|Year : 2019 | Volume
| Issue : 1 | Page : 14-21
Right versus left Colon cancer: Is there a difference in outcomes?
Aris Plastiras1, Evangelia Iosif1, Georgia Georgiou2, Amyn Haji1, Asif Haq1, Savvas Papagrigoriadis1, Joseph W Nunoo-Mensah1
1 Department of Colorectal Surgery, King's College Hospital, London, United Kingdom
2 Department of General Surgery, Hippokration Medical Centre, Athens, Greece
|Date of Web Publication||12-Mar-2019|
Mr. Joseph W Nunoo-Mensah
Department of Colorectal Surgery, King's College Hospital, Denmark Hill, London SE5 9RS
Source of Support: None, Conflict of Interest: None
Background: Colorectal cancer is a major healthcare problem due to its high prevalence and mortality rates. Objective: The objective of the study is to delineate the relationship between the location of the colon cancer and the outcomes. Design: This is a retrospective, single-center study including patients diagnosed with right and left colon cancer from January 2010 to December 2015. Setting: Patients with no rectal or synchronous metastatic disease were included in the study. Diagnosis was confirmed following a computed tomography and colonoscopy. Patients and Methods: Four hundred and seventy-five patients with colon cancer were included; 226 right-sided tumors (RCC) and 249 with left-sided colon cancer (LCC) underwent surgery. Main Outcome Measures: We compared right- and left-sided tumors in terms of epidemiological, histological, clinical, and perioperative characteristics, and we also attempted to determine whether there is a difference in the overall and per stage survival. Sample Size: Four hundred and seventy-five patients with colon cancer. Results: Patients with colon cancer were analyzed, 226 (47.5%) with RCC and 249 (52.4%) with LCC underwent surgery. Patients with RCC were more likely to be women, older, and with more comorbidities. Furthermore, RCC were more likely to be poorly differentiated (29.65%, P < 0.001) and more locally advanced at the time of diagnosis (P < 0.001). Controlling the differentiation for each stage, there was no statistical significant difference between left and right survival and recurrence (P > 0.05). When stratified according to tumor stage, Stage II LCC had better overall survival (odds ratio [OR], 1.694, 95% confidence interval [CI], 1.015, 2.827) and Stage III LCC had a better overall survival (OR, 1.403, 95% CI, 1.007, 2.143), disease-free survival (OR, 1.293, 95% CI, 1.011, 1.714), and less cancer-related deaths (OR, 0.282, 95% CI, 0.080, 1.000). Conclusions: Comparing similar stages, patients with LCC appear to have better oncological outcomes irrespective of tumor differentiation. Limitations: Single-center, retrospective study without excluding patients with hereditary cancers. Oncological biomarkers were not available in all patients, and further analysis was not performed.
Keywords: Colon cancer, colon cancer outcomes, colon cancer staging
|How to cite this article:|
Plastiras A, Iosif E, Georgiou G, Haji A, Haq A, Papagrigoriadis S, Nunoo-Mensah JW. Right versus left Colon cancer: Is there a difference in outcomes?. World J Colorectal Surg 2019;8:14-21
|How to cite this URL:|
Plastiras A, Iosif E, Georgiou G, Haji A, Haq A, Papagrigoriadis S, Nunoo-Mensah JW. Right versus left Colon cancer: Is there a difference in outcomes?. World J Colorectal Surg [serial online] 2019 [cited 2019 Oct 14];8:14-21. Available from: http://www.wjcs.us.com/text.asp?2019/8/1/14/254036
| Introduction|| |
Colorectal cancer is a major worldwide healthcare problem due to its high prevalence and mortality rates. It is the fourth most common cancer and the second leading cause of cancer-related deaths in both men and women in the UK. There were nearly 1.4 million new cases diagnosed worldwide in 2012 and more than 41,000 cases diagnosed in the UK in 2014. Deaths from colon cancer in the UK were nearly 16,000 in 2014.
