Survival Impact of Chronic Obstructive Pulmonary Disease or Acute Exacerbation on Patients with Rectal Adenocarcinoma Undergoing Curative Resection: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study

Simple Summary This study is the first to estimate the impact of smoking-related chronic obstructive pulmonary disease (COPD) in patients with rectal adenocarcinoma undergoing curative resection. In these patients, current smokers with smoking-related COPD had worse survival outcomes than nonsmokers without COPD. Moreover, hospitalization for COPD with acute exacerbation within 1 year before diagnosis was an independent risk factor for OS in these patients, with a higher number of hospitalizations being associated with poorer survival. Abstract Purpose: The survival effect of current smoking-related chronic obstructive pulmonary disease (COPD) and COPD with acute exacerbation (COPDAE) is unclear for patients with rectal adenocarcinoma undergoing curative resection. Methods: We recruited patients with clinical stage I–IIIC rectal adenocarcinoma from the Taiwan Cancer Registry Database who had received surgery. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into two groups by using propensity score matching based on COPD status to compare overall survival outcomes: Group 1 (current smokers with COPD) and Group 2 (nonsmokers without COPD). Results: In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) of all-cause mortality for Group 1 compared with Group 2 was 1.25 (1.04–1.51). The aHRs (95% cis) of all-cause mortality for frequency of ≥1 hospitalizations for COPDAE or ≥2 hospitalizations within 1 year before diagnosis were 1.17 (1.05–1.51) and 1.48 (1.03–2.41) compared with no COPDAE in patients with rectal adenocarcinoma undergoing curative resection. Conclusion: In patients with rectal adenocarcinoma undergoing curative resection, being a current smoker with COPD (Group 1) was associated with worse survival outcomes than being a nonsmoker without COPD (Group 2). Being hospitalized at least once for COPDAE within 1 year before the diagnosis of rectal adenocarcinoma is an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for COPDAE within 1 year before diagnosis was associated with poorer survival.


Introduction
Cigarette smoking has been associated with increased incidence and mortality of colorectal cancer (CRC) [1]. A meta-analysis of 106 observational studies estimated that, compared with never smokers, the risk of CRC and the mortality risk from CRC were higher among smokers (relative risk (RR) 1.18, 95% confidence interval (CI) 1.11-1.25 and RR 1.25, 95% CI 1.14-1.37, respectively) [2]. For both incidence and mortality, the association was stronger for rectal cancer than colon cancer [1]. For these and many other reasons, smoking should be avoided, especially by CRC survivors [3][4][5][6][7][8]. At least four randomized trials have explored health behavior interventions specifically for CRC survivors [9][10][11][12]. Numerous epidemiologic studies have indicated that smoking is the most critical risk factor for chronic obstructive pulmonary disease (COPD) [13][14][15][16][17][18][19]. In addition, regardless of smoking status, COPD is also an independent risk factor for rectal cancer [20] and is also a strong predictor for intensive care unit admission and mortality after CRC surgery [21,22]; this is as preexisting COPD is an independent risk factor for high-grade complications after treatments [23]. Taken together, both COPD and smoking are independent risk factors or prognostic factors for survival in patients with CRC.
Nevertheless, colon and rectal cancer are different tumor types [24], and a recent consensus has proposed abandoning the designation "CRC" [24]. Anatomically, the risk of rectal cancer is four times higher than that of colon cancer [25], and physical activity helps prevent colon cancer but not rectal cancer [26][27][28]. Clear differences exist in molecular carcinogenesis [29], pathology [30], surgical topography and procedures [31], and multimodal treatments [32,33]. Long-term survival rates in patients with colon cancer are higher than in those with rectal cancer, irrespective of multimodal therapy [24]. Surgery for rectal cancer is associated with higher morbidity and mortality, and with higher local recurrence rates than surgery for colon cancer [24]. Therefore, smoking, COPD, and severity of COPD (COPD with acute exacerbation, COPDAE) may influence overall survival (OS) in patients with rectal cancer as surgery for rectal cancer has higher morbidity and mortality rates than colon cancer [24]. Here, we focused on the impact of the presence and severity of smoking-related COPD on the survival of patients with rectal adenocarcinoma undergoing curative resection.
Data are lacking regarding whether smoking-related COPD or its severity is an independent prognostic factor for OS in patients with rectal adenocarcinoma undergoing curative resection. If these conditions are identified as independent prognostic factors of OS in patients with rectal adenocarcinoma, they can serve as simple and valuable prognostic factors for these patients. Therefore, we conducted a head-to-head propensity score matching (PSM) study to estimate the survival outcomes for patients with smoking-related COPD and nonsmokers without COPD with rectal adenocarcinoma undergoing curative resection. This is the first study to estimate the survival impact of smoking-related COPD on patients with rectal adenocarcinoma undergoing curative resection.

