|Year : 2019 | Volume
| Issue : 3 | Page : 241-247
The impact of kidney function on colorectal cancer patients with localized and regional diseases: An observational study from Taiwan
Sum-Fu Chiang1, Jinn-Shiun Chen2, Reiping Tang3, Chien-Yuh Yeh2, Pao-Shiu Hsieh2, Wen-Sy Tsai2, Jeng-Fu You2, Hsin-Yuan Hung2, Cheng-Chou Lai2, Jr-Rung Lin4, Jy-Ming Chiang2
1 Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Lin-Kou; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
2 Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Lin-Kou, Taiwan
3 Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Lin-Kou; Chang Gung University College of Medicine, Linkou, Taiwan
4 Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan
|Date of Web Publication||19-Jul-2019|
Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Lin-Kou, Taoyuan
Source of Support: None, Conflict of Interest: None
BACKGROUND: Impaired kidney function is associated with different diseases. However, its impact on colorectal cancer has not been clarified. In order to understand the effect of preoperative kidney function on the outcome of patients with cancer, we analyzed colorectal cancer patients with localized or regional diseases.
MATERIALS AND METHODS: In total, 3731 stage I to III colorectal cancer (CRC) patients were analyzed in Chang Gung Memorial Hospital. Modification of Diet in Renal Disease (MDRD) formula was used for estimated glomerular filtration rate (eGFR). Receiver operating characteristic (ROC) analysis for kidney function cut-off value; Chi-square method, independent t test, or analysis of variance (ANOVA) method for clinicopathological factors; Kaplan–Meier method for disease-free survival (DFS); Cox proportional hazard model for multivariate analysis.
RESULTS: Among colon cancer patients, low eGFR (MDRD <70) was associated with more male patients, T2 stage, patients without adjuvant chemotherapy, and patients with elevated creatinine level. Low eGFR is a significant risk factor only for stage III colon cancer (hazard ratio 1.70, 95% CI: 1.28–2.26; P < 0.001). Furthermore, postoperative adjuvant chemotherapy did not significantly increase 5-year DFS for both high and low eGFR groups in stage II patients (5 yrs DFS, 94.8% vs. 84.1%, P = 0.098 for high eGFR subgroup; and 75.0% vs. 75.8%, P = 0.379 for low eGFR subgroup). However, significant improvement of 5-yrs DFS after chemotherapy was found in low eGFR stage III colon cancer patients (64.7% vs. 39.4%, P < 0.001 for low eGFR subgroup). In contrast, no significant DFS difference was caused by chemotherapy for high eGFR stage III subgroup (70.5% vs. 63.9%, P = 0.110).
CONCLUSIONS: Although low eGFR is an independent risk factor for stage III colon cancer. However, the adjuvant chemotherapy impacts on stage III colon cancer patients differently according to eGFR status.
Keywords: Colorectal cancer, estimated glomerular filtration rate, prognosis, renal disease, survival
|How to cite this article:|
Chiang SF, Chen JS, Tang R, Yeh CY, Hsieh PS, Tsai WS, You JF, Hung HY, Lai CC, Lin JR, Chiang JM. The impact of kidney function on colorectal cancer patients with localized and regional diseases: An observational study from Taiwan. Indian J Cancer 2019;56:241-7
|How to cite this URL:|
Chiang SF, Chen JS, Tang R, Yeh CY, Hsieh PS, Tsai WS, You JF, Hung HY, Lai CC, Lin JR, Chiang JM. The impact of kidney function on colorectal cancer patients with localized and regional diseases: An observational study from Taiwan. Indian J Cancer [serial online] 2019 [cited 2020 Nov 24];56:241-7. Available from: https://www.indianjcancer.com/text.asp?2019/56/3/241/263028
| » Introduction|| |
Impaired kidney function or renal impairment (RI) has been shown to affect a number of diseases and is associated with a dismal clinical outcome.,,,,,,,,, Furthermore, associations between RI and renal malignancies have been reported repeatedly.,,,,,,,,, However, the influence of the degree of RI in patients with malignant diseases is less well defined. In addition, some authors have reported increasing risk of development of nonrenal malignancies after renal failure.,,,,,,,, RI may cause innate and adaptive immunity deficiency  with adverse consequences including shortened lymphocyte survival, lymphopenia, inhibition of lymphocyte transformation, and suppressor T-cell activity.,,
Preoperative kidney function is clinically important for patients' outcome and is considered a cancer-independent comorbidity.,,,, Precise measurement of renal function, defined by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) is very useful for cancer patients in clinical practice. MDRD was developed for the purpose of understanding the effect of protein restriction on renal disease. Previous reports have shown that eGFR calculated by MDRD equation is associated with an increased risk of cancer death, specifically for all-cause, lung, and prostate cancer in men aged 50 and over.,, However, very few studies have explored the relationship between eGFR and colorectal cancer.
