Trends in management and outcomes of colon cancer in the United States over 15 years: Analysis of the National Cancer Database

Management of colon cancer has changed over the last few decades. We assessed the trends in management and outcomes using the US National Cancer Database (NCDB). A retrospective analysis of all patients with colonic adenocarcinoma between 2005 and 2019 was conducted. The cohort was divided into three equal time periods: Period 1 (2005–2009), Period 2 (2010–2014), and Period 3 (2015–2019) to examine treatment and outcomes trends. The primary outcome was 5‐year overall survival (OS). The study included 923,275 patients. A significant increase in patients with stage IV disease was noted in Period 3 compared to Period 1 (47.9% vs. 27.9%, respectively), whereas a reciprocal reduction was seen in patients with locally advanced disease (stage II: 20.8%–12%; stage III: 14.5%–7.7%). Use of immunotherapy significantly increased from 0.3% to 7.6%. Mean 5‐year OS increased (43.6 vs. 42.1 months) despite the increase in metastatic disease and longer time from diagnosis to definitive surgery (7 vs. 14 days). A reduction in 30‐day readmission (5.1%–4.2%), 30‐ (3.9%–2.8%), and 90‐day mortality (7.1%–5%) was seen. Laparoscopic and robotic surgery increased from 45.8% to 53.1% and 2.9% to 12.7%, respectively. Median postoperative length of hospital stay decreased by 2 days. Rate of positive resection margins (7.2%–6%) and median number of examined lymph nodes (14–16) also improved. Minimally invasive surgery and immunotherapy for colon cancer significantly increased in recent years. Patient outcomes including OS improved over time.

What's New?
Although colon cancer outcome remains strongly associated with disease stage at diagnosis, basic understanding and treatment of colon cancer have advanced significantly in recent years.
The authors of the present study assessed the impact of these advances on trends in colon cancer treatment and outcomes using data from the US National Cancer Database over the period 2005-2019.Retrospective analysis revealed an increase in patients who presented with metastatic colon cancer within the study timeframe.Nonetheless, 5-year overall survival improved, possibly owing to enhanced use of immunotherapy and minimally invasive surgery, coupled with decreased resection margins and hospital stays.

| INTRODUCTION
Colon cancer is one of the leading causes of cancer-related death around the world.It is the third most common cancer, annually diagnosed in more than 100,000 patients in the United States. 1 The lifetime risk for developing colon cancer is approximately 4%, with a significantly higher risk in patients with a positive family history. 2e outcomes of colon cancer are strongly related to disease stage at diagnosis.Early colon cancer is potentially curable and is associated with good overall survival.Conversely patients diagnosed with metastatic disease usually have dismal outcomes. 3This observation is the main reason for implementing screening programs in healthcare systems, although there is still some controversy on the optimal method of screening for colon cancer. 4,5 recent years, the treatment of colon cancer has undergone significant changes.Although the main goals of care have remained the same, significant improvements were seen in the diagnostic and therapeutic methods. 6,7Novel diagnostic tests, which may omit the need for endoscopic screening in the future, were recently introduced. 8,9In addition, imaging measures allowing for more accurate diagnosis and staging, along with a significant change in surgical techniques, contributed to an improvement in patient outcomes. 10,113][14][15][16] Furthermore, follow-up for recurrence and metastatic disease has also significantly improved as novel biomarkers with higher sensitivity and specificity for colonic neoplasia allow more accurate long-term evaluation of patients with colon cancer. 17spite these advances, the approach to colon cancer has remained static for decades.Unlike treatment paradigms for rectal cancer that have significantly shifted towards neoadjuvant systemic therapy and the use of radiation, enabling organ preservation in some patients, the use of these treatments in colon cancer remains under investigation.As our understanding of the disease has improved as well as the technological advancements introduced in recent years, we were prompted to assess the trends in colon cancer treatment and outcomes using the US National Cancer Database (NCDB) that is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons (ACS) and the American Cancer Society and includes nearly a million patients.

| PATIENTS AND METHODS
This study was a retrospective analysis of all patients with colonic adenocarcinoma in the NCDB over a 15-year time period

| Study outline
In order to assess the trends in characteristics, treatment, and outcomes of colon cancer, the cohort was subdivided into three equal

| Statistical analysis
Statistical analyses were performed using EZR (version 1.55) 18 and R software (version 4.1.2).Continuous data were expressed as mean and standard deviation when normally distributed or otherwise as the median and interquartile range (IQR).Student t-test or one-way ANOVA test was used to analyze continuous variables.
Categorical data were expressed in the form of numbers and percentages and were analyzed using Fisher exact test or Chi-square test.
Kaplan-Meier statistics and log-ranks tests were used to detect differences in overall survival between the time periods.

