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Hindawi Journal of Oncology Volume 2019, Article ID 4315032, 12 pages https://doi.org/10.1155/2019/4315032 Research Article Colon Cancer Sidedness, Presentation, and Survival at Different Stages 1 1 1 1 Mark B. Ulanja , Mohit Rishi, Bryce D. Beutler, Mokshya Sharma, 1 1 1,2 Darryll R. Patterson, Nageshwara Gullapalli, and Santhosh Ambika University of Nevada, Reno School of Medicine, Department of Internal Medicine, Mill Street, W-, Reno, NV , USA Renown Institute for Cancer, Mill Street, W-, Reno, NV , USA Correspondence should be addressed to Mark B. Ulanja; mulanja@unr.edu Received 15 November 2018; Revised 4 February 2019; Accepted 10 February 2019; Published 21 February 2019 Academic Editor: Reza Izadpanah Copyright © 2019 Mark B. Ulanja et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Several prognostic factors have been used to guide therapy for colon cancer (CC). However, the relationship between CC laterality (sidedness) and prognosis remains under investigation. Objectives. To assess the effect of laterality on CC presentation and survival, using a Surveillance, Epidemiology, and End Results (SEER) population-based cohort. Methods.Aretrospectivecohort study using data from the SEER program (2007-2015). Results. Of the 163,980 patients with CC, 85,779 (52.3%) presented with right- sided CC (RCC) and 78,201 (47.7%) with left-sided CC (LCC). Stage distributions were as follows: stage I, 24.1%; stage II, 27.3%; stage III, 28.2%; and stage IV, 20.4%. In an adjusted modified Poisson regression approach for risk ratio (RR), patients with LCCs were more likely to be male (RR = 1.14; 95% CI 1.12-1.15, p<0.001). As compared to stage I, stage II cancers (RR = 0.88, 95% CI 0.87- 0.90, p<0.001) were less likely to be LCC. Stage IV CC was slightly less likely to be left-sided (RR = 0.98, 95% CI 0.98, 0.96-1.00, p = 0.028). The median overall survival (OS) for RCC was 87 months. The median OS for LCC was not established, as more than half of the patients diagnosed with LCC were still living at the time of the analysis. In adjusted Cox proportional Hazard model, individuals with stage I, III, and IV LCCs had superior OS as compared to those with matched-stage RCC (adjusted HR = 0.87; 95% CI 0.85-0.88, p<0.001). However, OS was worse among those with stage II disease who presented with LCC (adjusted Hazard ratio [aHR] = 1.06; 95% CI 1.02-1.11, p = 0.004). CC-specific survival (CSS) was superior for LCC versus RCC for stages III and IV but worse for II. Conclusions. In this population-cohort study, LCC is associated with superior OS and CSS survival. eTh overall survival advantage was attributed to stage I, III, and IV disease. Individuals presenting with stage II disease exhibit superior survival if the CC is right-sided. 1. Introduction artery, whereas the distal colon and rectum are derived from the hindgut and receive blood via the inferior mesenteric Colon cancer (CC) is one of the most common malignancies artery. in the United States and represents the second leading cause Several studies have explored the prognostic value of of death in the Western world [1]. A number of prognostic laterality with inconsistent results. Indeed, while some inves- factors are used to guide therapy, but the value of CC laterality tigators have reported superior survival among individuals with right-sided colon cancer (RCC), others have found no (sidedness) in prognosis remains controversial. eTh differ- ences between the right and left colon have been hypothesized difference in survival between left- and right-sided diseases to be due to histologic, genetic, and immunologic features, [2–4]. One 2016 study demonstrated that RCC is associated allofwhich mayconferprognosticvalue.Notably,the with prolonged survival using propensity score matching right and left colon are anatomically and embryologically [4]. However, a meta-analysis [5] of 15 studies performed different: the proximal colon is derived from the midgut and that same year