Aims: The aim of this study was to examine the characteristics of patients with right and left sided colon tumors, effects of tumor localization in early and advanced stage colon cancer patients.

Methods: This retrospective study enrolled with histologically confirmed 249 primary colorectal cancer (CRC) patients at medical oncology department of Adnan Menderes University between 2013-2017.

Results: Sixty-six (26.9%) of the patients were right sided colon tumor and 81 (33.1%) of them were left sided colon and 98 (%40.0) rectum tumor. At the time of diagnosis, 51 (77.2%)and 139 (77.7%) patients were diagnosed as early stage, 15 (32.8%) and 40(22.3%) patients were diagnosed as metastatic stage in right side and left side tumors, respectively (p=0.949). In early stage colorectal cancers, left sided tumors were significantly more common in males (p=0.027), recurrence developed earlier in female patients in right sided (p=0.043). Female sex, young age were independent unfavorable prognostic factors for the relapse time in early stage right colon cancer patients. Positive and unknown PANRAS mutation status were found to be unfavorable prognostic factors for both right and left side tumors. In metastatic stage colorectal cancers liver metastasis was found to be more common in the left side tumors. Patients with PANRAS mutant left sided tumors lived longer than PANRAS negative patients (49.0 vs 25.5 months respectively, p <0.001). OS was 11 months and PFS was 1.8 months longer with anti-EGFR agents in first-line treatment in right sided tumors, however it was not statistically significant. In left sided tumors, there was no difference in OS, but PFS was longer with anti-VEGFR agents in first-line treatment but it was not significant (13 months vs 6.3 months). In PANRAS positive patients with antiVEGFR treatment, OS and PFS were longer in the left side tumors(OS 49.0 months vs 30.6 months PFS 13.2 months vs 7.2 months, p=0.784). In multivariate analysis young age and negative PANRAS mutation were found to be negative prognostic factors on OS.

Conclusion: I believe that the low number of patients and the fact that there is a single center study affect the statistical significance of the data. However, I think that new literature information in the right and left colon tumors should be investigated more extensively. Therefore much largely scaled prospective studies are needed and also the further studies should be focused on clinicopathological and genetic factors and their effects on OS, PFS and DFS separately on the right and the left colon.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in many countries.¹ Therefore, this malignancy has always been intensely investigated and widely discussed. Recent studies focused on the differences between right and left colon cancer. These studies showed that tumours from different locations of the colon behave molecularly and clinically different. These differences were attributed to the genetic factors, environmental factors, the differentiation of embryogenic origins of the right and left colon as well as the bacterial flora.^2,3 Studies investigating the differences between the right and left colon tumours revealed that right colon tumours were more common in women with higher grades and advance stage at diagnosis than the left colon tumours. Mucinous histology was found to be higher in the right colon tumours. Microsatellite instability, CpG island methylator phenotype (CIMP)-high, mutagenic metabolites of cytochrome p450, MAPK signalling, RAS, BRAF and PIK3CA were more commonly detected in right colon tumours. Chromosomal instability, activation of the epithelial growth factor receptor (EGFR) pathway, KRAS, DCC and P53 mutations, HER1 and HER2 gene amplification and aneuploidy were observed more frequently in left colon tumours.^3–6

Based on these findings many studies were performed regarding the evaluation of treatment options. Current phase 3 studies and meta analysis showed that, overall survival (OS) of the patients with the right colon tumours was shorter than the patients with the left colon tumours.  In addition, when the efficacy of the treatments and progression free survival (PFS) were analized, tumour location was found to be important for the treatment choice in colon cancer. Studies showed that patients with RAS wild-type left-sided colon cancer had a significantly greater survival benefit from the addition of EGFR treatment compared with anti-vascular endothelial growth factor (VEGF) treatment to standard chemotherapy.^1,3,7 In addition, anti-VEGF treatments were found to be more effective in right colon tumours.These new findings changed the colon cancer treatment algorithms all over the world.

The aim of this study was to examine the characteristics of patients with right and left colon tumors, effects of tumor localization in early and advanced stage colon cancer patients, as well as the efficacy of treatment on overall survival (OS), the progression free survival (PFS) and the disease free survival (DFS) to update our treatment options.

Patient selection

This retrospective study enrolled  with histologically confirmed primary colorectal cancer (CRC) patients who underwent CRC treatment at medical oncology department of Adnan Menderes University between 2013-2017. Clinical information on each patient  was obtained from  the database of hospital  medical  records. All of the patient files which were accessible were included in the study. Only 249 CRC patients' data were able to be reached. The study was approved by the medical ethics committee of Adnan Menderes University. Since the study was retrospective, no approval form was obtained from the patients.

