|Year : 2023 | Volume
| Issue : 1 | Page : 1-6
Profile of patients of colon cancers treated without any targeted therapies and comparison of treatment outcome between left- and right-sided tumors: A retrospective study from a tertiary cancer center in South India
KN Lokesh1, Lalatendu Moharana1, Lokanatha Dasappa1, Linu A Jacob1, Suresh Babu1, AH Rudresh1, LK Rajeev1, Smitha Saldanha1, Pravin Khandare1, Vaibhav Amale1, Antony G F. Thottian1, Amit Sharma1, Shwetha Ninutha1, Amit Pandey1, Pragyan Paramita2
1 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Dayananda Sagar Medical College, Bengaluru, Karnataka, India
2 Department of Paediatrics, Dayananda Sagar Medical College, Bengaluru, Karnataka, India
|Date of Submission||30-Dec-2022|
|Date of Decision||03-Apr-2023|
|Date of Acceptance||11-Apr-2023|
|Date of Web Publication||26-Apr-2023|
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru - 560 029
Source of Support: None, Conflict of Interest: None
Introduction: Left- and right-sided colon cancers differ in pathology, tumor biology, and response to therapies. In our country, most of the patients with carcinoma of colon, do not afford targeted therapies and are treated with chemotherapy only, for their metastatic diseases. Aims: The present study aimed to find out differences in terms of survival outcomes between right- and left-sided colon carcinoma patients who were treated without any targeted therapy or immunotherapy. Materials and Methods: Retrospectively, data of patients of carcinoma colon who were diagnosed and treated in between January 2010 and August 2017 were collected. The different clinicopathological and survival parameters were compared between right-sided and left-sided colon carcinoma patients using Kaplan–Meier models, unadjusted Cox regression models, and Cox models stratified by stage. Results: Mean disease-free survival (DFS) for Stage I, II, and III patients was 37.9 months, 33.7 months, and 28.9 months, respectively, and mean progression-free survival (PFS) in 1st line for metastatic disease was 8.1 months. Mean PFS for metastatic diseases in 1st line was not different significantly between left- and right-sided tumors (left vs. right: 8.1 months vs. 8.5 months, P = 0.72). For nonmetastatic disease, mean overall survival (OS) was significantly better in left-sided tumors (left vs. right: 46.2 months vs. 39.6 months, P = 0.019). Those with metastatic disease at presentation, OS did not vary with side (left vs. right: 24.5 months vs. 24.2 months, P = 0.89). Among the patients, who had undergone curative surgery, either upfront or after conversion chemotherapy, left-sided tumors were found to have higher mean DFS and OS (left vs. right, DFS: 31.2 months vs. 20.4 months, P = 0.006, hazard ratio [HR] = 0.54, 95% confidence interval [CI]: [0.38–0.77]; OS: 46.4 months vs. 39.6 months, HR = 0.51, 95% CI = [0.31–0.84], P = 0.008). Conclusion: Patients with left-sided nonmetastatic tumors or metastatic tumors that could undergo curative surgery had higher DFS and OS. Among the patients who did not undergo curative surgery, and were treated with chemotherapy alone, PFS and OS were similar for tumors of both sides. With only chemotherapy without any targeted agents for the metastatic disease, there was no difference in survival with the side.