| Description of the entire cohort
Overall, 923,275 patients with colonic adenocarcinoma were included in the NCDB during the study time period.The mean age was 68.0 ± 13.5 years and 50.5% of patients were female.The majority (83%) of patients were white and 12.8% were Black.The vast majority of patients (85.3%) lived in metropolitan areas and 12.8% lived in urban areas.More than half (57.5%) of the patients were Medicare-insured and 33.1% were privately insured.
Tumor histology was non-mucinous adenocarcinoma in 89.2% of patients, whereas mucinous adenocarcinomas and signet ring-cell carcinomas accounted for 9.3% and 1.5% of patients, respectively.Sixty-eight percent of patients had moderately differentiated adenocarcinoma, while 18  A significant increase of patients presenting with stage 4 disease was noted from 27.9% in Period 1 to 31.8% in Period 2 and to 47.9% in Period 3 (p < .001).Conversely, the percentage of patients with stage 1-3 disease decreased from 61.7% in Period 1 to 42.2% in Period 3 (p < .001).Patients with mucinous carcinoma slightly decreased from 10.3% in Period 1 to 8.3% in Period 3 (p < .001).A similar decrease was seen in rates of poorly differentiated adenocarcinoma (19.9% in Period 1 to 16.7% in Period 3) ( p < .001),while a slight increase was seen in moderately differentiated adenocarcinoma (67.1%-69.2%)(p < .001).Demographic, clinical, and tumor characteristics are given in Table 1.
A significant increase in immunotherapy treatment was seen, rising from 0.3% in Period 1 to 2.1% in Period 2 and up to 7.6 in Period 3 (OR = 4.46, 95%CI 4.36-4.56;p < .001)(Supplementary Figure 1).The use of radiation therapy slightly decreased from 1.7% in Period 1 to 1.2% in Period 3 (OR = 0.85, 95%CI 0.83-0.86;p < .001).This was mainly seen in adjuvant radiation therapy that decreased from 1.4% in Period 1 to 0.9% in Period 3. A summary of treatment trends is shown in Table 2.   3.