In this study, we retrospectively analyzed treatment outcomes of stage I–III CRC patients in our hospital to understand the relationships between RI and patients with colon cancer, and their relationship to postoperative adjuvant chemotherapy.
| » Materials and Methods|| |
Patients and eGFR evaluation
We followed the methods of Chiang et al. 2012. We obtained patient- and tumor-related information from the Registry of Colorectal Cancer in Chang Gung Memorial Hospital. Different physicians of the same department in this institute adopted similar follow-up routines and adjuvant treatment protocol. After primary tumor resection, all patients were subjected to a follow-up program that included outpatient visits every 3–6 months for physical examination and carcinoembryonic antigen (CEA) test. Patients also received chest X-ray, abdominal sonography, or abdominal computed tomography and colonoscopy every 1 to 3 years. The variables included age, gender, body weight, body height, tumor location, tumor size, histologic grading, TNM stage, family history, personal history, preoperative laboratory data, operation, adjuvant therapy, and follow-up status. Between January 1998 and December 2003, a total of 3857 consecutive patients of stages I to III underwent curative resection for primary colorectal adenocarcinoma. Of these 3857 patients, 14 who had anal cancer, 11 with indefinite primary site, and 2 with unknown primary site were excluded. Furthermore, 99 cases of synchronous colon and rectal cancer were excluded from further analysis. After exclusion of 1231 patients due to incomplete records for eGFR calculation of the remaining 3731 patients, there remained 1202 with colon adenocarcinoma and 1288 with rectal adenocarcinoma. This study was approved by the Institutional Review Board at Chang Gung Memorial Hospital (IRB number 104-1675B).
MDRD formula, reported by Levey et al. in 1999, was calculated as below:
eGFR = 170 × Serum Creatinine −0.999 × Age −0.176 × [0.762 if Female] × [1.180 if Black] × BUN −0.170 × Albumin +0.318
The cutoff value of eGFR determined by receiver operating characteristic (ROC) analysis
To our knowledge, no reference can be found regarding the eGFR value as a prognostic factor of colorectal cancer patients' outcome. Thus, ROC analysis was performed for MDRD cutoff value in discriminating CRC patients' outcome. Colon cancer and rectal cancer patients were analyzed separately. Five-year disease-free survival (DFS) was set as outcome. Statistical significance was set at P < 0.05. Also, Youden's J statistic was done for best cut-off point selection. The formula is “J = Sensitivity + Specificity – 1”. All analyses were performed using the statistical software, Statistical Package for the Social Sciences (Version 13.0, SPSS Inc., Chicago, IL).
Clinicopathological factors of colorectal cancer and eGFR
After ROC analysis for eGFR was undertaken, we used the best eGFR cutoff value for prognosis of patients with colon- or rectal cancer. Differences in clinicopathologic features among the two eGFR groups were assessed by the Chi-square method. Mean values between different clinopathological characteristics were compared by independent t test or ANOVA method. Statistical significance was set at P < 0.05. All analyses were performed using the statistical software, Statistical Package for the Social Sciences, release 11.0 (SPSS, Chicago, IL).
