Differences in clinical presentation, patient demographics, and tumor biology between right- and left-sided colon cancers have long been reported in the literature,3–10
but it is unclear whether these differences translate into clinically meaningful prognostic differences. We found that, after controlling for multiple patient, disease, risk adjustment, and treatment variables, there was no overall difference in 5-year mortality between right- and left-sided colon cancers. More important, this relationship is not consistent across tumor stage. Stage II right-sided cancers had lower mortality, and stage III right-sided cancers had higher mortality.
Our results across all stages combined differ substantially from two recent studies by Meguid et al11
and Benedix et al.12
With SEER data, Meguid et al11
reported that right-sided cancers had a higher risk of mortality than left-sided cancers across all stages (HR, 1.04; 95% CI, 1.02 to 1.07) when analysis was controlled for age, sex, ethnicity, tumor characteristics (ie, stage, size, grade), number of lymph nodes examined, and year of diagnosis. However, when their adjusted results were stratified by stage, they reported no difference in mortality between right- and left-sided cancers for stage I (HR, 1.003; P
= .93) and lower mortality for right-sided stage II cancers (HR, 0.91; P
< .001), which was more similar to our results. Notably, they were not able to risk adjust or control for chemotherapy administration with the data set, and their inclusion and exclusion criteria differed. They included all patients in the SEER database from 1988 to 2003 who underwent surgical resection for a primary diagnosis of invasive colon adenocarcinoma for all AJCC stages I to IV, and they excluded patients who died within 60 days of surgery. We limited our sample to AJCC stages I to III and excluded patients who died within 30 days of surgery. Benedix et al12
showed an even higher risk of mortality for right-sided cancers (odds ratio, 1.12; P
= .02) compared with left-sided cancers than Meguid et al,11
but again showed conflicting results when stratified by stage. Their unadjusted analysis showed significantly shorter 5-year survival for right-sided cancer for stage I (78% v
= .01) and stage III (55% v
< .01) but not for stage II (74% v
72%). This study included approximately 17,000 German patients with colon cancer, and analysis was controlled for multiple patient- and disease-related variables, including comorbidity (but not including chemotherapy administration). Inclusion and exclusion criteria also differed from our study. Similar to the study by Meguid et al,11
Benedix et al12
included all four stages of colon cancer and did not limit patients to age 66 or older.
The reasons for the inconsistent relationship between mortality and tumor location by stage is not clear, but it is most likely related to tumor biology. One specific aspect of tumor biology that lends particular credence to our findings is microsatellite instability (MSI). Multiple studies have found that patients with MSI-positive tumors have a better overall prognosis and that MSI status is an independent favorable predictor of survival.19–23
MSI is predominantly seen in right-sided colon cancers,10
and less than 5% of left-sided cancers show MSI.7
MSI-positive tumors also have a more favorable stage profile. Jernvall et al24
estimate that 20% to 25% of stage II right-sided cancers are MSI positive and that fewer than 15% of stage III right-sided tumors have this same attribute, with even fewer in stage IV colon cancers. Additional evidence that stage III right-sided cancers may be more biologically distinct from stage II right-sided cancers is that MSI-positive status has also been associated with a significantly decreased risk of lymph node (odds ratio, 0.31; 95% CI, 0.17 to 0.56) and distant organ (odds ratio, 0.13; 95% CI 0.05 to 0.33) metastases.22
This study has several limitations. First, we examine only Medicare beneficiaries age 66 years and older at the time of diagnosis, which may limit the applicability of our findings to younger patients with colon cancer. However, the risk of colon cancer increases with age, and the average age of diagnosis of patients with nonfamilial colon cancer is older than 65 years.25
Second, unmeasured factors, such as patient preferences or provider practice patterns, may play a role in patient outcome. If these unmeasured factors are also associated with tumor location, our results could be subject to unmeasured confounding. However, we included a wide variety of clinically relevant patient, disease, risk adjustment, and treatment variables. Finally, MSI tumor status was not available in this data set, which prohibits direct testing of our hypothesis that MSI is a major contributor to the decreased mortality seen in stage II, right-sided colon cancers.
Despite these limitations, our findings have important implications different from previous studies. Prior research has reported an increase in mortality for right-sided colon cancers compared with left-sided colon cancers. Conversely, this study shows no significant difference in mortality after more extensive adjustment and limiting of the sample to a more homogeneous group of patients who have a more narrow age distribution (limited to age 66 years and older as a result of Medicare linkage) and patients considered for surgery with a curative intent (by excluding AJCC stage IV and patients undergoing palliative procedures). We also highlight that the relationship between mortality and tumor location in colon cancer is not straightforward. Specifically, this relationship is stage dependent; stage II right-sided cancers show decreased mortality than left-sided tumors, and stage III right-sided tumors show increased mortality. We hypothesize that a major reason for this inconsistent relationship between mortality and tumor location by stage is due to tumor biology and, more specifically, MSI status. Additional research needs to be done to confirm this hypothesis, which, if confirmed, may significantly impact decisions regarding treatment of patients with right-sided colon cancer. More specifically, these results can help inform the treatment decision process for patients with stage II colon cancers for whom use of adjuvant chemotherapy is controversial.