Study Population
The study was a propensity score-matched, nationwide, population-based retrospective cohort study. For this cohort study, we enrolled patients from the Taiwan Cancer Registry Database (TCRD) with a diagnosis of rectal adenocarcinoma between 1 January 2009, and 31 December 2017. The index date was the date of diagnosis, and the follow-up duration was from the index date to 31 December 2019. The TCRD contains detailed cancer-related information of patients, including the pathologic stage, cigarette smoking habit, treatment modalities, pathologic data, irradiation doses, chemotherapy regimen and dosage, margin status, and grade of differentiation [34][35][36][37][38]. The study protocols were reviewed and approved by the Institutional Review Board of Tzu-Chi Medical Foundation (IRB109-015-B).

Inclusion and Exclusion Criteria
The diagnoses of the enrolled patients were confirmed after reviewing their pathological data, and the patients with newly diagnosed rectal adenocarcinoma were confirmed to have no other cancers or distant metastases. Rectal adenocarcinoma was defined based on the National Comprehensive Cancer Network (NCCN) guidelines as follows: cancer whose distal border is within 12 cm of the anal verge as determined by rigid proctoscopy [39]. The patients were included if they had received a rectal adenocarcinoma diagnosis and surgery, were ≥20 years old, and had pathologic stages I-IIIC without metastasis, according to the American Joint Committee on Cancer criteria (AJCC, 8th edition). The standard surgery for rectal adenocarcinoma in our study was complete (curative) resection. Neoadjuvant CCRT followed by surgery would be performed for pre-surgery clinical T3 or lymph node positive (AJCC clinical stage II-IIIC) based on NCCN guidelines in Taiwan [39][40][41]. Patients were excluded if they had a history of other cancers before the index date, unknown pathologic types, missing sex data, no smoking habit, unclear pathologic staging, or nonadenocarcinoma histology. In addition, patients with unclear differentiation of tumor grade, missing perineural invasion (PNI) status, missing lymphovascular invasion (LVI) status, or unclear margin status were excluded. The adjuvant treatments of adjuvant radiotherapy (RT), adjuvant chemotherapy, or target therapy were allowed based on NCCN guidelines in Taiwan [39]. Furthermore, we also excluded patients having unclear Charlson comorbidity index (CCI) scores, undergoing curative resection >3 months after the index date, or having unclear preexisting comorbidities. Smokers were defined as current smokers who had rectal adenocarcinoma receiving surgery. We categorized the enrolled patients into two groups based on their current smoking and COPD status to compare all-cause mortality: Group 1 (current smokers with smoking-related COPD) and Group 2 (never-smokers without COPD). We also estimated the survival outcome associated with the severity of smoking-related COPD (frequency of hospitalization for COPDAE with 0, ≥1, and ≥2 hospitalizations within 1 year before the index date) and of patients with stage I-IIIC rectal adenocarcinoma undergoing curative resection. The incidence of comorbidities was scored using the CCI [42,43]. Diabetes, hyperlipidemia, hypertension, chronic kidney disease (CKD), and cardiovascular diseases were excluded from the CCI scores to prevent repetitive adjustment in multivariate analysis. Only comorbidities observed within 6 months before the index date were included; they were coded and classified according to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes at the first admission or after more than two repetitions of a code were issued at outpatient department visits. Supplemental Figure S1 shows the flowchart of patient selection.