Overall survival, DFS, and time-to-event probabilities were computed using univariate analysis by the Kaplan–Meier method. Differences were estimated by log–rank test. Date of first recurrence was defined as the first date when the existence of local recurrence and/or distant metastases was confirmed by histology of biopsy specimens or reoperation and/or by radiologic studies. The index date for survival calculation was determined as the date of surgery for CRC. The end point was evaluated based on overall survival or DFS. The median follow-up period for surviving patients with regular follow-up program was 85.2 months, ranging between 2.1 and 139.1 months for colon cancer, and 74.6 months, ranging between 2.4 and 136.7 months for rectal cancer. Furthermore, multivariate analysis was also conducted for clinicopathological factors using Cox proportional hazard models. Statistical significance was set at P < 0.05. All analyses were performed using the statistical software, Statistical Package for the Social Sciences (Version 13.0, SPSS Inc., Chicago, IL).
| » Results|| |
The cutoff value of eGFR by MDRD equation for colon cancer and rectal cancer
With the hypothesis that eGFR may have an effect on the outcome of colorectal cancer patients, ROC analysis of eGFR was undertaken. Five-year DFS was set as outcome. We analyzed colon cancer and rectal cancer separately. Initially, 200 colon cancer patients and 200 rectal cancer patients were selected randomly as training sets [Figure 1]a and [Figure 1]c. For colon cancer, eGFR 70 had the highest Youden's index in both the training set and the test set. The area under curve (AUC) was 0.572 in the test set of colon cancer (P < 0.001). For eGFR 70 in colon cancer patients, the sensitivity was 64.7%, and the specificity was 48.3% [Figure 1]b. For rectal cancer, eGFR 75 had better Youden's index, while the AUC was 0.525 in test set (P = 0.124) [Figure 1]d. The ROC analysis of eGFR showed better performance in colon cancer than in rectal cancer. Based on the above findings, we chose eGFR 70 and eGFR 75 for colon cancer and rectal cancer patients' analysis.
|Figure 1: The ROC analysis of stage I to III colorectal cancer. The training data set comes from 200 patients with colon cancer (a), and 200 patients with rectal cancer (c). The test data set comes from patients with colon cancer (b), and rectal cancer (d), after excluding training data set. The AUC was higher in colon cancer than in rectal cancer. J: Youden's index|
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The impact of eGFR on clinicopathologic factors and survival of colorectal cancer patients
The distribution of high (≧70) and low (<70) eGFR and mean eGFR values among different clincopathologic factors for colon cancer [Table 1] and [Table 2] and rectal cancer [Supplement Table 1] and [Table 2] was prepared. In colon cancer patients, the low eGFR group (MDRD <70) had significantly more male patients, more T2 stage, more patients without adjuvant chemotherapy, and more patients with elevated creatinine level (Cr>=1.5 ng/dL) [Table 1]. The eGFR mean values are shown in [Table 2], significantly lower mean eGFR values were observed in older patients (age ≧65), male patients, patients with HTN or DM, smaller tumor size (<5 cm), better histologic grade, and patients without adjuvant chemotherapy. For rectal cancer patients, significantly greater N0 stage, more patients without radiotherapy, more patients without chemotherapy, and elevated creatinine level were observed in the low eGFR group [Supplement Table 1]. Furthermore, low eGFR mean values were significantly associated with older patients (age ≧ 65), patients with HTN or DM, patients without radiotherapy, and patients without adjuvant chemotherapy [Supplement Table 2].
|Table 1: Clinicopathological features of two eGFR groups in colon cancer|
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|Table 2: Comparison of means of eGFR among different clinicopathological factors in colon cancer|
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In general, as shown in [Figure 2](a), stage I–III colon cancer patients with low eGFR (MDRD <70) had significantly worse 3-year, 5-year, and 10-year DFS (DFS, 78.7%, 69.4%, 58.3%, respectively), compared to patients with high eGFR (MDRD ≧70) (DFS, 86.8%, 80.1%, 73.2%, respectively) (P < 0.001, Log Rank test). For rectal cancer, shown in [Figure 2](d), stage I–III rectal cancer patients with low eGFR (MDRD <75) had significantly worse 3-year, 5-year, and 10-year DFS (78.3%, 66.3%, 54.8%, respectively), compared to patients with high eGFR (MDRD ≧ 75) (DFS, 83.0%, 71.1%, 61.6%, respectively) (P = 0.008, Log Rank test).