Various studies have reported a shift in the anatomical subsite distribution of colorectal cancer from the distal toward the proximal large bowel.,, In the past few decades, there has been a tendency to differentiate right-sided tumors from left-sided tumors, according to different characteristics in regard to their clinical presentation, epidemiology, and patient demographics as well as molecular biology. Right-sided tumors (RCC) are typically present in more advanced stages as bulky, exophytic lesions that infiltrate the lumen and cause symptoms of anemia, whereas left-sided tumors (left-sided colon cancer [LCC]) are diagnosed earlier due to change in the bowel habit and obstructive symptoms. The majority of published studies highlight a higher incidence of RCC in women and elderly patients compared to LCC.,,, Furthermore, there are well-described differences in the molecular biology pattern of the two tumors.,,, The major tumorigenic pathways responsible for the development of colorectal cancer: the chromosomal instability (CIN) pathway with activation of oncogenes and deactivation of tumor suppressor genes, the genetic instability pathway due to alteration of mismatch repair (MMR) genes, and finally, the pathway with hypermethylation of oncogene promoters. However, it still remains under ongoing research whether these differences translate into actual significant difference in tumor prognosis and mortality.
Many studies have tried to delineate the relationship between cancer location and cancer-related mortality with the majority of them concluding that RCC are associated with higher mortality compared to LCC.,, However, conflicting results have emerged when results were adjusted according to tumor stage.,, In this study, we did not only compare right- and left-sided tumors in terms of epidemiological, histological, clinical, and perioperative characteristics, but we also attempted to determine whether there is a difference in the overall survival, mortality, and more importantly, if this difference is consistent across the different tumor stages.
| Patients and Methods|| |
This is a retrospective, single-center study including 475 patients with right or left colon cancer. All patients who were diagnosed and treated in our institution with primary adenocarcinoma of the colon from January 2010 to December 2015 were enrolled in the study. Patients with synchronous metastatic disease were excluded from the analysis even if in published data, they do have a reasonably good survival for their advanced tumor stage. This implies that only patients with American Joint Committee on Cancer (AJCC) Stage I–III and/or tumor/node/metastasis (TNM) stage with M = 0 (absence of metastatic disease) were included in the study. Patients with rectal cancer were excluded as the treatment differs from the rest of the colonic tumors. Distal sigmoid tumors were included in our data analysis although rectosigmoid ones were not. Diagnosis was confirmed in all patients following a computed tomography (CT) scan of their abdomen and pelvis followed by a chest CT Scan for staging completion and full colonoscopy. The management plan and all results were discussed, decided, and confirmed in the multidisciplinary team meeting. All the data were retrieved from the encrypted electronic patients' records (Allscripts Sunrise™ Electronic Health Record).
Patients who met the inclusion criteria were divided into two groups. The first group included patients with right-sided tumors, defined as cecum, ascending colon, hepatic flexure, and transverse colon. The second group included patients with left-sided tumors, including splenic flexure tumors, descending colon, and sigmoid colon. In addition to the tumor subsite, AJCC stages were used to stratify our comparison and analysis, and therefore, right-sided – Stage I tumors were compared with left-sided – Stage I tumors. Similarly, right-sided Stage II and III were compared to left-sided Stage II and III, respectively. The main outcome measures were tumor recurrence (local and distal), disease-free survival (DFS) period, cancer-related death, and overall survival between right- and left-sided 'similar' cancer groups.
Patient-related variables analyzed in the study were sex, age, body mass index (BMI), and American Society of Anesthesiologists (ASA) score. Examined treatment-related variables were emergency state of the operation (e.g., secondary to obstruction), postoperative anastomotic leak, mean length of hospital stay, need for reoperation, and administration of adjuvant chemotherapy. Finally, tumor-related characteristics include the stage of the tumor according to TNM, stage of the tumor according to AJCC, and the differentiation of the tumor and the positive lymph node ratio in the pathological report.