showed a signicfi ant survival benetfi for is perfused primarily by branches of the superior mesenteric left-sided colon cancer (LCC). Further subgroup analyses 2 Journal of Oncology Cancers Excluded: 1. Squamous cell carcinoma (n=2,784) 2. Gastrointestinal stromal tumors(n= 511) Histologic diagnosis of 3. Carcinoid tumors(n= 18,142) Colon Cancers 2007-2015 4. Neuroendocrine(n=4,229) N =612,291 5. Malignant melanoma(n=277) 6. Sarcoma(n=89) 7. Neoplasm, malignant(n= 13,425) 8. Other unspecified malignancies(n=17,854) Other variables excluded: 1. Age<18 and age >89(n=11,001) 2. Large Intestine, NOS(n= 14,526) 3. Rectum (n= 109,962) 4. No available information on AJCC N =554,980 staging(145,854) 5. Unknown tumor stage(n= 19,812) 6. Stage 0 or in situ tumor (n= 14,848) 7. Reporting source autopsy and/or death Certificates (n= 501) 8. Dead (missing/unknown cause of death(n=3, 090) 9. Specific cause of death not available, not first tumor(n=71,406) Included in Final Analysis N = 163,980 Figure 1: Patients’ cohort flowchart showing exclusion and inclusion criteria. demonstrated significant prognostic differences in Western 2. Methods countries. The 2016 American Society of Oncology annual meeting and the 2016 European Society of Medical Oncology .. Study Design and Study Population. Thisisaretrospective annual meeting described poor survival for patients with cohort study using the SEER database for identification of metastatic RCC [6], especially those with RAS wild-type CC from all the registries captured in the SEER 18 program tumors [7, 8]. (San Francisco, Connecticut, Detroit, California, Kentucky, These conflicting findings and previously published stud- Louisiana, New Jersey, Greater Georgia, Hawaii, Iowa, New ies [2, 3, 9] have renewed our interest in investigating the Mexico, Seattle, Utah, Alaska, San Jose-Monterey, Los Ange- eeff ctoflateralityonCCsurvival. les, Rural Georgia, and Metropolitan Atlanta) who had a Journal of Oncology 3 Table 1: Patient’s demographic and clinical characteristics. characteristics Sidedness (laterality) P-value Right sided cancer Left sided cancer N = 85,779 (%) N = 78,201 (%) Age Mean (SD∗) 68.5± 12.7 63.0± 13.0 <0.001 Age group (years) <∗ , ( .) , .) <0.001 50-69 35,523 (41.4) 41,258 (52.8) 70-89 43,458 (50.7) 25,397 (32.5) Gender Male , ( .) (.) <0.001 Female 45,390 (52.9) 34,791 (44.5) Race Hispanic 8,579 (10.0) 9,325 (11.9) Black 11,607 (13.5) 9,182 (11.7) <0.001 White 59,370 (69.2) 50,391 (64.4) Others 6,223 (7.3) 9,303 (11.9) Insurance Insured 57,449 (67.0) 49,801 (63.7) Medicaid 9,362 (10.9) 10,553 (13.5) <0.001 insured/no specifics 14,922 (17.4) 12,677 (16.2) uninsured 2,470 (2.9) 3,161 (4.0) unknown 1,576 (1.8) 2,009 (2.6) Marital status Married 44,909 (52.4) 42,824 (54.8) Divorced 7,971 (9.3) 7,483 (9.6) Separated 905 (1.1) 1,048 (1.3) <0.001 Single 12,187 (14.2) 13,303 (17.0) Unknown 4,167 (4.9) 4,385 (5.6) Widowed 15,640 (18.2) 9,158 (11.7) Geographic region Northeastern 13,587 (15.8) 12,189 (15.6) Midwestern 8,801 (10.3) 6,789 (8.7) <0.001 Western 41,869 (48.8) 40,144 (51.3) Southern 21,522 (25.1) 19,079 (24.4) Tumor Grade Grade I , ( . ) , (. Grade II , (. , (.) Grade III , (.) , (. ) <. Grade IV , (.) , (. ) Unknown , (.) , (. ∗AJCC (6th Edition stages) I 19,321 (22.5) 20,240 (25.9) II 25,989 (30.3) 18,744 (24.0) <0.001 III 23,914 (27.9) 22,391 (28.6) IV 16,555 (19.3) 16,826 (21.5) Histology Mucinous adenocarcinoma , (. ) , (.) Adenocarcinoma NOS , (.) , ( .) Signet ring cell carcinoma , (. ) (. ) <0.001 Adenocarcinoma in adenomatous polyps , (.) , (. Others (papillary, adenosquamous, medullary) , (.) , (.) 