Colorectal Cancer in Upper Egypt, Does Age Make A Difference in Survival?

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1 Med. J. Cairo Univ., Vol. 78, No. 2, March: , Colorectal Cancer in Upper Egypt, Does Age Make A Difference in Survival? HODA H. EISA, M.D. The Department of Clinical Oncology, Faculty of Medicine, Assiut University. Abstract Background: The incidence of colorectal cancer (CRC) in patients under 40 years in Egypt is rising. However, the prognosis in this subset of patients is controversial. Young age is not yet a poor prognostic marker in CRC. The Aim of this Study: Was to determine the correlation between age, clinicopathologic features and outcomes of patients with CRC. Patients and Methods: 102 patients with histologically confirmed CRC were treated between 2004 and 2008 at the Oncology Department of Assiut University Hospital but only (89) patients were eligible for the study. The clinicopathologic features of 36 patients under 40 years (group I) were compared with 53 older patients (group II). Patient gender, Karnofsky performance status (KPS), duration of symptoms, symptoms, stage at presentation, lymph node involvement, site, histologic grade and survival rates were compared. Results: Patients under 40 years constituted 40.4% of all CRC patients. The male to female ratio was 1.3:1 for group I and 1.5:1 for group II. Most tumours in both groups were located in the rectum (47.2% for group I and 39.6% for group II). Most patients in group I presented with an advanced stage (Dukes C and D), constituting 58.3% while most of those patients in group II presented with early stages (Dukes A and B) constituting 58.5%. Most patients in group I had worse pathologic features where mucinous/ signet ring and poorly differentiated tumours constituted 41.7% and 25% respectively. Most patients in group II presented with well and moderately differentiated tumours (69.8%). There was no significant difference n survival between the two groups where 2- year survival rate was 83.3% and 71.7% and 5- year survival rate was 38.9% and 30.2% for group I and II respectively. On univariate analysis, tumour stage at presentation. Lymph node involvement and KPS were significantly predictive for overall survival. On multivariate analysis, stage at presentation and KPS were the main independent prognostic factors affecting overall survival of young CRC patients. Conclusions: The incidence of CRC in young patients in upper Egypt is increasing. Most of the tumours were located in the rectum. Young patients had more advanced stage and Correspondence to: Dr. Hoda H. Eisa, The Department of Clinical Oncology, Faculty of Medicine, Assiut University, Assiut, Egypt. worse pathologic features. However, the survival in this young group was not significantly different from the older group. Stage of the tumour, L.N. involvement and KPS were the main prognostic factors for survival. Key Words: Colorectal cancer Young age Survival. Introduction COLORECTAL cancer (CRC) is the fourth commonest form of cancer occurring worldwide. It represents 9.4% of all incident cancer in men and 10.1% in women [1]. In Egypt it contributes 6.5% of all cancers [2]. CRC in Egypt has no age predilection and more than one third of tumours affect young population. The high prevalence in young people can neither be explained on a hereditary basis nor can be attributed to bilharziasis [3]. Controversies still exist regarding the features and prognosis of CRC in young patients. Several reports have described the poor prognostic factors for the survival in young patients with CRC. These factors include advanced stage at presentation, delay in diagnosis and poorly differentiated carcinoma [4]. However some studies show no difference in survival in the young and old patients despite the aggressive behaviour of the disease in the young patients [5,6]. The aim of this study is to determine the incidence of CRC in young adults in upper Egypt compared to the same type of cancer in older patients. Also to determine the clinical and pathological characteristics at presentation and their impact on patients survival. Patients and Methods The study population consisted of 102 patients with histologically confirmed CRC who were treated at Oncology Department of Assiut University between 2004 and 2008, but only eighty nine (89) 145