Statistical analysis was conducted using SPSS (IBM Statistical Package for Social Sciences v. 21.0, Chicago, IL, USA) and GraphPad Prism 6 (GraphPad Software, San Diego, CA, USA). Parameter distributions were not normal as indicated by Kolmogorov–Smirnov test, and differences among patient groups were evaluated with the nonparametric Kruskal–Wallis and Mann–Whitney tests, as appropriate. Logistic regression analyses were applied to assess the association between right or left side of cancer in terms of recurrence, cancer-related death, DFS, and overall survival. We compared overall and 5-year DFS with Kaplan–Meier curves by log-rank test. The analysis was performed separately for the AJCC Stage I, II, and III. P < 0.05 was considered statistically significant.
| Results|| |
The study included 475 patients, of which 226 (47.5%) were diagnosed with right-sided colon cancer and 249 (52.5%) with left-sided colon cancer. Demographic and tumor characteristics of the 475 participants are shown in [Table 1]. Patients with RCC were more likely to be women and older (P < 0.001, P = 0.001, respectively). Patients who underwent left-sided colectomy showed a trend to have higher ASA score (23.7%) than right-sided colectomy patients (15.9%, P = 0.003).
|Table 1: Demographic and tumor characteristics of patients with right and left colon cancer|
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Most of the LCC patients were more obese than RCC patients according to their BMI (P = 0.003). In a subgroup analysis, we observed an obesity paradox as patients with a BMI 30–34.9 had shorter length of stay (LOS) and less anastomotic leaks (P = 0.045, P = 0.061, respectively).
There was no difference in adjuvant chemotherapy among the two groups (P = 0.411). No difference was observed also among emergency or elective operation procedure between the two patient groups (P < 0.579). The mean length hospital stay was longer in left-sided colon cancer patients (P = 0.006).
Concerning anastomotic leakage, a higher rate was observed in the RCC (5.9%) compared to LCC (3.8%), but it did not reach any statistical significance (P = 0.063). There was no significant difference as well between LCC and RCC patient groups in terms of need for reoperation (P = 0.844).
Regarding tumor characteristics, RCC were found to be more poorly differentiated (29.65%) compared to left-sided (4.42%) ones (P < 0.001). Comparing further the differentiation for each stage, no statistical significant difference was found in overall survival and DFS between left and right outcomes (P > 0.05).
In addition, the tumor T stage in RCC was more advanced on presentation than LCC (P < 0.001). There was no difference in the rest of the tumor characteristics (N stage, M stage, AJCC stage, positive lymph node ratio) among the right- and left-sided tumors. In our study, almost one-eighth of both right and left colon cancer patients had metastatic disease at the time of diagnosis (12.6%). From patients with metastatic disease on diagnosis, 40% were ≤64 years of age and almost one-fifth (18.33%) were ≤55 years of age.
On logistic regression analysis [Table 2], AJCC Stage II LCC patients have a longer overall survival than Stage II RCC patients (odds ratio [OR], 1.694, 95% confidence interval [CI], 1.015, 2.827). AJCC Stage III LCC patients have a longer overall survival (OR, 1.403, 95% CI, 1.007, 2.143) and longer DFS than RCC-sided patients of the same stage (OR, 1.293, 95% CI, 1.011, 1.714) and less cancer-related death rate (OR, 0.282, 95% CI, 0.080, 1.000). There was no difference in the rate of recurrence among LCC and RCC colon cancer patients according to AJCC stage of the patients.
|Table 2: Summary of the logistic analysis of right-sided colon cancer versus left-sided colon cancer patients in terms of recurrence, cancer-related death, disease-free survival, and overall survival according to the American Joint Committee on Cancer stage|
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The median survival time was 56 months. The median survival for patients with LCC was higher than RCC (73 vs. 66 months, P = 0.01) [Figure 1]. The median DFS time was 50 months. The median DFS for patients with LCC was more prolonged compared to RCC (72 vs. 65 months, P = 0.05) [Figure 2]. Analysis of the median overall survival with respect to AJCC stage showed a significantly decreased survival for Stage II RCC (67 RCC vs. 78 months LCC, P = 0.04) and Stage III (54 RCC vs. 60 months LCC, P = 0.05) but not for Stage I (83 RCC vs. 85 months LCC, P = 0.83) [Figure 1]. Analysis of the median DFS with respect to AJCC stage showed a significantly decreased survival for Stage III RCC (53 RCC vs. 63 months LCC, P = 0.05) but not for Stage I (74 RCC vs. 79 months LCC, P = 0.54) or Stage II (69 RCC vs. 75 months LCC, P = 0.14) [Figure 2].