The following clinicopathological characteristics were collected: sex (male vs. female), age (< 65 years vs. ≥ 65 years), stage, date of diagnosis, date of death, tumor location, presence or absence of adjuvant therapy, recurrence date, chemotherapy treatments at metastatic stage, progression date and mutation status .

Statistical analysis

All analyses were conducted by www.e-picos.com, New York, NY. Continuous variables were presented by means and standard deviation values and categorical variables were expressed by frequencies and percentages. The relationship among the categorical variables was analyzed with the Chi-square Test.Univariate survival analysis was performed using the Kaplan-Meier method with the log-rank test. A COX regression analysis was run to understand multivariate interaction of prognostic factors. A p-value less than 0.05 was considered as statistically significant.

Patient characteristics and treatment properties

In total, 146 (59.6%) male and 99(40.4%) female patients were included. The characteristics of the 245 patients are summarized in Table 1. There were 27 (11%) stage I, 69 (28.2%) stage II, 11 (4.5%) stage IIIA, 70 (28.6%) stage IIIB, 13 (5.3%) stage IIIC and 55 (22.4%) stage IV diseases. Sixty-six (26.9%) of the patients were right sided colon tumor and 81 (33.1%) of them were left sided colon and 98 (%40.0)  rectum tumor. At the time of diagnosis, 51 (77.2%) and 139 (77.7%) patients were diagnosed as early stage, 15 (32.8%) and 40 (22.3%) patients were diagnosed as metastatic stage in right side and left side tumors, respectively (p=0.949).

Relation between the clinical outcome and the tumor localization in early stage CRC patients

Primary tumor location and patient characteristics in early stage CRC patients were shown in Table 2. Left side tumors were significantly more common in males (p=0.027). There were no statistically significant differences between the right and left side tumors in other clinicopathological parameters. The relationship between relapse time and clinical parameters were examined between right and left colon in Table 3. Recurrence developed earlier in female patients when compared to the male patients in right colon tumors (p=0.043). COX Regression analyses showed that stage and positive and unknown PANRAS mutation status were independent unfavorable prognostic factors for relapse time in early stage CRC (Table 4). Cox analysis was performed separately for the right and the left colon (Table 5). Female sex, young age were independent unfavorable prognostic factors for the relapse time in early stage right colon cancer patients. Positive and unknown PANRAS mutation status were found to be unfavorable prognostic factors for both right and left side tumors.

Relation between the clinical outcome and the tumor localization in metastatic stage CRC patients

Primary tumor location and patient characteristics in metastatic stage CRC patients were shown in Table 6. Data also included patients who developed recurrence after adjuvant therapy. Liver metastasis was found to be more common in the left side tumors. However, other parameters were not statistically significant. OS and PFS were analyzed between right and left side tumors and compared the parameters in metastatic stage CRC (Table 7&8). Male patients had a longer OS than female patients in right sided tumors (49.1 vs 15.9 months respectively, p <0.036). Patients with PANRAS mutant left sided tumors lived longer than PANRAS negative patients (49.0 vs 25.5 months respectively, p <0.001). OS was 11 months and PFS was 1.8 months longer with anti-EGFR agents in first-line treatment in right sided tumors, however it was not statistically significant. In left sided tumors, there was no difference in OS, but PFS was longer with anti-VEGFR agents in first-line treatment but it was not significant (13 months vs 6.3 months). In PANRAS positive patients, antiEGFR treatment can not be applied. Therefore, it is the only kind of data pertaining to this patient group. With antiVEGFR treatment, OS and PFS were longer in the left side tumors compared to the right side tumors. However, in PANRAS positive group, it was not statistically significant (OS 49.0 months vs 30.6 months PFS 13.2 months vs 7.2 months, p=0.784). In multivariate analysis young age and negative PANRAS mutation were found to be negative prognostic factors on OS. There were not able to determine any statistically significiant prognostic factor on PFS. Cox analysis was performed separately for right and left colon like early stage CRC patients.  However, in cox regression analysis, I could not show effective prognostic factor for OS or PFS.

