
After adjusting for all other covariates, age, gender, ethnicity, Charlson/Deyo comorbidity index, geographic location, insurance status, median family income, year of diagnosis, and colectomy remained independent predictors of OS in stage II colon cancer ( Table 4).

Overall Survival Advantage of Adjuvant Chemotherapy by Tumor Sidedness
After adjusting for covariates, tumor sidedness was noted to demonstrate a significant survival benefit in thenonchemotherapy subgroup ( Table 5). In this subgroup right sided tumors had improved survival compared to left sided tumors (adjusted HR 0.92, 95% CI 0.88-0.96). This survival difference based on tumor location was however compensated with administration of chemotherapy, as demonstrated by the absence of significant OS benefit in the adjuvant chemotherapy subgroup analysis.
Furthermore, the OS benefit of adjuvant chemotherapy was confirmed in the subgroup analyses based on tumor sidedness. Irrespective of tumor location, adjuvant chemotherapy was associated with improved 5-years OS outcomes.

DISCUSSION
In stage II colon cancer, surgical resection is the mainstay of treatment with a wide 5-years OS range which highlights the heterogeneity that exists among stage II colon cancers in term of recurrence. The survival benefit of adjuvant chemotherapy in stage III patients is well-established but a definitive benefit in stage II patients remains unclear (8-16, 22-24, 28-30). Some of these studies have demonstrated disease specific and/or overall survival benefit of adjuvant chemotherapy in stage II colon cancers with high-risk features. Current clinical practice guidelines and the consensus statement from the recent Cochrane review recommend discussion of adjuvant chemotherapy with stage II colon cancer patients having high risk features (19, 20, 31). As a result, there is a wide variation regarding the decision to administer adjuvant chemotherapy among individual physicians, institutions, and countries.
The current study was undertaken to provide a better assessment of the OS benefit of adjuvant chemotherapy in stage II colon cancer with regard to various high-risk features including pT4, inadequate lymph node evaluation, high grade tumors and those with positive surgical margins, along with the other important prognostic factor of tumor sidedness (which was considered as a surrogate for MSI status) (32,33). We found that after controlling for various patient, tumor, and treatment characteristics, adjuvant chemotherapy had a significant OS benefit in stage II colon cancer. This is consistent with the findings of earlier studies including the QUASAR trial (12) and a retrospective analysis by Casadaban et al. (24). Single-agent chemotherapy fared as well as multi-agent chemotherapy when compared to no adjuvant chemotherapy (Figure 2). Though the overall use of adjuvant chemotherapy decreased with advancing age; the elderly and very elderly patients were more likely to receive single-agent chemotherapy ( Table 2) compared to young patients. Despite this difference, the outcomes favored adjuvant chemotherapy, which is in line with findings from the ACCENT database and the MOSAIC trial (9,34).
In the multivariate Cox proportional hazards model analysis, patients with right sided tumors had better OS compared to left sided tumors. A previous retrospective analysis by Weiss et al. (30) using the Surveillance, Epidemiology and End Results (SEER)-Medicare data showed no OS benefit of adjuvant High-risk features in stage II colon cancer traditionally included pT4, tumor perforation or bowel obstruction, high grade or poorly differentiated tumors, lympho-vascular invasion and <12 lymph nodes examined. According to the current guidelines, it is recommended to discuss adjuvant chemotherapy with patients having any one or combination of these risk factors (19,20). Using the current study cohort, we evaluated the odds of adjuvant chemotherapy administration, from 2004 to 2009, based on some of these high-risk features that were available through NDCB. These included pT4, high-grade tumors and examination of <12 lymph nodes. As depicted in Table 3, patients with pT4 lesions were more likely to receive chemotherapy than those with pT3 lesions. Verhoeff et al. (23) analyzed data from the Netherlands Cancer Registry and found improved survival outcomes with adjuvant chemotherapy in patients with pT4 stage II colon cancer. Tumors with undifferentiated histology or higher-grade were more likely to receive adjuvant chemotherapy. This is in contrary to the idea of poorly differentiated tumors being clinically correlated to MSI-H status, which portends a poor response to 5-FU based chemotherapy (21,35). Inadequate lymph node evaluation was shown to carry a poor prognostic effect on OS in a recent study by Reha et al. (36) using the NCDB. On the same note, patients with inadequate lymph node evaluation in our study cohort were more likely to receive adjuvant chemotherapy to help improve the odds of OS attributable to disease recurrence.
There are several limitations to this study. First, this is a nonrandomized, retrospective analysis that allows for a potential selection bias. Second, information on the type of chemotherapy regimen, adherence and completion rates were not available in the NCDB. This creates a heterogeneous population in which patients could receive substandard duration of therapy. Lack of information on the type of chemotherapy regimen was partially compensated by the availability of data on single vs. multi-agent chemotherapy. Analysis of certain data variables was restricted by availability in the NCDB file, including MSI status, disease specific mortality, colonic obstruction or perforation and missing information from the lympho-vascular invasion data collection.
Despite these limitations, the current study is the largest population-based analysis of stage II colon cancer only patients in the U.S. Though the previous study by Casadaban et al. (24) included nearly 4-times the number of patients in our study, their cohort included stage II colon cancer patients with other malignancies, who were excluded from our study cohort. Our study population included adult patients belonging to all age groups as compared to the SEER-Medicare study by Weiss et al. (30) that included patients aged 66 years and older.

CONCLUSION
The results of our study suggest the use of adjuvant chemotherapy in stage II colon cancer. There was a statistically significant 5-years OS benefit seen after adjusting for available patient, tumor and treatment characteristics including highrisk features as well as tumor location. Subgroup analysis further confirmed the survival benefit associated with adjuvant chemotherapy irrespective of tumor sidedness. However, owing to the observational nature of this study, interpretation and clinical application should be undertaken with caution. Future validation with prospective trials including MSI status is warranted.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.