Prognostic Analysis of Colorectal Cancer Patients with Diabetes Mellitus in China the Experience of a Single Institution

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1 original papers Adv Clin Exp Med 2011, 20, 4, ISSN X Copyright by Wroclaw Medical University Prognostic Analysis of Colorectal Cancer Patients with Diabetes Mellitus in China the Experience of a Single Institution Prognostyczna analiza chorych na raka jelita grubego i cukrzycę w Chinach doświadczenia jednej instytucji Department of Oncological Surgery, Zhejiang Cancer Hospital, Hangzhou, China Abstract Background. Diabetes mellitus (DM) plays an important role in cancer prevalence and outcomes. Many studies have shown that DM increases the risk of colorectal cancer (CRC), but this association is controversial. Objectives. The aim of this study was to investigate the outcomes and prognostic factors related to DM among CRC patients. Material and Methods. A retrospective analysis was conducted of 773 patients with CRC treated at Zhejiang Cancer Hospital from January 2000 to December Based on medical records, the authors investigated the differences between patients with and without DM and analyzed the impact of DM among CRC patients. The overall cumulative probability of survival was calculated by the Kaplan-Meier method, and the difference between the two groups of patients was assessed by the log-rank test. Univariate and multivariate analyses using the Cox regression proportional hazard model were performed to evaluate the prognostic parameters for survival. A conditional logistic regression analysis was also performed to evaluate the prognostic parameters for recurrence. Results. Among the 773 patients, 75 patients had DM (9.70%). The mean age of the DM group was significantly higher than the non-dm group. The prevalence of CRC patients with DM was closely related to increasing age. The body mass index (BMI) was significantly higher in the DM group than in the non-dm group. The existence of lymph metastases was also significantly higher in the DM group than in the non-dm group. According to the Kaplan-Meier method, the five-year survival rate was 58.7% in the DM group and 65.3% in the non-dm group; no significant differences were found between the two groups in overall survival rates. A multivariate Cox regression analysis of survival showed that TNM stage, lymph metastases, gross type and surgery type were significantly related to survival rates. A logistic regression analysis of recurrence showed that TNM stage (p = 0.005), lymph metastases (p = 0.002) and surgery type (palliative resection vs. radical resection, p = 0.036) were associated with a fold, fold and fold increased risk of recurrence, respectively. Conclusions. DM did not affect overall survival, but was associated with an increased risk of recurrence in patients with CRC (Adv Clin Exp Med 2011, 20, 4, ). Key words: colorectal cancer (CRC), diabetes mellitus (DM), prognostic analysis, recurrence, survival. Streszczenie Wprowadzenie. Cukrzyca (DM) odgrywa ważną rolę w występowaniu raka i wynikach leczenia. Wiele badań wykazało, że DM zwiększa ryzyko raka jelita grubego (CRC), ale ten związek jest kontrowersyjny. Cel pracy. Zbadanie rezultatów leczenia i czynników prognostycznych związanych z cukrzycą wśród pacjentów z CRC. Materiał i metody. Przeprowadzono retrospektywną analizę 773 pacjentów z CRC leczonych w Zhejiang Cancer Hospital od stycznia 2000 do grudnia 2005 r. Na podstawie dokumentacji medycznej autorzy badali różnice między pacjentami z DM i bez i ocenili wpływ DM wśród pacjentów z CRC. Łączne prawdopodobieństwo przeżycia obliczono metodą Kaplana-Meiera, a różnicę między dwiema grupami chorych oceniano za pomocą testu log- -rank. Przeprowadzono jednowymiarową i wielowymiarową analizę za pomocą modelu regresji proporcjonalnego hazardu Coxa w celu oceny czynników rokowniczych przeżycia. Przeprowadzono również warunkową regresję logistyczną do oceny czynników rokowniczych nawrotu choroby.