2 146 Colorectal Cancer in Upper Egypt patients were eligible for the study. CRC was initially diagnosed by colonoscopy and biopsy revealing the histopathological diagnosis of adenocarcinoma. Radical resection was done for resectable cases but for irresectable cases only palliative proximal colostomy was done at the Department of surgery, Faculty of Medicine, Assiut University. The patients were divided into 2 groups, group I <40 years (36 patients), and group II 40 years (53 patients). For every patient, age, sex, family history of cancer, any pre malignant factor, duration of symptoms, symptoms, and tumour characteristics were recorded. Tumour characteristics assessed were as follow: Location, size, depth and the histological type and grade. The modified Dukes classification of Astler Coller was used for classifying the stage of cancer of each patient. Adjuvant therapy: Patients with high risk stage II and stage III colon cancer were given standard adjuvant chemotherapy (six cycles of 5- flourouracil 420mg/m 2 with leucovorin 20mg/m 2 / day for 5 days given every three weeks). Stage II was considered as high risk when any of the following features was present: T 4, bowel perforation, or clinical bowel obstruction, inadequate lymph node sampling (<12 L.N.), lympho-vascular or perineural invasion, tumour involvement of surgical margins and poorly differentiated histology. Patients with high risk stage II and stage III rectal cancer received post operative chemoradiation therapy (4500cGy/ 25 F/5 weeks with concomitant 5-flourouracil 375mg/m 2 with leucovorin 20mg/m 2 / day for 3 days on days 1-3 and 31-33). All patients were treated in the prone position using box technique. The treatment volume included the primary tumour with adequate margins (2-3 cm) and regional lymph nodes. Then, they completed 6 cycles of chemotherapy with the same schedule prescribed in colon cancer. Follow-up: The follow-up period ranged from 12 to 49 months (median 26 months). After completion of adjuvant therapy, patients were evaluated every 2-3 months for the first two years then every 6 months thereafter. Physical examination, including abdominal examination, was performed at each follow-up visit. CT scan of the abdomen and colonoscopy were done every 6 months or when clinically indicated. Statistical procedures: Statistical analysis was carried out using: The SPSS soft ware package (version 13) SPSS Chicago I (USA). Data were presented as "mean, median" for numeric variables and "number, percentage" for non parametric data. For quantitative data, student s test was used. Survival rates were calculated from the time of diagnosis of CRC using Kaplan Meier product limit method. The significance of difference was tested with the log-rank test. To assess the prognostic factors for survival, univariate analysis was carried out on the different clinicopathologic variables. Differences were regarded as significant at a p-value of <0.05. Variables showing significance under univariate analysis were tested with multivariate analysis. Results Demographic features (Table 1): In the present study, patients under the age of 40 (group I) constituted 40.4% of the all patients of CRC presented at Oncology Department of Assiut University Hospital. The ages of all patients ranged from 15 to 70 years with a mean of 42.5 years. In group I, the age ranged from years with a mean age of 27.2 years ( ±SD 5.49), while it ranged from 40 to 70 years in group II with a mean age of 52.7 years (±SD 7.63) (p<0.000). The sex distribution included 58.4% males and 41.6% females in all patients with male to female ratio In group I, there were 55.6% males and 44.4% females. while in group II, there were 60.4% males and 39.6% females. The male: Female ratio was 1.3:1 for group I and 1.5:1 for group II (p=1.03). Table (1): Demographic data of the 89 patients. Item Group I Group II p-value Age: Mean ± S.D 27.22±± ±±7.63 Median p<0.000 Sex: Male 20 (55.6%) 32 (60.4%) Female 16 (44.4%) 21 (39.6%) p=1.03 Clinical characteristics (Tables 2,3): The duration of symptoms: Ranged from 2 days to 18 months with about 39.3% of all patients presented within 3 months. In group I, half of the patients had a duration of symptoms <3 months while 32.1% of patients in group II had the same duration (p=0.07). Bleeding per rectum and abdominal pain were the most common symptoms constituting 54% and 42.7% of all patients respectively. The next most common presenting symptoms was change in bowel habit (40.4%) either diarrhea or constipation. The other presenting symptoms were intestinal obstruction (11.2%), abdominal mass (6.7%), rectal pain (5.6%), weight loss (3.4%), and anaemia (1.1%).