|Figure 2: The Kaplan–Meier survival analysis for colon and rectal cancer according to eGFR. High and low eGFR groups were separated by 70 for colon cancer (a-c), and 75 for rectal cancer (d). The low eGFR group had worse DFS|
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The impact of eGFR on adjuvant chemotherapy for stage III colon cancer
Because of the more obvious effect of eGFR in colon cancer patients than in rectal cancer patients, we further performed multivariate analysis of eGFR effect on all colon cancer patients and on each stage (stage I–III) colon cancer patients, respectively. As shown in [Table 3], eGFR is a significant risk factor by multivariate analyses only in stage III colon cancer and patients with low eGFR (MDRD <70) had significantly higher risk (hazard ratio 1.70, 95% CI: 1.28–2.26; P < 0.001).
|Table 3: Multivariate analysis for clincopathological factors and eGFR in colon cancer patients. Cox proportional hazard analysis was used|
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We found survival benefit from adjuvant chemotherapy to be affected by eGFR level differentially [Figure 2]b and [Figure 2]c. As shown in [Figure 2](b) and (c), stage II and III colon cancer patients with high eGFR, receiving adjuvant chemotherapy had the best 3-year, 5-year, and 10-year DFS, in contrast, stage II and III colon cancer patients with low eGFR, without adjuvant chemotherapy had the worst outcome. Patients with low eGFR receiving chemotherapy and patients with high eGFR without chemotherapy had modest DFS [Figure 2]b and [Figure 2]c. Furthermore, as shown in [Figure 2]b, for stage II colon cancer patients receiving postoperative adjuvant chemotherapy, there was no significant survival benefit of 5-year DFS for both high and low eGFR groups (stage II, 5 yrs DFS, 94.8% vs. 84.1%, P = 0.098 for high eGFR subgroup; 75.0% vs. 75.8%, P = 0.379 for low eGFR subgroup). However, significant improvement of DFS after chemotherapy was found in stage III colon cancer patients (stage III, 5 years DFS, 70.5% vs. 63.9%, P = 0.110 for high eGFR subgroup; and 64.7% vs. 39.4%, P < 0.001 for low eGFR subgroup) [Figure 2]c. In other words, improvement of DFS in low eGFR groups for stage III colon cancer patients was more obvious compared with other colon cancer patients. Thus, eGFR level differentially affected treatment outcomes of stage II and III colon cancer patients with adjuvant chemotherapy. Furthermore, low eGFR may not exclude adjuvant chemotherapy, since those patients (MDRD <70) who received chemotherapy had comparable survival to patients with high eGFR. And adjuvant chemotherapy could improve outcome both in patients with higher and low eGFR.
CEA status had different impact on the effect of eGFR
While eGFR quartiles affected the DFS of stage III colon cancer patients who underwent postoperation adjuvant chemotherapy [Figure 3]a, we found those with preoperative abnormal CEA (CEA >5) had worse outcome than those with normal CEA in CKD (chronic kidney disease) stage 1 and 2 [Figure 3]b and [Figure 3]c. Thus, combining preoperative CEA and eGFR level as predictors of chemotherapy response, eGFR may facilitate CEA as a predictor of prognosis in stage III colon cancer patients receiving postoperative adjuvant chemotherapy [Figure 4]. Patients with normal CEA of the same CKD stage still had better survival. Compared to poor responders (shorter survivors), there were more good responders (longer survivors) with normal CEA and high eGFR. It may be explained by better compliance of chemotherapy, although more studies are still needed. However, low eGFR seems not to be an exception of postoperative adjuvant chemotherapy.