2 474 Wyniki. Wśród 773 pacjentów 75 chorowało na cukrzycę (9,70%). Średni wiek pacjentów chorych na cukrzycę był znacznie większy niż w grupie bez cukrzycy. Częstość występowania CRC u chorych na cukrzycę była ściśle związana z wiekiem. Wskaźnik masy ciała (BMI) był znacząco większy w grupie z cukrzycą niż w grupie bez cukrzycy. Istnienie przerzutów do węzłów chłonnych było istotnie większe w grupie z cukrzycą niż w grupie bez cukrzycy. Według metody Kaplana-Meiera, 5-letnie przeżycie miało 58,7% pacjentów w grupie z cukrzycą i 65,3% w grupie bez cukrzycy, nie stwierdzono istotnych różnic między grupami w ogólnej przeżywalności. Wieloczynnikowa analiza regresji Coxa dotycząca przeżycia wykazała, że stadium TNM, przerzuty do węzłów chłonnych, typ makroskopowy i rodzaj zabiegu były istotnie związane z czasem przeżycia. Analiza regresji logistycznej nawrotu wykazała, że stopień TNM (p = 0,005), przerzuty do węzłów chłonnych (p = 0,002) i rodzaj operacji (resekcja paliatywna vs radykalna resekcja, p = 0,036) wpływają na odpowiednio krotnie, 11,938-krotnie i 11,004-krotnie większe ryzyko nawrotu. Wnioski. Cukrzyca nie wpływa na całkowity czas przeżycia, ale wiąże się ze zwiększonym ryzykiem nawrotu u chorych z CRC (Adv Clin Exp Med 2011, 20, 4, ). Słowa kluczowe: rak jelita grubego, cukrzyca, analiza prognostyczna, nawrót, czas przeżycia. China is a country with a large population, and it is experiencing an increasing number of diabetes mellitus (DM) cases, with an estimated 42.3 million patients predicted by 2030 [1]. Many studies have revealed that a history of DM significantly increases the incidence of cancer [2 5]. The association between DM and colorectal cancer (CRC) has been studied most actively. Many reports have demonstrated that the risk of CRC is increased in DM patients [6, 7]. In addition, a meta-analysis of epidemiologic studies reported that DM is associated with a moderate increased risk of CRC overall [8]. As the prevalence of DM increases, the prevalence of CRC with DM will increase. There are, however, still controversies about how DM affects outcomes in patients with CRC. The aim of this study was to investigate the outcomes and prognostic factors related to DM among CRC patients. Material and Methods A retrospective analysis was conducted of 773 patients with CRC treated at Zhejiang Cancer Hospital from January 2000 to December Among the 773 patients, 75 cases (9.7%) had DM; among these, two patients had diabetes type 1 and 73 patients had diabetes type 2. Standardized criteria were used to identify DM: two consecutive fasting glucose levels 7.0 mmol/l (126 mg/dl) or both 1- and 2-hour blood levels 11.1 mmol/l (200 mg/ dl) obtained during a standard oral glucose tolerance test. All the patients underwent colorectal surgery (radical resection or palliative resection), and a final CRC diagnosis of adenocarcinoma was confirmed by histopathology. The mean follow-up duration was 4.5 years. On the basis of the patients medical records, the authors investigated the differences between the CRC patients with and without DM. The relationship between DM and such factors as age, gender, body mass index (BMI), tumor size and location, the existence of lymph metastases, TNM stage, histological differentiation, gross type, surgery type, recurrence and survival was analyzed. Statistical Analysis The statistical analysis was conducted with SPSS 17.0 software (SPSS Inc., Chicago, IL, USA). The distribution of baseline characteristics between patients with and without DM patients was evaluated using either Fisher s exact or χ 2 tests in the case of categorical variables or the Student s t-test in the case of continuous variables. The overall cumulative probability of survival was calculated by the Kaplan-Meier method, and the difference between the two groups of patients was assessed by the log-rank test. Univariate and multivariate analyses using the Cox regression proportional hazard model were performed to evaluate the prognostic parameters for survival. A conditional logistic regression analysis was also performed to evaluate the prognostic parameters for recurrence. A p-value less than 0.05 was considered to be statistically significant. Results The baseline characteristics for the DM and non-dm patients are presented in Table 1. The mean age of the DM group was 62.5 ± 10.8 years (range: 37 to 84 years), which was significantly higher than the non-dm group s mean age of 56.8 ± 7.5 (p = 0.012). The prevalence of CRC patients with DM was closely related to age (r = 0.824, p = 0.023): 3.30% for patients < 40 years in age (3/91), 5.53% for the year-olds (14/253), 8.85% for the year-olds (17/192), 20.31%

3 Prognostic Analysis of CRC with DM in China 475 Table 1. Baseline characteristics of colorectal cancer (CRC) patients with and without diabetes mellitus (DM) Tabela 1. Wyjściowa charakterystyka chorych na raka jelita grubego (CRC) z i bez cukrzycy (DM) DM (n = 75 cases) (Chorzy na cukrzycę) Non-DM (n = 698 cases) (Chorzy bez cukrzycy) P-value Age years (Wiek lata) 62.5 ± ± Gender n, % (Płeć) male female 48 (64.0) 27 (36.0) 406 (58.2) 292 (41.8) BMI (kg/m 2 ) 25.3 ± ± Tumor size cm (Rozmiar guza cm) 5.1 ± ± Tumor location n, % (Umiejscowienie guza) colon rectum 22 (29.3) 53 (70.7) 157 (22.5) 541 (77.5) TNM stage n, % (Klasyfikacja TNM) I II III IV 14 (18.7) 35 (46.7) 19 (25.3) 7 (9.3) 79 (11.3) 378 (54.2) 163 (23.4) 28 (4.1) Lymph metastases n, % (Przerzuty do węzłów chłonnych) no yes 47 (62.7) 28 (37.3) 523 (74.8) 176 (25.2) Gross type n, % (Typ makroskopowy) mass infiltrative ulcerative 42 (56.0) 27 (36.0) 6 (8.0) 347 (49.7) 234 (33.8) 117 (16.8) Differentiation n, % (Zróżnicowanie) good moderate poor 17 (22.7) 51 (68.0) 7 (9.3) 153 (22.0) 436 (62.5) 109 (15.5) Surgery type n, % (Rodzaj operacji) radical resection palliative resection 67 (89.3) 8 (10.7) 657 (94.1) 42 (5.9) Recurrence n, % (Nawroty) no yes 53 (70.7) 22 (29.3) 582 (83.4) 116 (16.6) BMI body mass index. BMI wskaźnik masy ciała. for the year-olds (26/128), 14.10% for the year-olds (11/78) and 12.90% for the patients > 80 years (4/31) (Fig.1). Among the subjects, 454 (58.7%) were male and 319 were female (41.3%), and there was no significant difference in gender distribution between the DM and non-dm groups (p = 0.388). The body mass index (BMI) was significantly higher in the DM group than in the non-dm group (25.3 ± 2.4 kg/m 2 vs ± 3.7 kg/m 2 ; p = 0.003). The existence of lymph metastases was also significantly higher in the DM group than in the non-dm group (37.3% vs. 25.2%; p = 0.027). There were no significant differences between the two groups in tumor size and location, gross type, TNM stage, histological differentiation and surgery type. Tumor recurrence was significantly higher in the DM group than in the non- DM group (29.3% vs. 16.6%; p = 0.010). According to the Kaplan-Meier method, the five-year survival rate was 58.7% in the DM group and 65.3% in the non-dm group; no significant differences were found between the two groups in overall survival rates (Fig. 2; p = 0.099). In a univariate Cox regression analysis of survival (Table 2), there were significant differences in TNM stage (Fig. 3A; p = 0.004), lymph metastases (Fig. 3B;