|Figure 1: Kaplan–Meier survival estimates for patients with right-sided versus left-sided colon cancer overall survival. (a) Overall survival – All stages combined. (b) Overall survival Stage I. (c) Overall survival Stage II. (d) Overall survival Stage III|
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|Figure 2: Kaplan–Meier survival estimates for patients with right-sided versus left-sided colon cancer disease-free survival. (a) Disease-free survival – All stages combined. (b) Disease-free survival Stage I. (c) Disease-free survival Stage II. (d) Disease-free survival Stage III|
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The overall 5-year survival rate was higher for LCC patients compared to RCC patients (71 vs. 60 months, P = 0.01) [Figure 1]. Analysis of the 5-year survival with respect to AJCC stage showed significantly better survival for patients with LCC Stage II (74 vs. 61 months, P = 0.04) and Stage III (58 vs. 50 months, P = 0.05) but not for LCC Stage I (84 vs. 79 months, P = 0.53) [Figure 1]. The 5-year DFS showed better survival for patients with LCC (62 vs. 54 months, P = 0.05) [Figure 2]. Further analysis of the 5-year DFS according to the AJCC stage revealed a significant difference between LCC and RCC only for Stage III (41 RCC vs. 51 months LCC, P = 0.05) and no difference for Stage I (70 RCC vs. 73 months LCC, P = 0.54) or Stage II (57 RCC vs. 66 months LCC, P = 0.13) [Figure 2].
| Discussion|| |
Differences between right- and left-sided colon cancers have been outlined in various studies and have been demonstrated in clinical presentation, epidemiology and patients' demographics, and molecular biology.,,,,
Regarding clinical presentation, RCC typically present later at a more advanced stage as bulky, exophytic lesions that infiltrate the lumen and cause symptoms of anemia, weight loss, or at later stages as palpable abdominal masses. On the other hand, LCC are diagnosed at an earlier stage due to the narrower lumen of the descending and sigmoid colon which causes bleeding symptoms or change in bowel habit and obstruction.,,
There is increasing evidence that RCC are more frequent in women, older patients, and patients with significant comorbidities., Similarly, our study showed that RCC were more common in females and elderly patients (P < 0.001, P = 0.001). Patients who underwent left-sided colectomy (23.7%) were found to be more comorbid (ASA III and above) than those who underwent right-sided (15.9%) colectomy (P = 0.003).
Another interesting association that has been reported in the literature is the relationship between the patient's BMI and the prognosis of the tumor. The impact of obesity on the outcomes postcolorectal surgery is controversial. A recent study from Lee suggested that overweight patients had a significantly shorter length of hospital stay compared to underweight patients possibly due to the protective effect of the nutritional status in obese patients compared to cachectic ones. Similarly, Renehan and Sperrin recently concluded that overweight people had a lower mortality after the diagnosis of colon cancer, therefore, the intentional weight loss postcancer diagnosis is not recommended., In contrast, it is well known that raised BMI is a risk factor for the development of colorectal cancer, and many studies have associated obesity with colon cancer recurrence and cancer-specific mortality., In our study, LCC patients were more overweight than RCC patients (P = 0.003), and in subgroup analysis, overweight patients had a shorter LOS (P = 0.045) and slightly lower number of anastomotic leaks (P = 0.061).
Regarding postoperative complications, some studies have shown no difference in postoperative morbidity between RCC and LCC, while others have reported higher incidence of postoperative complications in patients with left-sided colectomies. Benedix et al. have found that patients that underwent left colectomies had higher incidence of intraoperative complications such as bleeding, ureteric, or bladder injury while right-sided colectomy patients had a higher incidence of major postoperative complications (pulmonary embolism and cardiovascular complications). In terms of anastomotic leak incidence, there was no significant difference between the two groups in this study. In our study, we tried to investigate whether there was a difference in the incidence of anastomotic leak between the two groups and therefore a difference in the need of reoperation and as a result a prolonged hospital stay. However, we observed no significant difference in the incidence of anastomotic leak between the two groups and no difference in the need of reoperation. The longer mean length of hospital stay in LCC patients (P = 0.006) is probably associated with parameters not examined in our study such as unreported complications (postoperative ileus, delirium, pneumonia, atrial fibrillation). Results in literature are controversial with other studies reporting a similar LOS between the two groups, a longer LOS in patients with RCC, or a longer LOS in patients with LCC, especially in laparoscopic procedures.