3 Hoda H. Eisa 147 In group I, bleeding per rectum, abdominal pain and bowel habit change were the main presenting symptoms constituting 49.4%, 41.7% and 30.6% respectively. In group II, most patients presented with change in bowel habit constituting 47.2%. The next most common symptoms were bleeding per rectum and abdominal pain both constituted 43.4% (p=0.24) (Table 2). Regarding the site: The most common site was the rectum constituting 47.2% and 39.6% for group I and II respectively. The next most common site was right colon constituting 22.2%, and 28.3% for group I and II respectively. The other sites of affection for group I were the sigmoid, and left colon constituting 16.7% and 13.9% while for group II they were sigmoid colon, transverse colon and left colon constituting 15.1%, 9.4% and 7.5% respectively (p=0.3) (Table 3). As regards the stage: Most of the patients in group I presented with advanced stage (Dukes C and D) constituting 58.3% while most of the patients in group II (58.5%) presented with Dukes A and B (p=0.340). In the present study, 49.4% of all patients had regional lymph node metastasis. In group I, 58.3% had lymph node involvement while it was 43.4% for group II with no significant difference (p=0.121). Analysis of tumour grade revealed that most of the patients in group I had mucinous/ signet ring and poorly differentiated histological types constituting 41.7% and 25% respectively. In group II most of the patients had well and moderately differentiated tumours (69.8%). ( p=0.005). Table (2): The presenting symptoms in 89 patients in relation to age. Symptoms Group I Group II p-value Bleeding per rectum 25 (69.4%) 23 (43.4%) Abdominal pain 15 (41.7%) 23 (43.4%) Habit change 11 (30.6%) 25 (47.2%) Intestinal obstruction 3 (8.3%) 7 (13.2%) Rectal pain 3 (8.3%) 2 (3.8%) Abdominal mass 1 (2.8%) 5 (9.4%) Weight loss 1 (2.8%) 2 (3.8%) Anaemia 1 (1.9%) Table (3): Clinical data of 89 patients is respect to age. Item Group I Group II p-value KPS%: <70% 5 70% 31 (13.9%) (86.1%) Stage: Dukes A 3 (8.3%) Dukes B 12 (33.3%) Dukes C 16 (44.4%) Dukes D 5 (13.9%) 14 (26.4%) 39 (73.6%) 5 (9.4%) 26 (49.1%) 14 (26.4%) 8 (15.1%) p=0.124 p=0.340 Location of the tumour: Rectum 17 (47.2%) 21 (39.6%) Sigmoid 6 (16.7%) 8 (15.1%) Left colon 5 (13.9%) 4 (7.5%) Transverse colon 5 (9.4%) Right colon 8 (22.2%) 15 (28.3%) p=0.300 Tumour differentiation: I + II 12 (33.3%) 37 (69.8%) III 9 (25%) 9 (17.0%) Mucinous/signet ring 15 (41.7%) 7 (13.2%) p=0.005 * Lymph node involvement: Yes 21 (58.3%) 23 (43.4%) No 15 (41.7%) 30 (56.6%) p=0.121 Survival: Median follow up in all patients was 26 months, (range months). Median follow up in group I and II were 30 months and 25 months (range months for group I and months for group II). The median survival was 30 and 25 months for group I and II (p=0.378), which is not significant, Fig. (1). Patients in group I had 2-year survival rate of 83.3% while it was 71.7% for group II (p=0.235) which is not significant. The 5-year survival rate was 38.9% and 30.2% for group I and II respectively (p=0.475) which is not significant. Prognostic factors: On univariate analysis, tumour stage ( p<0.000), KPS (p=0.0001) and lymph node involvement (p=0.01) were significantly predictive for overall survival. However sex, duration of symptoms,site of the tumour and histological type were insignificant Multivariate analysis was done for the significant variables in univariate analysis. Stage at presentation (p=0.04), and KPS (p=0.008) were found to be independent prognostic factors for overall survival.