4 476 Table 2. Univariate Cox regression analysis of overall survival for CRC patients with DM Tabela 2. Jednoczynnikowa analiza regresji Coxa całkowitego przeżycia dla pacjentów z CRC i cukrzycą DM cases (n, %) (Chorzy na cukrzycę) 5-year survival (%) (5-letnie przeżycie) RR (95.0% CI) (Ryzyko względne) P-value (Istotność statystyczna) Gender (Płeć) male female 48 (64.0) 27 (36.0) (0.288~1.362) Age years (Wiek lata) 60 > (45.3) 41 (54.7) (0.512~2.110) BMI (kg/m 2 ) 25 > (29.3) 53 (70.7) (0.536~2.529) Tumor size cm (Rozmiar guza cm) 5 > 5 31 (41.3) 44 (58.7) (0.514~2.115) Tumor location (Umiejscowienie guza) colon rectum 22 (29.3) 53 (70.7) (0.501~2.505) TNM stage (Klasyfikacja TNM) I II III IV 14 (18.7) 35 (46.7) 19 (25.3) 7 (9.3) (0.383~2.799) (0.906~7.569) (1.490~14.427) Lymph metastases (Przerzuty do węzłów chłonnych) no yes 47 (62.7) 28 (37.3) (1.069~4.402) Gross type (Typ makroskopowy) mass infiltrative ulcerative 42 (56.0) 27 (36.0) 6 (8.0) (~4.676) (1.285~10.496) Differentiation (Zróżnicowanie) good moderate poor 17 (22.7) 51 (68.0) 7 (9.3) (0.446~2.768) (0.998~10.787) Surgery type (Rodzaj operacji) radical resection palliative resection 67 (89.3) 8 (10.7) (1.301~7.799) BMI body mass index, RR risk ratio, CI confidence interval. BMI wskaźnik masy ciała, RR ryzyko względne, CI przedział ufności. p = 0.028), gross type (Fig. 3C; p = 0.021), and surgery type (Fig. 3D; p = 0.007). Differentiation was not an influential parameter for the survival rate (p = 0.058), but the five-year survival was higher in the cases of well-differentiated and moderately-differentiated tumors than poorly-differentiated ones (64.7, 60.8 and 28.6% respectively). A conditional multivariate Cox regression analysis of survival

5 Prognostic Analysis of CRC with DM in China 477 Table 3. Multivariate Cox regression analysis of overall survival for CRC patients with DM Tabela 3. Wieloczynnikowa analiza regresji Coxa całkowitego przeżycia pacjentów z CRC i DM 95% CI for RR β SE Wald df Sig. RR lower upper Gender (Płeć) Age (Wiek) BMI Tumor size (Rozmiar guza) Tumor location (Umiejscowienie guza) TNM stage (Klasyfikacja TNM) Lymph metastases (Przerzuty do węzłów chłonnych) Gross type (Typ makroskopowy) Differentiation (Zróżnicowanie) Surgery type (Rodaj zabiegu chirurgicznego) BMI body mass index, RR risk ratio, CI confidence interval. BMI wskaźnik masy ciała, RR ryzyko względne, CI przedział ufności. Table 4. Logistic regression analysis of recurrence for CRC patients with DM Tabela 4. Analiza regresji logistycznej nawrotu dla pacjentów z CRC i DM 95% CI for OR β S.E. Wald df Sig. OR lower upper Gender (Płeć) Age (Wiek) BMI Tumor size (Rozmiar guza) Tumor location (Umiejscowienie guza) TNM stage (Klasyfikacja TNM) Lymph metastases (Przerzuty do węzłów chłonnych) Gross type (Typ makroskopowy) Differentiation (Zróżnicowanie) Surgery type (Rodaj zabiegu chirurgicznego) BMI body mass index, OR odds ratio, CI confidence interval. BMI wskaźnik masy ciała, OR iloraz szans, CI przedział ufności.