Propensity Score Matching and Covariates
To reduce the effects of potential confounders when all-cause mortality between Groups 1 and 2 were compared, we performed 2:1 PSM with a caliper of 0.2 for the following variables: sex, age, diabetes, hyperlipidemia, hypertension, CKD, cardiovascular diseases, CCI score, pathologic stage, grade of differentiation, LVI, PNI, margin status, income levels, adjuvant chemotherapy, and neoadjuvant concurrent chemoradiotherapy (CCRT) [44]. A Cox proportional hazards model was used to regress all-cause mortality on different COPD statuses, with a robust sandwich estimator used to account for clustering within matched sets [45]. Multivariate Cox regression analyses were performed to calculate hazard ratios (HRs) to determine whether the factors of different COPD status, frequency of hospitalization for COPDAE within 1 year before the index date, age, sex, diabetes, hyperlipidemia, hypertension, CKD, cardiovascular diseases, CCI score, pathologic stage, grade of differentiation, LVI, PNI, margin status, income levels, adjuvant chemotherapy, and neoadjuvant CCRT were potential independent predictors of all-cause mortality. Neoadju-vant CCRT has been considered as a covariate and matching in Table 1. We use pathologic stage as a confounding factor for our patients with rectal adenocarcinoma receiving surgery, as all patients received surgery having pathologic stages. We did not use clinical stages as another covariate, as there is quite strong collinearity between clinical stages and pathologic stages. Positive margin was defended as R1 resection. Potential predictors were controlled for in the PSM (Table 1), and all-cause mortality was the primary endpoint in both groups. We also supplied the characteristics of patients with rectal adenocarcinoma receiving surgery before matching as seen in Supplemental Table S1. Table 1. Characteristics of patients with rectal adenocarcinoma with or without smoking-related chronic obstructive pulmonary disease before surgery after propensity score matching.

Variables
Non

Statistics
After adjustment for confounders, all analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA). In a two-tailed Wald test, p <0.05 was considered significant. OS was estimated using the Kaplan-Meier method, and differences among the patient categories of non-COPD, COPD, and hospitalization for COPDAE were determined using the stratified log-rank test to compare survival curves (stratified according to matched sets) [46].

Propensity Score Matching and Study Cohort
PSM yielded a final cohort of 966 patients with stage I-IIIC rectal adenocarcinoma undergoing curative resection (644 and 322 in Groups 1 and 2, respectively) eligible for further analysis; their characteristics are summarized in Table 1. Age, sex, diabetes, hyperlipidemia, hypertension, CKD, cardiovascular diseases, CCI score, pathologic stage, grade of differentiation, LVI, PNI, margin status, incomes levels, adjuvant chemotherapy, and neoadjuvant CCRT were similar between the two groups due to PSM. Follow-up duration and hospitalization for COPDAE within 1 year before the index date were inconsistent and not matched between the two groups (Table 1).

Prognostic Factors of All-Cause Mortality after Multivariate Cox Regression Analysis
Multivariate Cox regression analysis indicated that COPD, ≥1 or ≥2 hospitalizations for COPDAE within 1 year before the index date, old age (>65 years old), CCI ≥1, pathologic stage ≥IIIA, and a moderate-high grade of differentiation were associated with poor OS (Table 2). No significant differences were observed in sex, diabetes, hyperlipidemia, hypertension, CKD, cardiovascular diseases, LVI, PNI, or margin status (   Figure 1 presents the Kaplan-Meier OS curves for the two groups. The OS of Group 1 was significantly inferior to that of Group 2 (p <0.001). The OS of patients with ≥1 or ≥2 hospitalizations for COPDAE within 1 year before diagnosis was significantly inferior to that of patients with 0 hospitalizations for COPDAE (p <0.001; Figure 2). The worst OS was observed in patients requiring ≥2 hospitalizations for COPDAE within 1 year before diagnosis compared with patients with ≥1 or 0 hospitalizations ( Figure 2). 0.057 aHR, adjusted hazard ratio; CIs, confidence intervals; AJCC, American Joint Committee on Cancer; CCI, Charlson comorbidity index; COPD, chronic obstructive pulmonary disease; COPDAE, COPD with acute exacerbation; CCRT, concurrent chemoradiotherapy; CKD, chronic kidney disease; and NTD, New Taiwan Dollar. * All covariates mentioned in Table 2 were adjusted. Figure 1 presents the Kaplan-Meier OS curves for the two groups. The OS of Group 1 was significantly inferior to that of Group 2 (p < 0.001). The OS of patients with ≥ 1 or ≥ 2 hospitalizations for COPDAE within 1 year before diagnosis was significantly inferior to that of patients with 0 hospitalizations for COPDAE (p < 0.001; Figure 2). The worst OS was observed in patients requiring ≥ 2 hospitalizations for COPDAE within 1 year before diagnosis compared with patients with ≥ 1 or 0 hospitalizations (Figure 2).