Keywords: Colon cancer, left versus right, survival, without targeted therapy
|How to cite this article:|
Lokesh K N, Moharana L, Dasappa L, Jacob LA, Babu S, Rudresh A H, Rajeev L K, Saldanha S, Khandare P, Amale V, F. Thottian AG, Sharma A, Ninutha S, Pandey A, Paramita P. Profile of patients of colon cancers treated without any targeted therapies and comparison of treatment outcome between left- and right-sided tumors: A retrospective study from a tertiary cancer center in South India. Oncol J India 2023;7:1-6
|How to cite this URL:|
Lokesh K N, Moharana L, Dasappa L, Jacob LA, Babu S, Rudresh A H, Rajeev L K, Saldanha S, Khandare P, Amale V, F. Thottian AG, Sharma A, Ninutha S, Pandey A, Paramita P. Profile of patients of colon cancers treated without any targeted therapies and comparison of treatment outcome between left- and right-sided tumors: A retrospective study from a tertiary cancer center in South India. Oncol J India [serial online] 2023 [cited 2023 Jun 4];7:1-6. Available from: https://www.ojionline.org/text.asp?2023/7/1/1/374817
| Introduction|| |
Right-sided and left-sided colon has a distinct embryological origin. Right-sided colon originates from the embryonic mid-gut whereas the left-sided colon originates from the embryonic hindgut. As a result of which, the two sides have distinct arterial supply, lymphatic drainage, and lumen environments. Left- and right-sided tumors as well differ in pathology and tumor biology.,,, Right-sided tumors have a flat histology and commonly possess mutations in the DNA mismatch repair pathways, whereas in the left-sided tumors, chromosomal instability pathways related mutations, such as KRAS, APC, and p53 mutations, are observed and these tumors demonstrate polypoidal morphology. Therapy responses are also known to be different between the two sides. Metastatic left-sided colorectal cancer patients are known to benefit more when targeted therapies such as anti-epidermal growth factor receptor (EGFR) therapy or anti-vascular endothelial growth factor (VEGF) agents are added to the 5-fluorouracil (5-FU)-based chemotherapy regimen. Right-sided colorectal cancer patients do not respond well to conventional chemotherapies, but demonstrate more promising results with immune therapies because of their higher antigenic load. The studies comparing the outcome of the tumors of the two sides have included the cases, who were treated with 5-FU-based chemotherapy regimens along with targeted agents such as anti-EGFR agents, i.e., cetuximab or panitumumab or anti-VEGF agents such as bevacizumab, for the metastatic diseases. There are few trials only to compare the differences in outcome if any between left- and right-sided tumors, which were treated with chemotherapy only. In a developing country like India, where most of the patients do not afford targeted therapies or immunotherapy and are treated with chemotherapy only, for their metastatic diseases, this study tries to find out differences if any between left- and right-sided tumors in terms of clinicopathological characteristics and survival outcomes.
The objectives of this study were to study the profile of patients of colon cancer and to compare the treatment o outcomes between left- and right-sided colon cancers, who had not received any targeted agents. The primary clinical endpoint was disease-free survival (DFS) or progression-free survival (PFS) for patients treated with curative or palliative intent, respectively. The secondary clinical objective was overall survival (OS).
| Materials and Methods|| |
Retrospectively, data of patients of carcinoma colon who were diagnosed and treated in our hospital, between January 2010 and August 2017 were collected, irrespective of the stage of presentation, but only those who had not received targeted therapies for their metastatic diseases were enrolled for this study. Consent for treatment was taken, but consent for participation in this study or ethical committee approval was not taken, in view of this being a retrospective study and no new interventions outside the guidelines were tested in this study. However, the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 2013. Patients were required to have undergone at least 2 years of follow-up unless they met with an event before that time. Tumors of cecum, ascending colon, and transverse colon up to the level of splenic flexure were grouped under right-sided tumors, whereas tumors of the splenic flexure, descending colon, and sigmoid colon were grouped under left-sided tumors for the study. Fluoropyrimidine-based (5-FU/capecitabine with or without oxaliplatin) regimens were used for adjuvant treatments, according to the indications of the individual patients. Upon progression to metastatic diseases and for the patients who had presented with metastatic/unresectable diseases, patients had received palliative chemotherapy regimens only, without any targeted therapies in any lines. Patients who were younger than 18 years of age, with chronic infections such as HIV/HBV/HCV, or who could not or did not receive any chemotherapy for whatever reasons, were excluded from the study.
All analyses were performed with IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY: IBM Corp. The primary and secondary endpoints were assessed and were compared between left- and right-sided tumors using Kaplan–Meier models, unadjusted Cox regression models, and Cox models stratified by stage. Statistical tests reported were two-sided, and P < 0.05 was used to declare statistical significance for the primary endpoint.
| Results|| |
A total of 369 patients were diagnosed with colon cancer during the study period. Out of them, 337 patients who met the inclusion criteria were enrolled in the study retrospectively, and their data were reviewed. The demographic and clinical characteristics of both the left- and right-sided colon cancer patients are depicted in [Table 1]. Out of the 337 patients, 209 (62.0%) patients had left-sided tumors and 128 (38.0%) had right-sided tumors. Fourteen (4.1%), 41 (12.2%), 148 (43.9%), and 134 (39.8%) had Stage I, II, III, and IV diseases at presentation, respectively. Sixty-six (19.6%) patients had liver-only metastasis at presentation (left vs. right: 42 [20.1%] vs. 24 [18.7%]).