4 148 Colorectal Cancer in Upper Egypt Cum Survival 1.0 Group survival Fig. (1): Overall survival of the 2 groups of patients ( p=378.0) About half of the patients under 40 years sought medical attention within 3 months after the symptoms had been commenced. The short duration of symptoms didn t seem to affect survival. This is in agreement with Lin, et al who suggested that symptom duration of up to one yearbefore presentation didn t affect the survival rate. Other reports, however, indicated symptom duration before presentation as a poor prognostic factor on the overall survival [15]. The most common presenting symptoms in the present study were bleeding per rectum, abdominal pain and bowel habit change similar to other reports Lin, et al. [14]. Discussion Although colorectal cancer (CRC) occurs predominantly in older patients, its incidence rates in young patients are rising O connell, et al. [4]. CRC has shown an increase in incidence in regions where previously, the incidence of this cancer was considered low. In Egypt, there is an increasing incidence of CRC where it shares the epidemiological characteristics of developing countries which are higher incidence in young patients and cancer of rectum predominates [7,8]. In the present study, colorectal patients under 40 years constitutes 40.4% of all patients of CRC. This result is nearly similar to other Egyptian reports in which the incidence of CRC in patients under 40 years ranged 35.6% to 38% [3,9]. In the western series, the incidence ranged from 2% to 34% [10,11]. The age incidence in Egyptian patients is much younger then reported in the west in which the mean age is about 65 years for all CRC patients while it was 31.6 years for young patients [2]. The young age incidence in our series is probably due to the young age structure of the Egyptian population. In the present series, there was insignificant male predominance. This result is in accordance to that of NCI, Cairo and South Egypt cancer institute [2,12]. On the other hand, this result was different from early reports from NCI Ciro, in which males predominated five times over females [13]. In western literature, a slight male predomince (1.2:1) was reported Lin [ 14]. The sex distribution of the patients under 40 years of this study was nearly similar to the early Egyptian reports Soliman, et al. [9]. In the western series, it was of almost equal incidence in both sexes [14]. In the old group, the male to female ratio was similar to the early Egyptian reports [ 9]. Correlation between the two age group and the stage of presentation revealed that the young group had more advanced stage while the old group were more likely to present with early stage. This finding is similar to other Egyptian series in which most of the young patients presented with an advanced stage at the time of diagnosis [2,3,8]. Most of the western series regarding young CRC patients agree on the fact that the disease is presented at an advanced stage [14,16]. As regards lymph node involvement, the result of this study is nearly similar to that of NCI report in which 46.5% had lymph node involvement while it is higher than a Figyre of 42.6% reported from USA [2,17]. In the young group, it was more than that of the old group which is similar to other series [11]. The rectum is the most common site to be involved where 42.7% of all patients had rectal tumours. In the early Egyptian publication from NCI, rectal carcinoma constituted 75-79% of cases [13]. In the later Egyptian series, the rectum constituted 68% of all CRC [7]. Conversely, the result of this study is different from other Egyptian publication where the distal colon was the most common site contributing 50.2% of cases followed by the rectum which constituted 27% of cases [2]. Studies from different regions have documented almost similar Figures where more than 50% of malignancy is present in the rectosigmoid [6,18]. The trend toward increased incidence of rectal cancer in patients under 40 years was confirmed in a review of the Surveillance Epidemiology and End Results (SEER) data base. This trend is confirmed by the Meyer, et al. [19]. Gastrointestinal cancer symposium showing increased incidence of rectal cancer and rectosigmoid cancer in patients under age 40.

