Diabetes mellitus (DM) is known to be an independent risk factor for the development of colorectal cancer (CRC).1, 2 The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls.3 However, it is unclear if the presence of diabetes in patients with CRC is associated with the cancer-specific survival of patients after cancer diagnosis.4 Some authors found that patients with CRC and diabetes are at greater risk of all-cause and cancer-specific mortality and have worse disease-free survival compared to those without diabetes.5 But other authors found that the presence of DM in patients with CRC was not associated with worse cancer-specific survival.4
Diabetes mellitus and DM related comorbidities may initiate difficulties during cancer specific treatment and may have an impact on cancer management and outcome. Colorectal cancer surgery is often followed by postoperative complications which may impact survival. The aim of our study was to find out if DM in patients with advanced colorectal carcinoma is associated with cancer-specific or overall survival.
This study included 200 consecutive patients (131 males, 69 females, mean age 63 years) with elective colorectal cancer surgery at the Institute of Oncology Ljubljana from September 2010 to March 2013. In 14 patients, curative resection of liver metastases was carried out during the same anesthesia. In all the patients, a laparotomy was performed. The exclusion criteria were preoperative infection, preoperative ileus and palliative surgical procedure.6, 7 All 200 patients were prospectively included in the study about the usefulness of biomarker index CD64 for neutrophils (iCD64n) for early detection of postoperative infection.6, 7 The study protocol was approved by the Republic of Slovenia National Medical Ethics Committee. Approval and written consent for the retrospective study of the long-term outcome of the patients was obtained from the Protocol Review Board (MZ 0120-28/2016-2, ERID-KSOPKR/20), and the Ethics Committee of the Institute of Oncology (ERID-KSOPKR/77, OIRIKE 0049).
Rectum, colon and both of them were affected by cancer in 68%, 30% and 2% of cases, respectively. Stage of tumor was evaluated clinically according to the nuclear magnetic resonance (NMR) investigation before the beginning of the treatment. The TNM classification was used for staging of colorectal cancer disease.8 Even 64% of patients had Stage 3 or 4 disease, so neo-adjuvant chemotherapy (CTX) and/or radiotherapy (RT) were carried out in 59% of cases. CTX and/or RT were carried out and finished six to eight weeks before surgery, as reported by Golo
DM was found in 39 (19.5%) of patients: 19 were treated only with metformin, 5 only with insulin, while 15 were treated with two or three different oral antidiabetics.
Data about gender, age, body mass index, presence of DM, American Society of Anesthesiologists (ASA) physical status score, stage of disease and postoperative complications were collected prospectively.
All patients had a follow-up at the Institute of Oncology Ljubljana. Cancer-specific survival was defined as the period from the first day of primary treatment (surgery, CTX or RT) to death from colorectal cancer, or the last follow-up. Overall survival was defined as the period from the first day of primary treatment (surgery, CTX or RT) to death from any cause, or the last follow-up. Disease-free survival was defined as the period from the first day of primary treatment to the radiologic or morphologic diagnosis of recurrence, or the last follow-up. The median duration of follow-up was 5.1 years (range 0.2–10.5 years).
The association between categorical variables was tested by the Pearson chi-square test or Fisher’s exact test, as appropriate. Univariate analysis was used to identify factors associated with cancer-specific and overall survival. Cancer-specific survival and overall survival were compared by log-rank test. All comparisons were two-sided, and a p-value of <0.05 was considered statistically significant. Survival curves were calculated according to the Kaplan–Meier method. Statistical analyses were performed using the SPSS software (IBM Corp., version 22.0 Armonk, NY).
Data about patient’s characteristics, tumor, treatment and outcome are presented in Table 1. The mean age of patients with and without DM was 65 and 62 years, respectively. There was no statistically significant difference in the age of patients with and without DM (p = 0.13). However, patients with DM had a higher ASA score (p = 0.0001) and BMI (p = 0.003) than those without DM. Furthermore, before surgical procedure, the illness marker was higher in patients with DM in comparison to those without DM (p = 0.02). However, higher disease stages were not more common in patients with DM in comparison to those without DM. Stage 3 or 4 disease was found in patients with DM and without DM in 62% and 65%, respectively (p = 0.72). So, also the proportion of patients treated with CTX and/or RT were not statistically different among patients with DM and without DM.
Patient’s characteristics, tumor, treatment and outcome
Characteristic | Without diabetes mellitus (N = 161) | With diabetes mellitus (N = 39) | p-value | |
---|---|---|---|---|
Age (years) - mean | 62.18 (SD ± 11.8) | 65.26 (SD ± 8.9) | 0.13 | |
Gender | Male | 106 | 25 | 0.84 |
Female | 55 | 14 | ||
American Society of | I | 14 | 0 | |
Anesthesiologists physical status | II | 95 | 10 | 0.0001 |
classification score | III | 47 | 29 | |
IV | 5 | 0 | ||
Body mass index (kg/m2) - mean | 26.83 (SD ± 4.20) | 29.06 (SD ± 4.1) | 0.003 | |
Insulin only | - | 5 | ||
Treatment of diabetes | Metformin only | - | 19 | - |
2 or 3 oral antidiabetics | - | 15 | ||
Phase angle (o) - mean | 5.47 (SD ±1.0) | 5.16 (SD ±0.9) | 0.11 | |
Illness marker - mean | 0.807 (SD ± 0.036) | 0.825 (SD ± 0.049) | 0.02 | |
Dry lean body mass (kg) - mean | 12.97 (SD ± 4.5) | 12.65 (SD ± 4.6) | 0.72 | |
Rectum | 113 | 24 | ||
Tumor site | Colon | 47 | 13 | 0.09 |
Rectum + Colon | 1 | 2 | ||
0 | 3 | 0 | ||
1 | 21 | 6 | ||
Stage TNM | II | 33 | 0.50 | |
III | 91 | 18 | ||
IV | 13 | 6 | ||
Preoperative radiotherapy | No | 67 | 18 | |
Yes | 94 | 21 | 0.61 | |
Preoperative chemotherapy | No | 90 | 22 | |
Yes | 71 | 17 | 0.95 | |
Surgical procedure | Low anterior resection | 73 | 13 | |
Miles + Hartman | 38 | 12 | 0.38 | |
Colon resection | 50 | 14 | ||
Synchronous resection of liver metastases | No | 151 | 35 | 0.48 |
Yes | 10 | 4 | ||
Duration of surgery (min) - mean | 175 (SD ±66) | 199 (SD ±64) | 0.034 | |
Loss of blood (mL) -mean | 584 (SD ±497) | 813 (SD ±812) | 0.027 | |
Postoperative transfusion of | ||||
packed red blood cells (mL) | 351 (SD ±516) | 603 (SD ±665) | 0.011 | |
-mean | ||||
Postoperative infection (any site) | No | 110 | 22 | 0.16 |
Yes | 51 | 17 | 0.16 | |
Re-operation | No | 153 | 35 | 0.21 |
Yes | 8 | 4 | 0.21 | |
Hospital stay (days) -mean | 14.4 (SD ±7.6) | 19.9 (SD ±10.6) | 0.028 | |
No | 111 | 28 | ||
Locoregional | 4 | 1 | 0.63 | |
Recurrence (N = 181) | Distant | 26 | 3 | |
Locoregional + distant | 7 | 1 | ||
Alive | 117 | 30 | ||
Dead of disease | 34 | 7 | ||
Outcome | Dead of other causes | 9 | 1 | 0.74 |
Dead - Unknown cause | 1 | 1 |
None of the patients had a laparoscopic procedure. A higher proportion of the patients with DM had massive bleeding (p = 0.027) and received blood transfusion (p = 0.011) in comparison to patients without DM. Surgical procedure (p = 0.034) as well as hospital stay (p = 0.028) was longer in patients with DM in comparison to those without DM. None of patients died during the first month after a surgical procedure (p < 0.0001).
The mean follow-up period was 4.75 years. Recurrence was diagnosed in 23% of patients with DM and in 25% of patients without DM (p = 0.63). Locoregional recurrence was detected in 2/39 (5%) patients with DM and in 11/161 (6.8%) patients without DM. Distant metastases after surgical procedure were detected in 4 patients with DM and 33 patients without DM. Altogether, 41 patients died of cancer and 12 patients of other causes. Cause of death was not statistically different in patients with DM in comparison to those without DM (p = 0.74). Colorectal cancer was the cause of death in 18% and 21% of patients with and without DM, respectively. All causes mortality in patients with DM and without DM was 23% and 27%, respectively.
Three-year cancer-specific survival (Figure 1) in patients with DM and without DM was 85% and 89%, respectively (p = 0.68). Three-year overall survival (Figure 2) in patients with DM and without DM was 82% and 84%, respectively (p = 0.63). Patients with colon and rectal cancer had estimated median survival of 75 and 108 months (p = 0.089), respectively. All patients were included in our statistical analysis of survival because there was only small number of patients with low stage tumor, colon cancer and/or presence of DM which precluded adequate subgroup analysis.
The aim of our study was to find out if DM in patients with advanced CRC was associated with cancer-specific and overall survival. In our 200 consecutive patients with elective surgical procedure for CRC, the presence of DM was not associated with cancer-specific or overall survival after the mean follow-up period of 4.75 years. Inversely, a meta-analysis of 26 observational studies on CRC has shown that patients with CRC and DM had a 17% increased risk of overall mortality and a 12% increased risk of cancer-specific mortality compared to those without DM.5 However, another meta-analysis has shown that persons with CRC and DM had a 32% increase in overall mortality compared to those without DM, but there were no associations between DM and risk of cancer-specific mortality.4 Bella
A substantial proportion of deaths in older persons with colorectal cancer can be attributed to chronic heart failure, diabetes mellitus, and chronic obstructive pulmonary disease.14 Polednak
Davila
Jeon
A limitation of this study is that it is retrospective, and the follow-up period is relatively short. Furthermore, there were only a small number of diabetics, which precluded analysis of the association between diabetes, stage of disease, location of cancer (rectum versus colon) and survival. Other limitations are the lack of information about diabetes type and age of diabetes onset, as well as the type and duration of diabetic therapy. Because of the relatively small number of diabetics, we could not analyze the association between different diabetic therapies (metformin and insulin) on outcome of patients. On the other hand, an advantage of our study is that a large proportion of patients had an advanced stage of disease with a higher risk of recurrence or progression of disease. All our patients were followed at our institution, so our data on recurrence and cause of death are very reliable.
The presence of DM was not associated with tumor stage, disease-specific survival or overall survival in a group of patients with advanced colorectal carcinoma treated at a cancer comprehensive center.