The median duration of follow-up was 25 months (range: 2 months to 60 months). During this time, there were a total of 273 (81.0%) events of progression (139 [68.5%] in the Stage Group I, II, and III combined and 134 [100%] in Stage Group IV). Of 134 upfront metastatic and 90 recurrent metastatic diseases, 87 were tested for RAS (left: 45 and right: 42) and 46 were tested for both RAS and BRAF (left: 25 and right: 21). 11/45 (24.4%) of left-sided tumors and 16/42 (38.1%) of right-sided tumors were found to be RAS mutated. 2/25 (8%) of the left-sided tumors and 1/21 (4.8%) of right-sided tumors were found to be positive for BRAF mutation. The mean duration of symptoms did not vary significantly between sides (left vs. right: 2 months vs. 2.2 months; P = 0.28).
All patients presenting with clinical Stages I and II had undergone upfront surgery [Table 2]. Thirty-two (21.6%) and nine (6.7%) of Stage III and Stage IV diseases at presentation, respectively, had undergone upfront surgery. Two hundred and forty-one (71.5%) patients (Stage III: n = 116; Stage IV: n = 125) were considered unresectable at presentation and had received conversion chemotherapy. Among them, 104 (43.1%) patients (Stage III: n = 78 [67.2%]; Stage IV n = 26 [20.8%]) could successfully undergo curative surgery after conversion chemotherapy.
The mean DFS for Stage I, II, and III patients was 37.9 months, 33.7 months, and 28.9 months, respectively. The mean PFS for metastatic diseases in 1st line was 8.3 months. Mean DFS was significantly longer in the left-sided tumors (left vs. right: 31.9 months vs. 22.5 months, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.48–0.79, P = 0.006) [Figure 1], but this difference was not statistically significant in any of the stage groups [Table 3] and [Figure 2]. Mean PFS for metastatic diseases in 1st line was not different significantly between left- and right-sided tumors (left vs. right: 8.1 months vs. 8.5 months, P = 0.72). Patients who received conversion chemotherapy, left-sided tumors could undergo curative resection more frequently than right (left vs. right: 47.5% vs. 37.3%, P = 0.01) [Table 2]. Patients who had undergone curative surgery, either upfront or after conversion chemotherapy, left-sided tumors were found to have longer mean DFS than right-sided tumors (31.2 months vs. 20.4 months, P = 0.006) [Table 4] and [Figure 1]. For the young patients (≤40 years), there was no significant difference in DFS according to the side of the tumor, unlike patients of age more than 40 years (age > 40 years; left vs. right: 31.1 months vs. 22.2 months, HR = 0.63, CI = 0.48–0.82, P = 0.02).
|Figure 1: PFS by side. Kaplan–Meier PFS estimate shows statistically significant differences between sides for the whole cohort and for the patients who had undergone curative surgery. P value (Log-rank test). PFS: Progression-free survival, DFS: Disease-free survival, KM: Kaplan–Meier|
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|Table 3: Disease-free survival for nonmetastatic and progression-free survival for metastatic disease, according to stage|
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|Figure 2: PFS by subset analysis. Comparison of PFS by side in standard clinicopathological subgroups: Left-sided tumors had significantly better PFS in patients of age group >40 years, Grade II and III tumors, and who under had undergone curative resection. P value (Log-rank test). PFS: Progression-free survival, HR: Hazard ratio, CI: Confidence interval|
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|Table 4: Disease-free survival/progression-free survival and overall survival in according to curative resection status|
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OS rate at 2 years for the cohort was 81.8% (left vs. right: 85.6% vs. 73.4%, P = 0.003). Mean OS was significantly better for the left-sided tumors (left vs. right: 41.3 months vs. 34.4 months, HR = 0.59, 95% CI = 0.42–0.85, P = 0.003). For patients who presented with nonmetastatic disease, mean OS was significantly better in left-sided tumors (left vs. right: 46.2 months vs. 39.6 months, P = 0.019). Those with metastatic disease at presentation, OS did not vary with side (left vs. right: 24.5 months vs. 24.2 months, P = 0.89). For patients who had undergone curative surgery, either upfront or after conversion chemotherapy, left-sided tumors had significantly higher mean OS (left vs. right: 46.4 months vs. 38.0 months, HR = 0.51, 95% CI = 0.31–0.84, P = 0.003). For different stage at presentation, there was no significant difference found when OS rate at 2-years compared between left- and right-sided colon cancer patients [Table 5].