In this study, the influence of primary tumor location in CRC was analyzed.  Although there were no significant differences in the survival times and the PFS between antiEGFR and antiVEGFR front-line targeted therapies for metastatic CRCs, left sided tumors were superior to right sided tumors in terms of the survival times and the PFS. When subgroup analyses were conducted, liver metastasis were found to be more common in the left sided tumors. In addition, male patients had a longer lifespan than female patients with the right side tumors. Also, patients with PANRAS mutant left side tumors lived longer than patients with PANRAS negative tumors. However, there was no difference in PANRAS mutation status and survival among the right-sided tumors.  Studies showed that patients with RAS wild-type right-sided colon cancer had a significantly greater survival benefit from the addition of VEGF treatment to the standard chemotherapy.^1,3,7 On the other hand,  in this study, although statistically not significant front-line anti-EGFR treatments were found to be more effective in right colon tumours on OS and PFS. Survival benefit between these treatments in the left side tumors (25.3 vs 25.6 months) were not detected in the analyses.  However antiVEGFR front-line targeted therapies provided better PFS in left side tumors (13 vs 6.3 months, not statistically significant, p=0.268). On the contrary, current phase 3 studies and meta analysis showed that patients with PANRAS wild-type left-sided colon cancer had a significantly greater survival benefit from the addition of antiEGFR treatment when compared with the antiVEGF treatments. Since the antiEGFR treatment can not be applied, I could not compare the antiEGFR and the antiVEGFR treatments in patients with positive PANRAS mutation. In this case, I analysed the PFS and OS time of the left and right sided PANRAS mutant tumors' which were all treated with antiVEGFR agent. OS  and PFS were longer in the left side tumors compared to the right side tumors, however it was not statistically significant (OS: 49.0 vs 30.6 months, PFS: 13.2 vs 7.2 months, p=0.784). In contrast, in Alliance study, left side tumors with KRAS mutant were associated with poorer OS compared with right side tumors with KRAS mutant.^3,8 Currently, data on PANRAS mutant left side tumors versus right side tumors are limited; therefore, the prognostic and predictive value of the primary tumour site within the PANRAS mutant population still requires evaluation. In multivariate analysis, young age and the negative PANRAS mutation status were found to be negative prognostic factors on OS, however the statistical effect of prognostic factors  could not be determined on PFS.

It has been shown that patients with right side tumors are older and more often female, and the disease is associated with advanced tumor stages, increased tumor size, poorly differentiated tumors, and the tumors with different molecular patterns. Many studies have demonstrated poorer OS and PFS in patients with right side tumors.^9,10 In this study, I examined the differences in clinicopathologic parameters between the right and the left sided colon cancers not only in metastatic disease but also in early stage CRC . In this study,  I showed that the left side tumors were significantly more common in males(p=0.027). I analysed clinical parameters affecting the relapse time in the right and left side tumors.  In this current study, DFS was found shorter in female with right side tumors (p=0.043). The other parameters did not provide statistically significant differences between the right and left side tumors.COX Regression analyses showed that advance stage (stage III) and the positive and the unknown PANRAS mutation status were independent unfavorable prognostic factors for DFS in early stage CRC. This multivariate analysis was performed separately for the right and the left colon. Female sex, young age were independent unfavorable prognostic factors for relapse time in earlystage right colon cancer patients. Positive and unknown PANRAS mutation status was found to be unfavorable prognostic factor for both right and left side tumors. The survival time after relapse was also examined. In the right side tumors, the survival time after recurrence was 44.5 months, while it was 74.9 months in the left side tumors. However,in contrast with the literature, DFS and OS were not found to be higher in left side, where they were found to be higher in right side tumors (DFS: 46,6 months vs 38.5 months OS: 50.7 months vs 44.7 months). However, these findings were not statisticaly significiant (p=0.607).

This study has several limitations. Firstly, as a retrospective study from a single institution with a small number of patients, the statistical power is obviously limited. Secondly, the regimens of the adjuvant chemotherapy and the front-line chemotherapy for the metastatic stage were different.

In conclusion, I found that early stage right and left side colon cancers were not significantly different in clinicopathological characteristics except male sex. Right side colon cancer had lower DFS than left side colon cancer in female patients. I also found that the survival time after recurrence was higher in left side cancers but showed no statistical difference compared with the right side cancers. Additionally, the positive and the unknown PANRAS mutation status and also stage III diseases  were found that independent unfavorable prognostic factors for DFS in early stage right side cancers.

In metastatic CRC patients, no signifcant differences in OS and PFS between antiEGFR and antiVEGFR front-line targeted therapies were detected, however left sided tumors were superior to the right sided tumors in terms of survival times and PFS. In contrast to the literature, front-line anti-EGFR treatments were found to be more effective in right colon tumours and front-line anti-VEGFR treatments showed better outcome in left side tumors on OS and PFS. None of the analyses detected statistically significant benefits between these treatments.Young age and positive PANRAS mutation were found to be negative prognostic factors on OS in metastatic stage CRC patients.

I believe that the low number of patients and the fact that there is a single center study affect the statistical significance of our data. However, I think that new literature information in the right and left colon tumors should be investigated more extensively. Therefore much largely scaled prospective studies are needed and also the further studies should be focused on clinicopathological and genetic factors and their effects on OS,PFS and DFS separately on the right and the left colon.

None.

Authors declare there is no conflict of interest.

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