Discussion
Cigarette smoking and COPD are both independent risk factors for rectal adenocarcinoma [1,2,20] However, no report has evaluated the association of preexisting smokingrelated COPD, severity of COPD, and survival outcomes among patients with rectal adenocarcinoma undergoing curative resection. Accumulating evidence indicates that smoking might be associated with increased mortality in patients with CRC [9][10][11][12]. Poor prognostic factors of OS in patients with rectal adenocarcinoma include older age [47,48], higher CCI score [49], advanced stage [50], PNI positive [51,52], LVI positive [53], moderate-poor differentiation [54][55][56], margin positive [57,58], low income [59], no adjuvant chemotherapy for advanced stages [60], or no neoadjuvant CCRT use [61]. However, few studies have assessed whether smoking-related COPD or COPDAE within 1 year before the diagnosis of rectal adenocarcinoma is an independent prognostic factor of OS in patients with rectal adenocarcinoma undergoing curative resection. Our study is the first head-to-head PSM design to analyze whether COPD or its severity might be poor prognostic factors in patients with rectal adenocarcinoma undergoing curative resection. Our study may be applied to accentuate the importance of smoking-related COPD management, particularly the identification of frequent exacerbators and the prevention of COPDAE, before rectal adenocarcinoma surgery are initiated.
In Table 1, potential comorbidities or cancer risk factors related with survival in COPD or rectal adenocarcinoma were considered as the covariates through head-to-head PSM and showed a balanced distribution in Groups 1 and 2. COPD has been linked to a