4 Journal of Oncology Table 1: Continued. characteristics Sidedness (laterality) P-value Right sided cancer Left sided cancer N = 85,779 (%) N = 78,201 (%) Treatment by surgery Surgery performed 79,083 (92.2) 70,079 (89.6) <0.001 No surgery (other reasons) 6,696 (7.8) 8,122 (10.4) T-staging <0.001 T0 14(0.02) 44 (0.06) T1 11,707 (13.7) 16,304 (20.8) T2 11,871 (13.8) 9,311 (11.9) T3 44,314 (51.7) 36,608 (46.8) T4 14,490 (16.9) 12,069 (15.4) Tx 3,383 (3.9) 3,865 (4.9) Nstaging N0 49,302 (57.5) 44,227 (56.6) N1 20,546 (24.0) 20,155 (25.8) <0.001 N2 14,311 (16.7) 11,865 (15.2) ∗Nx 1,620 (1.9) 1,954 (2.5) ∗SD = standard deviation, AJCC = American Joint Commission on Cancer, Nx = cancer in nearby lymph nodes cannot be measured, and<50 = 18-49. histologic diagnosis of colon cancers. SEER histology codes 3. Main Outcome Measures 8140, 8141, 8143, 8147, 8210, 8211, 8213, 8260, 8261, 8622, 8263, Our primary outcome of interest was overall survival (OS) 8480, 8481, 8490, 8510, and 8560 were used for CC diagnosed and colon cancer-specific survival (CSS) between right and between 2007 and 2015. eTh primary sites of tumor were left-sided colon cancers. Secondary outcome was the like- determined using International Classification of Diseases for lihood of presentation as left or right-sided cancers, for Oncology 3rd Edition (ICD-0-3), with the following site stages I-IV. eTh right-sided cancers were calculated using codes: C18.0, C18.2, C18.3, C18.4, C18.5, C18.6, C18.7, and cecum, ascending colon, hepatic flexure, and transverse C19-9. An index registry was used to classify patients into colon, while left-sided cancers were calculated using splenic various geographic regions: Midwestern (Detroit and Iowa), flexure, descending colon, sigmoid colon, and rectosigmoid Western (California, Los Angeles, San Francisco, Hawaii, junction. We estimated survival in months from the date of New Mexico, Seattle, Utah, Alaska, and San Jose-Monterey), diagnosis to the date of death for nonsurvivors; the end of the Southern (Rural Georgia, Kentucky, Louisiana, Metropolitan follow-up period was used to ascertain survival for survivors. Atlanta, and Greater Georgia), and North Eastern (New Patients were stratified into three groups based on age: young Jersey and Connecticut). The SEER registries continuously (<50 years[18-49 years]), middle-aged (50-69 years), and code and submit American Joint Committee on Cancer elderly (70 years or older[70-89]). (AJCC) 6th and 7th Edition stages for all cancers diagnosed in 2010 and beyond; patients diagnosed before 2010 are staged usingthe AJCC 6thedition only.TheAJCC6th edition .. Statistical Analysis. The baseline characteristics and was used in order to include all patients [10] diagnosed group differences were compared using Pearson’s Chi square between 2007 and 2015. Exclusion criteria include (1) age (X ) test for proportions. Nonparametric variables were younger than 18 years; (2) stage 0 or in situ tumor; (3) compared using the Mann–Whitney-U test. eTh Kaplan- unknown tumor stage; (4) unknown site of primary tumor; Meier method was used for survival analysis, and logrank (5) unavailable staging data; (6) patient deceased and cause test for equality of survival functions. Continuous variables of death unknown; and (7) history of previous cancer (Fig- were analyzed with the student t-test. Stepwise multivariable ure 1). Cox regression models were built using the forward method, adjusting for baseline demographics, treatment, and tumor .. Data Source. eTh SEER database is comprised of data characteristics. Variables included in the adjusted models had collected by the National Cancer Institute. The SEER pro- ap-value<0.05 for the outcome of interest in the univariate gram collects and publishes cancer incidence and survival analysis. es Th e variables remained in the final model if they data using population-based cancer registries that include were still signicfi ant at P <0.05 in the na fi l adjusted model, approximately 28% of the population of the United States. as a p-value<0.05 was deemed statistically significant in this The program routinely collects data on patient demographics, study. tumor sites, tumor morphology, staging, surgical treatment, Modiefi d Poisson approach with generalized linear model and follow-up. (glm) was used to estimate the risk ratio (RR) and confidence Journal of Oncology 5 .. Patient Characteristics. For the 163,980 patients [(80,181 1.00 (48.9%) female], 85,779 (52.3%) were right-sided CC (RCC) 0.90 and 78,201 (47.7%) were left-sided CC (LCC). Mean ages 0.80 (±SD) were [RCC (68.5 ± 12.7) and LCC (63.0 ± 13.0), p<0.001]. AJCC CC stage distributions were 24.1% stage 0.70 Log rank p<0.001 I, 27.3% stage II, 28.2% stage III, and 20.4% stage IV 0.60 (Table 1). For T4 colon cancers, right-sided cancers were more likely to be T4 (14,490 [54.6%]) versus left-sided colon 0.50 cancers (12,069 [45.44]%), [p<0.001]. RCCs were also more 0.40 likely to be N2 (14,311 [54.7%) versus LCC (11,865 [45.3%]), 0 20 40 60 80 100 120 [p<0.001]. For stage IV disease, there was no difference in Analysis time (months) proportion between left-sided and right-sided cancers [p = Right sided colon cancer 0.134]. Left sided colon cancer In adjusted Modiefi d Poisson regression approach for risk ratio (RR), patients with LCC were less likely to be middle Figure 2: Kaplan-Meier survival function for overall survival (OS) age(50-69)(RR=0.84;95%CI 0.83-0.85,p<0.001), old (70- for colon cancer laterality (sidedness). Right-sided colon cancer shows inferior OS over follow-up period. Left-sided colon cancer 89) (RR = 0.61; 95% CI 0.60-0.62, p<0.001) as compared to hassuperiorOSsurvivaloverfollow-up period. young (<50 years). LCC individuals were also more likely to be male (RR = 1.14; 95% CI 1.12-1.15, p<0.001). Stage II cancers (RR = 0.88; 95% CI 0.87-0.90, p<0.001) were less likely to be 1.00 LCC, and stage IV (RR = 0.98, 95% CI 0.96-1.00, P = 0.028) Log rank P<0.001 diseases only slightly, less likely to be LCC [Reference = Stage 0.75 I]. Grades III (RR = 0.73; 95% CI 0.71-075) and IV (RR = 0.68; 95% CI 0.65-0.71) CCs were less likely to be LCC, [Reference = Grade I] (see Table 2). 0.50 .. Colon Cancer Laterality and Survival. The median over- 0.25 allsurvival(OS)for right-sidedcoloncancer(RCC)was 87 months. eTh median OS for that of le-ft sided colon 0.00 cancers (LCC) could not be determined, as greater than 0 20 40 60 80 100 120 50%ofpatientswithLCCwere stilllivingatthe time of Analysis time (months) theanalysis(Figure 2).Themediancancer-specics fi urvival wasnot establishedfor LCCorRCC,asmorethanhalfof AJCC I AJCC III the patients included in the dataset were still living at the AJCC II AJCC IV time of the analysis (Supplementary Figure S1). Median OS for stages III and IV was 101 and 17 months, respectively Figure 3: Kaplan-Meier survival function for overall survival (OS) (Figure 3), while median CSS for stages IV diseases was for colon cancer stages. eTh AJCC I has superior OS, followed by 18 months (Supplementary Figure S2). The OS for colon AJCC II, and then AJCC III. The worst OS was in AJCC IV. AJCC I, cancer stages stratiefi d by sidedness is shown in Figures AJCC II, AJCC III, and AJCC IV = American Joint Commission on 4(a), 4(b), 4(c), and 4(d). In adjusted Cox proportional Cancer (AJCC) stages 1, 2, 3, and 4, respectively. Hazard model, those with LCC had superior OS (adjusted HR = 0.87; 95% CI 0.85-0.88, p<0.001) [Table 3]. Stages I (aHR = 0.90; 95% CI 0.86-0.95, p<0.001), III (aHR = 0.85; intervals calculated by using robust error variances method 95% CI 0.82-0.88, p<0.001),and IV(aHR=0.79;95%CI [11]. Model selection was done by using Akaike information 0.77-0.81, p<0.0001) hadsuperiorOSfor LCCbutworse criterion (AIC) [12]. Model with smallest AIC (244872) was OS for stage II (aHR = 1.06; 95% CI 1.02-1.11, p = 0.004) selected. All statistical analyses were performed using Stata LCC. version 14.2 (StataCorp, College Station, Texas, USA). The CC-specific survival (CSS) was better for LCC (aHR = 0.87; 95% CI 0.85-0.89, p<0.001) versus RCC. Although CSS was worse for LCC in stages II (aHR = 1.30, 95% CI 1.23-1.38, 4. Results p<0.001), it was better for stages III (aHR = 0.84; 95% CI 0.80- .. Study Population. Of the 612,291 patients with conrm fi ed 0.87, p<0.001) and IV (aHR = 0.79; 95% CI 0.77-0.81, p<0.001) histologic diagnosis of CC, those with diagnosis as malignant (Table 4). neoplasm[n =13,425],rectalcancer[n = 109,962],and For the entire cohort, the 3- and 5-year overall survival other cancers of no interest were excluded (Figure 1). 