There are three major tumorigenic pathways responsible for the development of colorectal cancer. The first and most common (80%–85%) pathway is characterized by CIN, and it involves the activation of oncogenes and the deactivation of tumor suppressor genes in various chromosomes, including 5q (APC), 17p (TP53), 18q (DCC), and K-ras leading to uncontrolled cell proliferation and therefore the progression from normal mucosa to adenoma and finally to carcinoma. The second pathway is characterized by genetic instability due to alteration of MMR genes, and when this involves the somatic cells, it leads to microsatellite instability (MSI). Tumors with high MSI (MSI-H) are usually found more proximally in the colon (right-sided tumors), have less aggressive clinical behavior, and have more favorable outcomes compared to microsatellite stable (MSS) tumors., Even though many studies advocate the better prognosis of MSI-H over MSS tumors for Stage II and Stage III colon cancer, there are conflicting findings when the benefit from administrating adjuvant chemotherapy,, is examined in patients with MSI versus MSS tumors and when the results are stratified according to the tumor stage., Finally, the third tumorigenic pathway involves the hypermethylation of oncogene promoters which leads to silencing of protein expression (CpG island methylator phenotype). Left-sided cancers and especially rectal cancers express TP53, APC, and COX-2 pathways more than right-sided cancers.
RCC are usually more poorly differentiated as demonstrated in various studies in the current literature contributing to their worse prognosis compared to the LCC., A linear correlation between tumor differentiation and distance from the ileocecal valve is reported by Benedix et al. showing that the more proximal the cancer was located to the ileocecal valve, the higher the incidence of poorly differentiated tumors and mucinous carcinomas was. These findings are consistent with other studies., Similarly, in our study, RCC were found to be significantly poorly differentiated compared to LCC (P < 0.001).
The median overall survival for patients with LCC was higher than RCC patients (73 vs. 66 months, P = 0.01). Similarly, overall 5-year survival rate for patients with LCC was higher than RCC patients (71 vs. 60, P = 0.01). In agreement with other studies in literature,,, RCC are likely to have worse prognosis compared to LCC because the tumors are more poorly differentiated (G3 = 25.2 months, P < 0.001) and more locally advanced (T4 = 27 months, P < 0.001). However, the worse outcome of the right colectomies may be attributed to the higher age and the higher ASA scores in this subgroup.
Even though patients with RCC were found to have worse overall prognosis than patients with LCC, when survival was analyzed according to the tumor stage, results are more complex and in some studies, controversial. In our study, Stage II LCC patients had a better overall survival than RCC patients of the same stage. Similarly, Stage III LCC patients demonstrated prolonged overall survival and DFS and less cancer-related deaths compared to same stage RCC patients. Benedix et al. showed shorter survival for right colon cancer patients with Stage I and Stage III tumors while other investigators showed better prognosis in Stage II RCC compared to LCC of the same stage.
There was no significant difference in the ratio of the infiltrated lymph nodes between RCC and LCC, and therefore, the more aggressive nature and the worse prognosis of the right tumors cannot be attributed to the higher ratio of nodal infiltration in our study. However, important point is that in both right and left colectomies, the average number of resected nodes was above the recommended number (n = 12) to accurately predict node negativity., Similarly, in literature, RCC are generally associated with higher numbers of examined lymph nodes. It is known that the number of involved lymph nodes reflects patient's improved immune response. Therefore, even though a high positive lymph node ratio may be associated with more locally advanced disease and worse prognosis, the causal relationship between lymph node counts and survival can be confounded by the tumor-host response since a stronger immunologic response leads to better survival.
We should acknowledge specific limitations in our present study. This is a single-center, retrospective study which included all consecutive patients without considering and excluding from the study, patients with hereditary cancers. Finally, information about oncological biomarkers was not available in all patients in this dataset and further analysis was not performed.
| Conclusion|| |
In conclusion, our study proved that RCCs and LCCs seem to represent distinct tumor entities, with RCC having higher incidence in older, female, more comorbid patients, poorly differentiated, and more locally advanced in diagnosis. Controlling the differentiation for each stage, there was no statistical significant difference between left and right outcomes. Our results suggest that patients with LCC had a better overall survival compared to patients with RCC similar to most existing published data irrespective of tumor differentiation.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]