5 Hoda H. Eisa 149 Analysis of the histological features revealed that young patients had mucinous/signet ring histology and poor tumour differnetiation more than that of the old group. This result is parallel to other Egyptian series, where mucinous histology constituted 38.5% for the young group versus 8.3% in the old group [13]. The high grade of CRC in young patients in this study resembled those of the other reports Al-Jaberi, et al. [18]. Alici, et al. [10] and O Connell, et al. [20]. Younger patients with CRC have long been thought to have a poorer prognosis than older patients [16]. Recent overseas reports, however, have disputed this. In the present study, the overall survival of young patients was slightly better than that of the old group but with no significance (p=0.378). This finding is in agreement with those reported in the literature, where the younger patients with CRC have the potential to do just as well as older ones [6,11]. In the univariate analysis, stage at presentation, lymph node involvement and KPS are predictors for overall survival in young patients with CRC in our study. Stage is one of the most common reproducible independent factors affecting prognosis. Young patients had more advanced stage at presentation, may be due to the aggressive behaviour of the tumour itself or delay in diagnosis. However, younger age had no more aggressive disease for a given stage. KPS is another predictive variable for prognosis in young patients. This finding is in accordance with that reported in the literature [14]. KPS may be the main factor in our study for the insignificant improvement of the overall survival of young patients in comparison to older patients. Lymph node involvement is another important prognostic factor for over all survival in this study, similar to other studies Alici, et al. [10]. However this factor was not evident in the multivariate analysis. In multivariate analysis, stage of the tumour and KPS were determined as independent prognostic factors for survival in CRC patients under 40 years. Therefore, advanced stage at presentation and KPS <70% were determined to be unfavorable prognostic factors for overall survival for patients under 40 years. The present data indicates that the incidence of CRC in patients under 40 years in Egypt is rising. The young Egyptian patients mainly presented with advanced stage and poor histological features. However, the overall survival was not significantly different from that of the old patients. References 1- BOYLE P. and LONGMAN J.S.: ABC of colorectal cancer. Epidemiology. Student BMJ. Mar., (10) 322 (7286), 611, EL-BOLKAINY N., NOUH M.A. and EL-BOLKAINY T.N.: Topographic pathology of cancer, 3rd edition. NCI Cairo P 1-6, p. 33-9, ABOU-ZEID A.A., KHAFAGY W., MARZOUK D.M., ALAA A., MOSTAFA I. and ELA M.A.: Colorectal Cancer in Egypt. Dis. Colon. Rectum, Sep., 45 (9): , O CONNELL J.B., MAGGARD M.A., LIU J.H., ETZIONI D.A. and LIVINGSTON E.H.: Rates of colon and rectal cancers are increasing in young adults. American Surgeon, VASTYAN A.M., WALKER J., PINTER A.B.,GERRARD A. and KAJTAR P.: Colorectal carcinoma in children and adolescents, a report of seven cases. Eur. J. Pediatr Surg. Oct., 11 (5): 38-41, KAN M.H., E.U. K.W., BARBEN C.P., SEO W. and CHOEN F.: Colorectal cancer in the young: a 12 years review of patients 30 years or less. Colorectal. May., 6 (3): 191-4, KHAFAGY W., EL-GHAZALY M., EL-SHOBAKY M. and KHAFAGY M.: Colorectal cancer. In Egypt-does it differ. Coloproctology, Vol. 22, No. 3, June EL-HENNAWY M.M., MOSSA M.E., EL-SAEIDY M.K.,SHAWKY A.M. BESSASS and BODOUR N.M.: Rectal carcinoma in Egyptian patients less than 40 years of age. Int. Surg. Jul. Sep., 88 (3): , SOLIMAN A.S., BONDY M.L., LEVIN B., HAMZA M.R., ISMAIL K., ISMAIL S., HAMMAM H.M., EL- HATTAB O.H., KAMAL S.M., SOLIMAN A.G., DORGHAM L.A., MCPHERSON R.S. and BEASLEY R.P.: Colorectal cancer in Egyptian patients under 40 years of age. Int. J. Cancer, Mar., 28: 71 (1): 26-30, ALICI S., AYKAN N.F., SAKAR B., GULISTAN B., KAYTAN E. and TOPOUZ E.: Colorectal cancer in young patients: characteristics and outcome. The Tohoku Journal of experimental Medicine. Vol., 199, No. 2. pp , QUAH H.A., JOSEPH R., SCHRAG D., SHIA J., GUILLEN J.G., et al.: Young age influences treatment but not outcome of colon cancer. Annals of surgical Oncology, 14: , ABD EL-WANIS M., MAXIMOUS D.W., EL-SAYED M.I. and MIKHAIL N.M.: Surgical treatment for locally advanced lower 1/3 rectal Ca after neoadjuvant chemoradiation with capecitabine: prospective phase II trial world Journal of Surgical Oncology, 7: 52, KENAWI M.M., EL-SAIED A., EL-BOLKAINY N. and BAHY ELDEEN H.N.: Relative frequency of gastrointestinal malignancies at NCI during 14 years ( ). Med. J. Cairo Univ., 58: 35-41, 1990.

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