163,980 was 70.0% and 60.2%, respectively (p<0.05). The 3-year patients were used in the na fi l analysis. The exclusion and overall survival for RCC and LCC was 67.6% and 72.5%, inclusion criteria for patients used in final analysis are shown respectively (p<0.001), while 5-year overall survival was in Figure 1. 58.1% for RCC and 62.4% for LCC (P = 0.003). Survival rate Survival rate 6 Journal of Oncology Table 2: Independent predictors of association between left versus right sided (reference) colon cancers. Characteristics Adjusted Risk Ratio (RR) 95% Confidence Interval P-value Male . (.-.) <. Race Hispanic (∗ref) Black 0.84 (0.82-0.86) <0.001 White 0.95 (0.94-0.97) <0.001 Others 1.16 (1.14-1.18) <0.001 Age <50 (ref) 50-69 0.84 (0.83-0.85) <0.001 70-89 0.61 (0.60-0.62) <0.001 Insurance Insured (ref) Medicaid 1.08 (1.07-1.10) <0.001 Insured/no specifics 1.02 (1.01-1.04) 0.002 Uninsured 1.05 (1.03-1.08) <0.001 Unknown 1.10 (1.07-1.13) <0.001 Marital status Married (ref) Divorced 1.01 (0.99-1.03) 0.345 Separated 1.04 (1.00-1.09) 0.042 Single 1.02 (1.01-1.04) 0.002 Unknown 1.03 (1.01-1.05) 0.007 Widowed 0.97 (0.95-0.99) 0.001 Geographic region Northeastern (ref) Midwestern 0.93 (0.91-0.95) <0.001 Western 0.96 (0.95-0.98) <0.001 Southern 0.97 (0.95-0.98) <0.001 AJCC6th edition Stage I (ref) II 0.88 (0.87-0.90) <0.001 III 1.01 (0.99-1.02) 0.460 IV 0.98 (0.96-1.00) 0.028 Tumor Grade Grade I (Ref) grade II . (. -.) . grade III . (. -. ) <. grade IV . (.-. ) <. Unknown . (.-. ) <. Histology Mucinous adenocarcinoma (ref) Adenocarcinoma NOS∗ . (. -.) <. Signet ring cell carcinoma . (. -.) . Adenocarcinoma in adenomatous polyps . (. -.) <. Others (papillary, adenosquamous, medullary) . (.-. ) <. Treatment No surgery (ref) Surgery performed 0.92 (0.90-0.94) <0.001 ∗ref = reference; NOS = not otherwise specified. Journal of Oncology 7 Table 3: Independent predictors of overall survival (OS) for colon cancer. Characteristics Adjusted HR (95% Confidence Interval) P-value Male 1.18 (1.16-0.1.20) <0.001 Race Hispanic (ref) Black 1.15 (1.11-1.20) <0.001 White 1.06 (1.02-1.09) <0.001 Others 0.89 (0.85-0.92) <0.001 Age < (ref) 50-69 1.26 (1.22-1.30) <0.001 70-89 2.60 (2.47-2.64) <0.001 Insurance Insured (ref) Medicaid 1.39 (1.36-1.43) <0.001 Insured/no specifics 1.14 (1.11-1.16) <0.001 Uninsured 1.31 (1.25-1.37) <0.001 Unknown 1.06 (1.00-1.13) 0.062 Marital status Married (ref) Divorced 1.21 (1.18-1.25) <0.001 Separated 1.17 (1.08-1.26) <0.001 Single 1.29 (1.26-1.32) <0.001 Unknown 1.12 (1.07-1.17) <0.001 Widowed 1.38 (1.35-1.42) <0.001 Geographic region Northeastern (ref) Midwestern 1.08 (1.05-1.12) <0.001 Western 1.06 (1.03-1.08) <0.001 Southern 1.14 (1.11-1.17) <0.001 AJCC6th edition Stage I (ref) II 1.30 (1.26-1.34) <0.001 III 2.06 (2.00-2.12) <0.001 IV 7.88 (7.63-8.13) <0.001 Tumor Grade Grade I (Ref) grade II . (. -.) <. grade III . (. -.) <. grade IV . (. -.) <. Unknown . (.-. ) <. Histology Mucinous adenocarcinoma (ref) Adenocarcinoma NOS . (. -.) <. Signet ring cell carcinoma . (.-. ) <. Adenocarcinoma in adenomatous polyps . (. -. ) <. Others (papillary, adenosquamous, medullary) . (. -.) <. Treatment No surgery (ref) Surgery performed 0.39 (0.38-0.40) <0.001 Laterality Right sided (ref) Left sided 0.87 (0.85-0.88) <0.001 ∗ref = reference;∗HR = hazard ratio. 8 Journal of Oncology 1.00 1.00 0.75 0.75 0.50 Log rank P= 0.0002 0.50 Log rank p<0.001 0.25 0.25 0.00 0.00 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Analysis time (months) Analysis time (months) Right sided colon cancer Right sided colon cancer Left sided colon cancer Left sided colon cancer (a) Kaplan-Meier survival function for overall survival (OS) for colon (b) Kaplan-Meier survival function for overall survival (OS) for colon cancer sidedness/laterality, stage 1 cancer sidedness/laterality, stage 2 1.00 1.00 0.75 0.75 0.50 0.50 Log rank P<0.001 Log rank P<0.001 0.25 0.25 0.00 0.00 