|Figure 3: The Kaplan–Meier survival analysis of all stage III colon cancer according to CKD stage (a), with normal CEA (b), and elevated CEA (c). All stage III colon cancer patients with abnormal CEA (c) had worse outcome|
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|Figure 4: The X–Y plot analysis of CEA and eGFR for stage III colon cancer. The distribution is shown in each quadrat (%). The distributions in good responders (disease-free survival ≧5 years) (a), and in poor responders (b) were shown|
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| » Discussion|| |
In this study, by using MDRD to estimate glomerular filtration rate, we clearly demonstrated that eGFR was significantly related to clinicopathological factors and affected treatment outcome of colorectal cancer patients. As a potential associated factor of the innate immune system, MDRD equation was used in our study. We further analyzed the impact of adjuvant chemotherapy related to eGFR level in this study. Our data showed that excess risk began to increase at eGFR >60 and survival impact was varied in relation to eGFR level in stage III colon cancer [Figure 3]. Finally, combining with preoperative CEA level, eGFR could further differentiate prognosis and help select patients with good response to adjuvant chemotherapy.
We followed the same strategy of our previous study about neutrophil-to-lymphocyte ratio (NLR). That study has revealed the association between NLR and CRC patients' outcome. Elevated NLR (>3) was associated with worse 5-year DFS. However, NLR was not shown to be related to adjuvant chemotherapy in that study (data not shown).
In stage III colon cancer, patients receiving adjuvant chemotherapy had more survival benefit than patients without adjuvant chemotherapy. However, patients' comorbidities were frequently posed a dilemma for clinicians determining adjuvant chemotherapy due to the need to find a balance between deleterious side effects and effectiveness of chemotherapy. As shown in [Figure 3], we showed eGFR as a stage independent predictor for colorectal patients' survival. In other words, adjuvant chemotherapy affected survival benefit with varied extent between high and low eGFR groups. Our data showed DFS of low eGFR group with chemotherapy was comparable with high eGFR group without chemotherapy. These findings suggest that RI should not be a reason for exclusion from adjuvant chemotherapy although the lowest eGFR quintiles subgroup without chemotherapy had the worst DFS [Figure 3].
Cancer mortality increasing with decreasing kidney function has been reported in previous literatures. Impaired kidney function had been repeatedly shown to affect treatment outcomes in cancer patients.,,,, A reversed association between kidney function and risk of cancer death was demonstrated by Magee. indicating that every 10 mL/min/1.73 m 2 lower eGFR was associated with a 22% higher risk of cancer death. Our finding, as shown in [Figure 3] was similar to that.
By what extent of kidney impairment is cancer risk increased in patients with CKD? Using ROC analysis, we found eGFR 70 for colon cancer, and eGFR 75 for rectal cancer, as cut off points. These cut off points for colon cancer and rectal cancer both dropped in CKD stage 2 (GFR 60–89), which is much earlier than CKD stage 5 (ESRD (end-stage renal disease), GFR <15). This finding reminds us to identify patients with early CKD for follow-up strategy modification. Although there is emerging evidence for an excess cancer risk in patients in early CKD stages, we were the first to indicate that renal function should be considered a predictor of CRC patients' outcome before renal failure.
Although the impact on DFS of patients with or without chemotherapy varied according to eGFR levels, the underlying mechanism remains to be further clarified. Possible mechanisms may be related to altered immunity in patients with kidney function impairment. Chronic kidney disease may alter innate and adaptive immunity.
Our study had some limitations. First, this was a prospective enrollment with retrospective analysis. Selection bias may present, and decisions regarding chemotherapy may be influenced by patients' condition or the judgment of clinicians. Second, the numbers of each subgroup were relatively small. Although some trends were obvious in survival analysis, they did not always reach statistical significance.
In conclusion, eGFR was a prognostic predictor of stage I to III CRC patients, especially for stage III colon cancer. Furthermore, by combining with preoperative CEA level, eGFR may not only be a prognostic factor, but may also help to differentiate responses of postoperative adjuvant chemotherapy. In stage III colon cancer, patients with varied eGFR may differentially benefit from postoperative adjuvant chemotherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]