| Discussion|| |
In our study, left-sided tumors were more common than right-sided tumors (62% vs. 38%). There was no difference in sex ratio between left- and right-sided tumors. Left-sided tumors were presented earlier, with a mean age of presentation of 50.2 years for left-sided tumors versus 57.5 years for right-sided tumors. About 24.9% of the patients with left-sided tumors had presented at or before 40 years of age, in comparison to only 9.4% of the right-sided tumors (P = 0.007). A retrospective analysis of the surveillance, epidemiology, and end results (SEER) database by Uslanja et al. revealed that left colon cancer was more common in young individuals, whereas right-sided cancers of colon were more common among the elderly. In our study, there was no significant difference in the mean duration of symptoms according to side. More number of right-sided tumors presented with metastatic disease upfront, left vs. right: 33.4% vs. 50%. Analysis of the SEER database by Ulanja et al. and another retrospective analysis from South Korea by Lim et al. also found that right-sided colon cancer patients more frequently presented with larger tumors as compared to those with left-sided tumors. In our study, there was no significant difference in the percentage of patients who presented with liver-only metastasis. Total peritoneal metastasis (left vs. right: 11.3% vs. 24.8%) was significantly more common in right-sided tumors. RAS mutation was found to be more common in the right side (left vs. right: 24.4% vs. 38.1%), whereas BRAF mutation was more common in the left side (left vs. right: 8% vs. 4.8%).
Among Stage III and Stage IV patients, left-sided tumors had undergo upfront surgery more frequently than right-sided tumors (left vs. right: 24.7% vs. 14.9% and 10% vs. 3.1% for Stage III and IV, respectively). More of the left-sided tumors could undergo curative resection after the conversion chemotherapy, for Stage III tumors (Left vs. Right: 71% vs. 60%). For Stage IV tumors, there was no significant difference in the rate of successful conversion with side.
Mean DFS or OS did not differ significantly between the sides in any of the stage groups, though they were numerically higher for the left-sided tumors in nonmetastatic stage groups (Stage I, II, III). Among the patients who could undergo curative surgery either upfront or after conversion chemotherapy, left-sided tumors were found to have better DFS and OS which was statistically significant. In a retrospective study from Canada by Karim et al., authors found no significant difference in survival with location. They concluded that disease laterality was not associated with long-term OS or cancer-specific survival (CSS). However, the authors could not conclude the definite reason behind the similar OS and CSS despite right-sided tumors being bulky and more aggressive. In a meta-analysis by Petrelli et al., left-sided colon cancer was associated with 19% absolute reduction in the risk of death. Notably, laterality was found to have a prognostic value independent of stage, race, and adjuvant chemotherapy. In this meta-analysis, survival discrepancy was most significant among individuals with Stage IV disease. Right-sided colon cancers are considered to have high microsatellite instability (MSI) and high MSI is considered a good prognostic factor. However, in spite of this, right-sided tumors having no better survival or poorer survival in comparison to left colon tumors can be explained by the following explanations. There are differences in the immunological responses between the sides. Right colon has a unique microbiome which secret interleukin-6, which in turn results in increased production of inflammatory cytokines and epithelial injury and this promotes the development of aggressive colon cancer.,,, BRAF mutations and cytosine-phosphate-guanine island methylator phenotype (CIMP) high mutations are considered poor prognostic factors. CIMP-high and BRAF mutations are more common in right-sided colon cancers.,, In our study, BRAF mutation was more common in left-sided tumors. This may explain, why in our study, metastatic left-sided colon cancers have no better prognosis than right-sided tumors.
Our study is a retrospective review. At the present era, targeted therapies such as monoclonal antibodies and tyrosine kinase inhibitors and immunotherapies have proven benefits when added in different lines of therapy in metastatic colon cancer, and significance of our study, in which patients have received only chemotherapy, lies only in resource scarce situations.
| Conclusion|| |
In our study of colon cancers, patients with left-sided tumors whether nonmetastatic or metastatic, who could undergo curative surgery, had higher DFS and OS. Among the patients who did not undergo curative surgery, and were treated with chemotherapy alone, PFS or OS was similar for tumors of both sides. From this finding, it could be concluded that left-sided tumors had favorable prognoses in comparison to right-sided tumors. However, for metastatic diseases, only chemotherapy is grossly inadequate. Moreover, targeted agents are required to cash on the favorable histopathological and molecular make-ups of the left-sided tumors. With only chemotherapy without any targeted agents for metastatic diseases, there is no difference in survival with the side.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]