6 478 number (n) < showed that TNM stage (risk ratio [RR] = 2.585, 95% confidence interval [CI] to 4.404; p = 0.000), lymph metastases (RR = 2.997, 95% CI to 7.266; p = 0.015), gross type (RR = 3.123, 95% CI to 6.037; p = 0.001), and surgery type (RR = 3.588, 95% CI to 9.717; p = 0.012) were significantly related to survival rates (Table 3). A logistic regression analysis of recurrence showed that TNM stage (p = 0.005), lymph metastases (p = 0.002) and surgery type (palliative resection vs. radical resection, p = 0.036) were associated with a 3.648, and fold increase in the risk of recurrence, respectively (Table 4). Discussion In the baseline parameters, the present study found no significant differences between patients > 80 total cases DM cases percentage 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% age (years) Fig. 1. The prevalence of CRC patients with DM was closely related to increasing age Ryc. 1. Częstość występowania CRC u chorych na cukrzycę była ściśle związana z wiekiem percentage (%) Fig. 2. Kaplan-Meier survival curves of overall survival for CRC patients with and without DM (p = 0.099) Ryc. 2. Krzywe przeżycia Kaplana-Meiera dla całkowitego przeżycia u chorych z CRC i z i bez cukrzycy (p = 0,099) with and without DM regarding gender, tumor size and location, TNM stage, histological differentiation, gross type and surgery type. However, as shown in Table 1, DM patients were significantly older and had lymph metastases and tumor recurrences more frequently than non-dm patients. These results are in agreement with several other previous reports [9 11]. In the present study, the prevalence of DM among CRC patients was closely related to age (r = 0.824, p = 0.023): A larger proportion of patients with DM were years old, while in the study of Shonka et al. [12] a larger proportion of patients with DM were 70 years at the time of diagnosis. There have been several reports showing that the prognosis for colorectal cancer is poor in DM patients. In a study conducted with 3759 surgically-treated CRC patients, the five-year survival rate was significantly lower in DM patients (57%) compared with non-dm patients (66%); the same study also showed that DM patients had a 42% increased risk of death from any cause and a 21% increased risk for recurrence after adjustment for other predictors of colon cancer [13]. Siddiqui et al. [14] suggested a correlation between poor glycemic control and a clinically aggressive course for CRC in DM patients, and a meta-analysis by Stein et al. [15] indicated that among CRC patients with DM the all-cause mortality rate is 32% higher than in patients without DM [16]. However, since Meyerhardt et al. [13] found that the cancer recurrence rate was higher in DM patients, it may be that the increased recurrence associated with DM is what led to the increased mortality rate. There are, however, still controversies about how DM affects outcomes in CRC patients. An epidemiological study by Kune et al. [17] reported that the prevalence of DM in CRC patients was the same as in the control group. Will et al. [18] reported that the risk of colorectal cancer was higher in DM patients, but found no difference in the mortality rate among DM patients. In addition, Shonka et al. [12] showed that DM did not affect either the stage at diagnosis or outcomes from colon cancer, and Jullumstrø et al. [19] indicated that DM is not a factor affecting TNM stage, tumor differentiation at presentation, the type of treatment or the short-term outcome from CRC. The present study found that the five-year survival rate in the DM group (58.7%) was significantly lower than the non-dm group (65.3%) (p = 0.099), suggesting that DM may negatively influence outcomes of CRC patients. Considering the fact that the recurrence rate in DM patients was significantly higher than in the non-dm patients (p = 0.010), this result coincides with the conclusion of Meyerhardt et al. [13] and Stein et al. [15], but differs from the findings of Noh et al. [11].