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Analysis time (months) Analysis time (months) Right sided colon cancer Right sided colon cancer Left sided colon cancer Left sided colon cancer (c) Kaplan-Meier survival function for overall survival (OS) for colon (d) Kaplan-Meier survival function for overall survival (OS) for colon cancer sidedness/laterality, stage 3 cancer sidedness/laterality, stage 4 Figure 4 Table 4: Overall survival (OS) for colon cancer sidedness (laterality) for AJCC stages. Unadjusted HR Adjusted HR AJCC 6th edition stages (95% Confidence interval) (95% Confidence interval) Left vs Right p-value Left vs Right P-value I 0.72 (0.68-0.75) <0.001 0.90 (0.86-0.95) <0.001 II 0.93 (0.89-0.96) <0.001 1.06 (1.02-1.11) 0.004 III 0.68 (0.66-0.71) <0.001 0.85 (0.82-0.88) <0.001 IV 0.74 (0.73-0.77) <0.001 0.79 (0.77-0.81) <0.001 All stages 0.76 (0.74-0.77) <0.001 0.87 (0.85-0.88) <0.001 5. Discussion that individuals with LCCs were more likely to be young, whereas RCCs were more common among older cohort. Our results demonstrate that laterality has an eeff ct on OS and Our results are consistent with those reported in a CSS for both early- and late-stage CC. LCC is associated with 2017 studybyLim et al.[13]. Investigatorsperformed a superior OS and CSS as compared to RCC among individuals retrospective analysis of 414 South Korean patients and found that patients with RCC more frequently presented with larger presenting with stages I, III, or IV diseases. However, for reasons that remain to be elucidated, patients presenting with neoplasms and more advanced nodal disease as compared to stage II disease exhibited inferior OS and CSS when the those with LCC. Individuals with RCC also exhibited inferior 5-year OS as compared to those with LCC (82.1% and 88.7%, primary neoplasm was located on the left side. We also noted Survival rate Survival rate Survival rate Survival rate Journal of Oncology 9 respectively). Our analysis revealed similar findings: the 5- There are several hypotheses that may explain our year OS of patients with RCC was signica fi ntly lower than that findings. There are significant immunological differences of patients with LCC at 58.1% and 62.4%, respectively. between the proximal and distal colon [18]. Inflammation, A systematic review and meta-analysis by Petrelli et al. epithelial injury, and increased cellular permeability are confirmed that LCC, as compared to RCC, is associated most common in the proximal region of the colon [19, with a signicfi antly reduced risk of death [14]. eTh Petrelli 20]. eTh se processes have been postulated to be due to group analyzed over 1.4 million patients across 66 studies interleukin-6 secreted by the unique microbiome present in and concluded that “bearing a tumor on the left side of that region of the bowel [21, 22]. It is therefore conceiv- the colon [is] significantly associated with an absolute 19% able that the poor prognosis observed in RCC is due, in reduced risk of death.” Notably, laterality was found to have part, to a chronic inflammatory process with consequent a prognostic value that was independent of stage, race, and carcinogenesis. Indeed, some authors have hypothesized that adjuvant chemotherapy. eTh Petrelli group also showed that the downstream production of proinflammatory cytokines the survival discrepancy between LCC and RCC is most promotes aggressive CC through increased epithelial prolif- significant among individuals with stage IV disease. Our eration, impaired apoptosis, and/or angiogenesis [23, 24]. analysis demonstrated that the overall survival advantage Microsatellite instability (MSI) colon cancers have a of LCC was primarily due to patients with stage I, III, significantly better prognosis [25]. Right-sided colon cancers and IV diseases. Indeed, left-sided tumors paradoxically are known to have high MSI. The presence of MSI alone might represented a negative prognostic factor among patients with not be able to explain the difference in mortality between stageIIdisease (Table4).ThePetrelligroup observed that right-sided and left-sided colon cancers. Phipps et al. [26] thepresenceofmicrosatelliteinstability (MSI)wasassociated found increased MSI positivity in RCC, but the overall out- with a favorable outcome in stage II CC. Interestingly, for come and survival were still poor. Further work by Yamauchi reasons that have yet to be established, stage II RCC is more et al. noted that frequencies of Cytosine-phosphate-Guanine likely than stage II LCC to be MSI-positive. er Th efore, the (CpG) island methylator phenotype (CIMP-high), MSI-high, prolonged survival associated with stage II RCC may be and BRAF mutations gradually increased from the rectum related to MSI. (<2.3%) to ascending colon (36-40%), followed by falls in the It is important to acknowledge studies reporting con- cecum (12-22%) [27]. The presence of BRAF mutations and tradictory results. In a recent population-based retrospec- CIMP-high mutations are associated with poorer prognosis tive cohort studybyKarim etal.,authorsuseddatafrom [26, 27]. This may explain poorer overall survival for RCC in the province of Ontario, Canada, and found no signicfi ant our cohort. difference in survival when comparing LCC and RCC and Interestingly, ouranalysisrevealedthatyoungindividuals concluded that “disease laterality is not associated with long- were more frequently affected by LCC whereas RCCs were term OS or CSS” [9]. Interestingly, however, investigators did more common among the elderly. eTh underlying cause of observethatRCC wasmorelikelytobestagedasT4and the relationship between age and tumor location has yet to have poorly differentiated histologic features as compared to be established. However, increasing age represents a negative LCC; it is unclear why survival was similar between the two prognostic factor in colon cancer [28]. Therefore, it is possible groups despite the more aggressive features associated with that the poorer overall survival observed in individuals with RCC. Limitations of the Karim group study include nonad- RCC in our cohort may be related to patient age, with justments for confounders that represent prognostic factors accompanying multiple comorbidities. in CC, such as race and ethnicity. Indeed, CC mortality rates Furthermore, thepoorerOSandCSSassociatedwith vary significantly between different ethnic groups [15, 16], and RCCs may be related to screening. Indeed, several studies thus not adjusting for these confounders was a significant have demonstrated that the lower incidence and mortality in limitation of the Karim et al.’s study. LCCs are due to relatively early diagnosis using colonoscopy The most significant decrease in survival associated with [29, 30]. While LCCs are more likely to present with obvious laterality is observed in patients with stage IV disease. Our symptoms such as rectal bleeding and alteration in bowel results are consistent with other studies that demonstrate habits leading to seeking early care, RCCs present more markedly decreased survival among individuals with RCC frequently with subtle symptoms such as microcytic anemia as compared to those with LCC [14, 17]. Indeed, this and weight loss which are not easily detectable until advanced was conclusively demonstrated in two separate studies by stage [31, 32]. Our study shows that RCCs were more likely to Loupakis and Paski et al. [17, 18] . eTh Loupakis group be T4 and advanced nodal (N) stages, and this may be related evaluated the association between tumor location and sur- to late diagnosis. vival parameters in patients with previously untreated stage RCCs, as compared to LCCs, were signicfi antly more IV CCs receiving first-line chemotherapy ± bevacizumab in likely to be mucinous (10.7% versus 5.0%) or signet cell three independent cohorts: a prospective pharmacogenetics ring carcinoma (1.4% versus 0.7%). This is consistent with study (PROVETTA) and two randomized phase III trials, previous reports in the literature [33, 34]. Mucinous adeno- AVF2107g and NO16966. In PROVETTA, patients with carcinoma produces mucin which dissects through tumor LCC exhibited superior OS. This was also the case in the walls and promotes tumor extension; this portends a poor AVF2107gandNO16966 trials.Theauthors concludedthat prognosis as well as a poor response to neoadjuvant and primary tumor location is an important prognostic factor in adjuvant chemotherapies [35, 36]. Indeed, the FIRE 3 [37] previously untreated stage IV CC. and CALGB/SWOG 80405 [8] trial subgroup analysis has 10 Journal of Oncology shown that antiepidermal growth factor receptor therapy Acknowledgments has a decreased benefit in patients with RCC. Signet ring WearethankfultoWeiYang,Ph.D.,M.D.,ExecutiveDirector, carcinomas are aggressive and have a propensity for extensive Nevada Center for Surveys, Evaluation and Statistics, for his intramural spread as well as peritoneal carcinomatosis [38]. suggestions and support. We also thank Paschal Awingura Consequently, these tumors are associated with an overall Apanga, MBchB, Ph.D. Candidate (Epidemiology), Univer- poor prognosis [39]. The superior OS and CSS for LCCs may sity of Nevada, Reno, for his contributions and suggestions therefore be due to the lower propensity for mucinous and throughout the process of putting this manuscript together. signet ring carcinomas to develop on the left side. Our study has some limitations. First, because of its ret- rospective nature we could not assess causation. In addition, Supplementary Materials the study design is inherently prone to selection bias. Second, Supplementary . Figure S1: Kaplan-Meier survival function the SEER database does not include known prognostic factors such as smoking status, diet, and obesity nor does it include for colon cancer-specific survival (CSS) for right-sided colon baseline data on comorbidities; this may therefore be subject cancer (RCC) and left-sided colon cancer (LCC). The curve to residual confounding, despite multivariable analysis. The almost merges aer ft 5 years of follow-up. The median colon SEER database also does not have information on nonsurgical cancer-specific survival could not be calculated from the cancer directed therapies. Furthermore, tumor markers such curve as more than half of the patients diagnosed with colon as MSI status and BRAF, which have prognostic value, could cancer were still living at the time of the analysis. not be determined. Despite these limitations, the major Supplementary . Figure S2: Kaplan-Meier survival function strength of this study is the large sample size, which allows for colon cancer-specific survival (CSS) for AJCC stages. The for a broad and generalizable perspective on presentation and AJCC I has superior survival, followed by AJCC II and then survival for CC laterality. AJCC III. Worst survival for AJCC IV. eTh median CSS could not be calculated for AJCC I-III, from the curve as more than half of the patients diagnosed with colon cancer were still 6. Conclusions living at the time of the analysis. AJCC I, AJCC II, AJCC In this population-cohort study, LCC have superior OS and III, and AJCC IV = American Joint Commission on Cancer (AJCC) stages 1, 2, 3, and 4, respectively. CSS survival. The overall survival advantage was also noted for LCC in stages I, III, and IV; however worse survival was noted for stage II. LCC is independently less likely to present References as stage II and IV diseases. eTh ndin fi gs of this study may support laterality as a prognostic indicator in considering [1] R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics, 2012,” treatment for colon cancer. CA: A Cancer Journal for Clinicians,vol.62, no.1,pp.10–29, [2] R.A.Meguid,M.B.Slidell,C.L.Wolfgang, D.C. Chang,and Data Availability N. Ahuja, “Is there a difference in survival between right- versus left-sided colon cancers?” Annals of Surgical Oncology,vol.15, The data is available at https://seer.cancer.gov/data and can be no. 9, pp. 2388–2394, 2008. accessed upon request. 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