Discussion
Cigarette smoking and COPD are both independent risk factors for rectal adenocarcinoma [1,2,20] However, no report has evaluated the association of preexisting smokingrelated COPD, severity of COPD, and survival outcomes among patients with rectal adenocarcinoma undergoing curative resection. Accumulating evidence indicates that smoking might be associated with increased mortality in patients with CRC [9][10][11][12]. Poor prognostic factors of OS in patients with rectal adenocarcinoma include older age [47,48], higher CCI score [49], advanced stage [50], PNI positive [51,52], LVI positive [53], moderate-poor differentiation [54][55][56], margin positive [57,58], low income [59], no adjuvant chemotherapy for advanced stages [60], or no neoadjuvant CCRT use [61]. However, few studies have assessed whether smoking-related COPD or COPDAE within 1 year before the diagnosis of rectal adenocarcinoma is an independent prognostic factor of OS in patients with rectal adenocarcinoma undergoing curative resection. Our study is the first head-to-head PSM design to analyze whether COPD or its severity might be poor prognostic factors in patients with rectal adenocarcinoma undergoing curative resection. Our study may be applied to accentuate the importance of smoking-related COPD management, particularly the identification of frequent exacerbators and the prevention of COPDAE, before rectal adenocarcinoma surgery are initiated.
In Table 1, potential comorbidities or cancer risk factors related with survival in COPD or rectal adenocarcinoma were considered as the covariates through head-to-head PSM and showed a balanced distribution in Groups 1 and 2. COPD has been linked to a number of comorbid conditions [62], such as diabetes, hyperlipidemia, hypertension, CKD, and cardiovascular diseases [63][64][65][66]. Proactive identification and treatment of comorbidities can improve outcomes [67]. Thus, we also considered the aforementioned comorbidities as covariates through the PSM design to balance distribution between the two groups (Table 1). Due to the head-to-head PSM design, all covariates were balanced, and all-cause mortality was significantly higher in Group 1 than in Group 2.
Multivariate Cox regression analysis indicated that COPD and ≥1 or ≥2 hospitalizations for COPDAE within 1 year before the index date were poor prognostic factors of OS (Table 2). Our study is the first study to estimate the survival impact of COPD ( Figure 1) and its severity (measured as number of hospitalizations) before the diagnosis of rectal adenocarcinoma in patients with rectal adenocarcinoma (Figure 2). The reason for this association may be that COPD, especially severe COPD, can increase the risk of more intolerable cardiotoxicity or treatment-related toxicity, decrease the cancer-treatment completion rate, or cause more major complications after treatment [21][22][23]68,69]. Another possible explanation is that smoking may cause more aggressive rectal adenocarcinoma [2], and active and heavy smoking is more common among COPDAE phenotypes [70]. Therefore, smoking-related COPD and COPDAE might be alternative preoperative markers of survival in patients undergoing curative resection for rectal adenocarcinoma. Furthermore, a higher number of hospitalizations for COPDAE within 1 year before the index date was associated with worse survival (Table 2 and Figure 2). Future clinical trials should verify whether these novel prognostic factors of OS for rectal adenocarcinoma identified in the current study affect survival rates. Moreover, in a future study, we aim to evaluate the duration of smoking cessation that may be effective for decreasing all-cause mortality in patients with rectal adenocarcinoma undergoing curative resection.
In addition, data from randomized trials and a meta-analysis [61] have suggested that the preoperative approach is associated with a more favorable long-term toxicity profile and fewer local recurrences than postoperative therapy; OS appears to be similar. Our findings for neoadjuvant CCRT also indicated similar OS outcomes between neoadjuvant CCRT or non-neoadjuvant CCRT after multivariate analysis (Table 2) [61].
The strength of our study was that it was the first and largest cohort study to estimate the survival outcomes of current smokers with smoking-related COPD compared with nonsmokers without COPD in patients with rectal adenocarcinoma receiving curativeintent treatments based on NCCN guidelines [39]. PSM led to comparable covariates between groups, and no selection bias was noted. No study has estimated the impact of COPD and hospitalization for COPDAE in patients with rectal adenocarcinoma undergoing curative resection, and all prognostic factors were evaluated.
This study has some limitations. First, all patients with rectal adenocarcinoma were enrolled from an Asian population; hence, our results should be cautiously extrapolated to non-Asian populations. However, no evidence has indicated differences in oncologic outcomes for rectal adenocarcinoma undergoing curative resection between Asian and non-Asian populations. Second, the diagnoses of all comorbid conditions were based on ICD-10-CM codes. The Taiwan Cancer Registry Administration randomly reviews charts and interviews patients to verify the accuracy of the diagnoses, and hospitals with outlier charges or practices are audited and heavily penalized if malpractice or discrepancies are identified. Nevertheless, to obtain crucial information on population specificity and disease occurrence, a large-scale randomized trial comparing carefully selected patients undergoing suitable treatments is essential. Third, there is a risk of bias in the study by limiting the cohort to surgical patients, as those patients did not reach surgery due to comorbidities such as COPD. However, the patients did not reach surgery due to multiple comorbidities such as cardiovascular diseases, dementia, poor self-care, or other severe comorbidities, not only COPD. In the current database, we cannot clarify the reasons that the patients did not reach surgery. These potential biases might exist in the study. Nevertheless, being hospitalized at least once for COPDAE within 1 year before the surgery of rectal adenocarcinoma is an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for COPDAE within 1 year before diagnosis was associated with poorer survival. The conclusion would not be turned over in the current study. Fourth, in order to diminish the potential bias of patients with rectal adenocarcinoma failing to receive standard of care treatment for rectal cancer, we have considered the therapeutic covariates such as neoadjuvant CCRT, adjuvant chemotherapy use, different pathologic stages, margin status, PNI, LVI, income levels, and adjuvant chemotherapy into the analysis. After PSM adjustment, we believe treatments were similar between the two groups. Finally, the TCRD does not contain information on dietary habits, socioeconomic status, or body mass index, all of which may be risk factors for mortality in patients with rectal adenocarcinoma. However, considering the magnitude and statistical significance of the observed effects in the current study, these limitations are unlikely to affect the conclusions.

Conclusions
Among patients with rectal adenocarcinoma undergoing curative resection, current smokers with smoking-related COPD had worse survival outcomes than nonsmokers without COPD. Hospitalization for COPDAE within 1 year before diagnosis was found to be an independent risk factor for OS in these patients, with a higher number of hospitalizations being associated with poorer survival.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/cancers13164221/s1, Figure S1: Flow-chart of patient selection, Table S1: Characteristics of patients with rectal adenocarcinoma with or without smoking-related chronic obstructive pulmonary disease before surgery before propensity score matching.

Conflicts of Interest:
The authors have no potential conflicts of interest to declare. The data sets supporting the study conclusions are included in the manuscript.