| Survival analysis
The mean 5-year overall survival slightly increased from 42.A significant increase in the use of immunotherapy from Period 1 to Period 3 was also noted in both right-sided and left-sided colon cancers (Supplementary Table 2).The odds of using immunotherapy    and improved healthcare that allows for providing medical and surgical treatments even for high-risk patients.A significant and alarming rise in patients presenting with metastatic disease was noted, as patients with stage 4 disease increased by 20% across the time periods.As screening programs have significantly improved in the last decades, [19][20][21] we postulate that the higher incidence of patients with stage 4 disease is partly due to referral bias and partly because patients with gastrointestinal symptoms either delayed seeking medical care or were underdiagnosed for a long period of time.Although the NCDB does not offer data about how clinical staging was achieved, we can assume that the increased use of advanced imaging like PET-CT and MRI contributed to the discovery of metastatic disease in more patients over time.Furthermore, since the NCDB collects data from centers that are part of the CoC registry, it is likely that patients with metastatic disease were referred to specialist centers that will create the same effect on the rate of patients with advanced disease.
Significant changes in the medical and surgical treatment of colon cancer were noted.First, although the proportion of patients treated with systemic chemotherapy remained stable over time, a significant increase was seen in the use of multi-agent chemotherapy, increasing by 61% during the study period.This is probably one of the main causes for which the 5-year overall survival improved in patients with stage III and IV disease as seen in the last period compared to earlier years. 22,23Unlike in rectal cancer where neoadjuvant therapy has now become the standard of care for locally advanced disease, 24 the sequencing of systemic treatment in colon cancer has changed little over time and is mostly given following surgery.This sequencing might soon change with emerging evidence about the clinical benefit of neoadjuvant therapy for locally advanced disease in colon cancer. 25other significant change in systemic treatment is the increased use of immunotherapy, which increased from 0.3% in Period 1 to 7.6% in Period 3.This significant increase is the result of important evidence emerging in recent years highlighting the benefits of immunotherapy, especially in metastatic colorectal cancer patients. 26,27For example, the seminal study by Le et al., 16 in which patients with metastatic colorectal cancer were treated with pembrolizumab.The study found significant improvement in progression free survival in patients with mismatch-repair deficient histology (78% compared to 11% in the control group).Of note, in our study, we noticed that immunotherapy was used more frequently for left-sided colon cancer than for right-sided cancers in the most recent time period.
As for surgical treatment, the most striking change over time is the 5-fold increase in the use of robotic-assisted surgery compared to the use of laparoscopy that also increased over time, albeit to a lesser extent.9][30][31] These findings correlate with the improvement in short-term outcomes seen in our study, including a 2-day reduction in the length of stay and a reduction in 30-day readmission and short-term mortality.
Furthermore, the reduction in the positive surgical margin rates demonstrates that the surgical treatment and capabilities has improved overtime.
These changes in colon cancer management contributed to the improvement in the long-term outcomes of patients, despite the fact that more patients presented with advanced disease in recent years.
The 5-year overall survival for the entire cohort improved from 42.1 months in Period 1 to 42.6-43.6months in Period 3.Although this may seem to be a minor improvement, we must consider the sample bias of large database cohorts that also contributes to the generalizability of these results.In an attempt to minimize bias and examine which patient population benefited most from treatment changes, we stratified the cohort based on the clinical TNM at presentation.Our results show that the greatest survival improvement was noted in patients with stage III and IV disease.This finding is consistent with several publications that reported similar findings.For example, Steenbergen et al 32 reviewed the outcomes of patients with colon cancer in the Netherlands, showing that the increase in adjuvant chemotherapy significantly improved the outcomes of stage III patients.A similar outcome was also seen in a study population in Nordic countries set to examine the survival trends in colorectal cancer between 1990 and 2016. 33ese changes in treatment and outcomes were also consistent when we divided the cohort based on the anatomic location of the tumor.The increase in minimally invasive surgery was seen in both right-and left-sided colon cancer, yet the adoption of robotic-assisted surgery was more notable in left colon cancer.A similar increase in the use of immunotherapy was also noted, more obviously in left colon cancers.As a result, we noted significant improvements in perioperative outcomes including lower conversion rates and lower rates of positive surgical margins, in addition to an improvement in the short-term postoperative outcomes.The improved short-term outcomes were associated with increased overall survival, showing a steady increase over time.These findings correlate with a recently published study from Norway, surveying the outcomes of right-and left-sided colon cancer over a period of four decades.Although the survival rates were better in both anatomic locations, the benefit was more pronounced in advanced left-sided tumors. 34r study has multiple limitations that mainly stem from the retrospective nature of the NCDB database and the lack of data on progression free survival and disease recurrence.The NCDB also lacks information about the decision-making process and does not detail the indications for neoadjuvant/adjuvant/systemic therapy.Furthermore, although we based our stratified survival analysis on clinical TNM staging at presentation, it is important to highlight that preoperative disease staging in colon cancer is problematic, and that more than or close to half of the patients did not have a registered clinical TNM staging.In addition, although many of the outcomes in our study were statistically significant, as is often seen in large database analysis, these changes have limited clinical significance and therefore should be taken into consideration when interpreting these findings.Nonetheless, our study is important because it highlights that the efforts to improve the short-and long-term outcomes of colon cancer patients are fruitful.
Furthermore, the significant improvement seen mostly in patients with locally advanced and metastatic disease, shows that multimodality treatment can significantly improve the prognosis of these challenging patients.The adoption of minimally invasive surgery and the subsequent implications on short-and long-term outcomes should encourage surgeons to adopt this surgical approach as the standard of care.However, the lack of standardization of preoperative clinical staging should also be addressed as the basis for tailored systemic treatment and in order to continue exploring therapeutic options in order to further improve the overall survival of patients with colon cancer.
The findings of our study underscore several pivotal advances in colon cancer management that could significantly shape future clinical practices.The marked increase in the use of multi-agent chemotherapy and immunotherapy, coupled with the shift towards minimally invasive surgical techniques, has already shown promising improvements in patient outcomes, particularly for patients with advanced stages of the disease.These trends highlight the potential for a more personalized approach to treatment, especially in the context of increasing comorbidities and the demographic shifts observed in our study.Furthermore, our analysis suggests an urgent need for enhanced screening strategies to address the rising incidence of metastatic disease at presentation.By integrating these insights into clinical practice, there is a substantial opportunity to not only refine treatment protocols but also focus on early detection and intervention.This could lead to a paradigm shift in the overall management of colon cancer, aiming to improve survival rates and quality of life for patients across all stages of the disease.

| CONCLUSIONS
We found significant improvements in short-term and survival outcomes of patients with colon cancer over the last 15 years.A significant increase in multi-agent chemotherapy, immunotherapy, and minimally invasive surgery was noted over the study period, contributing to improved overall survival of colon cancer patients, especially those presenting with locally advanced and metastatic disease.Efforts to further improve screening for colon cancer is needed to lower the rate of patients presenting with advanced disease.
(2005-2019).The NCDB includes hospital registry data from more than 1500 CoC-accredited hospitals in the United States.The NCDB and the hospitals participating in the NCDB are not responsible for the statistical validity of the analysis in this study or its conclusions.The NCDB Participant User File (PUF) was reviewed by two investigators (NH, SE).The study included all patients diagnosed with colonic adenocarcinoma (ICD-3 codes 8140/3, 8480-8481/3, 8490/3) recorded in the NCDB between 2005 and 2019.Both metastatic and non-metastatic cases were eligible for inclusion, regardless of the treatment method.Patients with a tumor histology other than adenocarcinoma and adenocarcinoma subtypes (mucinous and signet ring cell adenocarcinomas) were excluded.As for TNM staging, the NCDB used the 6th and 7th editions up until 2018.Patients staged since 2018 were staged using the 8th edition of the TNM classification.

A
. Date of diagnosis: defined as the date of initial diagnosis by a recognized medical practitioner for the tumor being reported either by clinical or microscopic confirmation.B. Time from diagnosis to first treatment: defined as the time between the date of initial diagnosis and the date of first course of treatment (surgery, radiation, systemic, or other therapeutic intervention) C. Time from diagnosis to chemotherapy: defined as the time from date of diagnosis to the date chemotherapy was first given to the patient.D. Time from diagnosis to definitive surgery: defined as the time from date of diagnosis to the date surgery of the primary site.
time periods: 2005-2009 (Period 1), 2010-2014 (Period 2) and 2015-2019 (Period 3).The following criteria were used in the analysis: age, sex, race, Charlson score, clinical and pathologic TNM stage, insurance status, geographic region, tumor histology, grade, number of lymph nodes examined, number of positive lymph nodes, receipt of chemotherapy, radiotherapy, immunotherapy, sequencing of systemic and radiation therapy, type and approach of surgery, and time from diagnosis to surgery and to first treatment.Outcome data included conversion from minimally invasive to open surgery, positive surgical margins, 30-and 90-day mortality, 30-day readmission, and 5-year overall survival.

3. 4 . 2 |
Outcomes of right versus left-sided colon cancerThe treatment and outcome trends of right-sided and left-sided colon cancer were consistent with the results of the entire cohort.A significant increase in the adoption of minimally invasive surgery together with a decreased used of open surgery was noted in both right and left colon cancer.The adoption of the robotic approach in left-sided colon cancer was 20% higher than for right-sided colon cancer in Period 3 (OR: 1.21, 95%CI: 1.17-1.24,p < .001)and 14% higher in Period 2 (OR: 1.14, 95%CI: 1.0879-1.2,p < .001).

1
Number of patients presenting with metastatic disease in 2004-2009 (Period 1), 2010-2014 (Period 2), and 2015-2019 (Period 3) F I G U R E 2 in surgical for colon cancer (2010-2019) to treat left-sided colon cancer in Period 3 was higher than for rightsided cancer (OR: 1.46, 95%CI: 1.42-1.5,p < .001).The use of chemotherapy remained fairly consistent over time for both right-and leftsided cancers.As for surgical outcomes, the rates of conversion from minimally invasive to open surgery slightly decreased over time (right colon: This study aimed to analyze the treatment and outcome trends in colonic adenocarcinoma to inform future practice and further improve patient outcomes.We used data over a 15-year period from the colon cancer NCDB database.This large cohort, that included approximately one million patients, was divided into three equal time periods.Our results demonstrate significant changes in several aspects of colon cancer treatment, including an increase in the use of multi-agent chemotherapy, immunotherapy, and minimally invasive surgery.The treatment trends were associated with a significant overall improvement over the years, especially in patients with locally advanced and metastatic disease, which are the most challenging cases that caregivers encounter.We found several interesting changes in the demographics and presentation of patients with colon cancer.Patients presented with more comorbidities reflected as higher Charlson Comorbidity index scores.This may be explained by the increased median of patients T A B L E 3 Change in outcome trends across the time periods. and tumor characteristics of patients with colon cancer treated between 2005 and 2009 (Period 1), 2010 and 2014 (Period 2), 2015 and 2019 (Period 3); MSI, microsatellite instability; IQR, interquartile range.