7 Prognostic Analysis of CRC with DM in China 479 A B C D Fig. 3. Kaplan-Meier survival curves according to the TNM stage (3A; p = 0.004); according to lymph metastases (3B; p = 0.028); according to gross type (3C; p = 0.021); and according to type of surgery (3D; p = 0.007) Ryc. 3. Krzywe przeżycia Kaplana-Meiera w zależności od klasyfikacji TNM (3A, p = 0,004), od przerzutów do węzłów chłonnych (3B, p = 0,028); od typu makroskopowego (3C, p = 0,021) oraz w zależności od rodzaju operacji chirurgicznej (3D, p = 0,007) In the present study, TNM stage, lymph metastases, gross type and surgery type had significant impact on survival, and TNM stage, lymph metastases and surgery type were also significantly related to recurrence rates in CRC patients with DM. In conclusion, this study found that the prevalence of DM among CRC patients was closely related to age. DM did not affect overall survival, but was associated with an increased risk of recurrence in patients with CRC. There potential limitations of the present study include the relatively small number of patients, as well as the fact that the prognostic analysis was retrospective, the mean follow-up duration was short and the study was conducted by a single institution. Moreover, it did not provide enough information on the details of the treatment of DM patients. References [1] Wild S, Roqlic G, Green A, Sicree R, King H: Global prevalence of diabetes: estimates for the year 2000 and projections for Diabetes Care 2004, 27, [2] Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, Tsugane S: Diabetes mellitus and the risk of cancer: Results from a large-scale population-based cohort study in Japan. Arch Intern Med 2006, 166,

8 480 [3] Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL: Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 2008, 47, [4] Larsson SC, Orsini N, Brismar K,Wolk A: Diabetes mellitus and risk of bladder cancer: A meta-analysis. Diabetologia 2006, 49, [5] Larsson SC, Mantzoros CS, Wolk A: Diabetes mellitus and risk of breast cancer: A meta-analysis. Int J Cancer 2007, 121, [6] Limburg PJ, Vierkant RA, Fredericksen ZS, Leibson CL, Rizza RA, Gupta AK, Ahlquist DA, Melton LJ 3rd, Sellers TA, Cerhan JR: Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: A populationbased, retrospective cohort study. Am J Gastroenterol 2006, 101, [7] Yang YX, Hennessy S, Lewis JD: Type 2 diabetes mellitus and the risk of colorectal cancer. Clin Gastroenterol Hepatol 2005, 3, [8] Larsson SC, Orsini N, Wolk A: Diabetes mellitus and risk of colorectal cancer: A meta-analysis. J Natl Cancer Inst 2005, 97, [9] Payne JE, Meyer HJ: The influence of other diseases upon the outcome of colorectal cancer patients. Aust N Z J Surg 1995, 65, [10] Polednak AP: Comorbid diabetes mellitus and risk of death after diagnosis of colorectal cancer: A population- -based study. Cancer Detect Prev 2006, 30, [11] Noh GY, Hwang DY, Choi YH, Lee YY: Effect of diabetes mellitus on outcomes of colorectal cancer. J Korean Soc Coloproctol 2010, 26, [12] Shonka NA, Anderson JR, Panwalkar AW, Reed EC, Steen PD, Ganti AK: Effect of diabetes mellitus on the epidemiology and outcomes of colon cancer. Med Oncol 2006, 23, [13] Meyerhardt JA, Catalano PJ, Haller DG, Mayer RJ, Macdonald JS, Benson AB 3rd, Fuchs CS: Impact of diabetes mellitus on outcomes in patients with colon cancer. J Clin Oncol 2003, 21, [14] Siddiqui AA, Spechler SJ, Huerta S, Dredar S, Little BB, Cryer B: Elevated HbA1c is an independent predictor of aggressive clinical behavior in patients with colorectal cancer: a case-control study. Dig Dis Sci 2008, 53, [15] Stein KB, Snyder CF, Barone BB, Yeh HC, Peairs KS, Derr RL, Wolff AC, Brancati FL: Colorectal cancer outcomes, recurrence and complications in persons with and without diabetes mellitus: a systematic review and meta-analysis. Dig Dis Sci 2010, 55, [16] Chen CQ, Fang LK, Cai SR, Ma JP, Yang GX, Yang W, Zhan WH, He YL: Effects of diabetes mellitus on prognosis of the patients with colorectal cancer undergoing resection: a cohort study with 945 patients. Chin Med J (Engl) 2010, 123, [17] Kune GA, Kune S, Watson LF: Colorectal cancer risk, chronic illnesses,operations and medications: case control results from the Melbourne Colorectal Cancer Study Int J Epidemiol 2007, 36, [18] Will JC, Galuska DA, Vinicor F, Calle EE: Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 1998, 147, [19] Jullumstrø E, Kollind M, Lydersen S, Edna TH: Diabetes mellitus and outcomes of colorectal cancer. Acta Oncol 2009, 48, Address for correspondence: Ji-Feng Feng Department of Oncological Surgery Zhejiang Cancer Hospital No. 38 Guangji Road Hangzhou China Tel.: Jifzhejiang@gmail.com Conflict of interest: None declared Received: Revised: Accepted: