Abstract
We aimed at evaluation of the clinicoepidemiologic data of patients with gastric carcinoma in the Egyptian Delta as regards the etiologic factors, behavior, presenting symptoms, and tumor location, grade, and stage with highlighting of the treatment modalities, survival, and prognostic factors. Three hundred cases with gastric carcinoma were enrolled, diagnosed, and treated in a tertiary oncology center in the Egyptian Delta. Data were collected as regards the etiology, presenting symptoms, family history, comorbid conditions, treatment modalities, responses, recurrences, and survival outcomes. Univariate and multivariate analyses were done to correlate the different clinicopathologic factors with the overall and disease-free survivals. Male to female ratio was 2:1. The median age was 43 years. The main tumor location was in the gastric body. Pain was the commonest presenting symptom (36%). Most of the cases were stage IV (42.0%). Only 49% of cases were operable. On multivariate analysis, age more than 60 years, performance status 3–4, high grade, diffuse type, T4 lesions, N2 and N3, and the presence of metastasis were independently associated with worse OS. We report a clinic-epidemiologic study of gastric carcinoma in the Egyptian delta; the age at presentation was a decade earlier than that recorded in the USA and Europe; most of the cases were sporadic, located mostly at the body. Most of the cases were presented at stage IV with poor response to neoadjuvant therapy with a poorer overall survival than that recorded in the USA and Europe.
Keywords: Epidemiology, Gastric, Cancer, Surgery
Introduction
Gastric cancer constitutes the fourth most common cancer all over the world. It is the second cancer in mortality approaching 900,000 annual deaths [1]. Many risk factors were described including the hereditary factor that was estimated to be around 9% [2], salty food [3, 4], smoking [5], Helicobacter pylori-associated gastritis [6], and chronic atrophic gastritis [7]. Unfortunately, most of the cases are advanced at diagnosis with a modest 5-year survivals of less than 30% [8]. Due to the dilemma of late presentation of gastric cancer, any patient around the age of 70 who present with a vague abdominal pain must be investigated for gastric cancer [9]. Resection with R0 was significantly associated with better prognosis [10]. Lymph node metastases as the usual with most of epithelial cancers were the most important prognostic factor [11]. The recent National Comprehensive Cancer Network guidelines recommend at least 15 lymph node retrieval for evaluation of nodal status. This could be achieved with D1 or modified D2 nodal dissection [8]. It was clear nowadays that the addition of chemoradiotherapy gives better recurrence-free and overall survivals rather than surgery alone [12]. This may be administered as neo-adjuvant, adjuvant, or perioperative regimen [8]. In this work, we tried to highlight the current status of gastric carcinoma in the Egyptian Delta through assessment of cases admitted to a tertiary oncology center as regards patients demographics, presenting symptoms, the commonest tumor location, the commonest histologic type, the most frequent stage at presentation, the commonly used treatment options, and outcome of this disease in this locality in comparison with the state in the USA and Europe.
Patients and Methods
Three hundred cases who were treated for gastric carcinoma in a tertiary cancer center in the Egyptian Delta throughout the period from January 2010 until June 2016 were enrolled. After the approval of the local institutional ethical committee review board (Code: R/17.07.51), all patients were treated according to panel decision with either surgery alone or surgery after neo-adjuvant therapy or surgery followed by adjuvant treatment. Collected data included patient demographics; the presenting symptoms; current performance status; tumor characteristics as location, grade, histology, staging, and marker status; the used treatment modalities; and the final outcome as regards relapse rate, disease progression, and mortality rates. Both univariate and multivariate analyses were made to correlate the clinic-pathologic data with the outcome as regards disease-free and overall survivals. Data were shown in a descriptive manner with numbers and percentage.
Results
Table 1 shows patients’ characteristics. The median age was 43 years with a range between 24 and 74 years. Most of the patients were males (66.7%). History of smoking was positive in 120 out of 200 males (60%). Family history was positive only in two cases (0.7%). Pain was the commonest presenting symptom (36%) followed by vomiting (21.3%) and dyspepsia in 20.7%. Most of the patients showed a performance status ECOG score 2 at presentation (124 cases; 41.3%). Table 2 shows tumor characteristics; the commonest tumor location was in the body (158 cases; 52.7%) followed by the Pyloric antrum (56 cases; 18.7%). The commonest tumor grade (according to Broder’s classification) was grade III (98 cases; 32.7%). Most of the cases were of the intestinal type (178 cases; 59.3%). The most frequent stage was IV (126 cases; 42%) with a 126 metastatic cases (41.1%). The commonest metastatic site was the peritoneum with development of malignant ascites. Both CEA and CA19.9 were normal in nearly half of the cases (Table 2). On exploration, 147 cases (49%) underwent resection while in 121 cases, resection was precluded and bypass was done in 32 cases which means that 153 cases were irresectable (51%) (Table 3). Some of the recorded metastatic cases were not detected preoperatively and was detected with laparoscopic evaluation to have either liver or peritoneal metastatic disease. Total gastrectomy was performed in 70 cases while subtotal and distal radical gastrectomies were performed in 77 patients. All were done with a modified D2 resection. Among the resected cases, margins were negative in 72.1%. Table 3 shows also the number of cases who received systemic therapy and radiotherapy either in the neoadjuvant or in the adjuvant settings (Table 3). Table 4 shows response among cases who received neoadjuvant therapy. In our institution, the indications of neoadjuvant chemotherapy were mainly for T3 and T4 tumors and any nodal positivity in radiology. In most of the cases, we used a combination of epirubicin, cisplatin, and capecitabine. On follow-up, the median disease-free survival of the studied cases was 12 months. All relapses after curative treatment occurred in the first post-operative year with a cumulative disease-free survival at 3 and 5 years was 32% (Fig. 1). The median overall survival of the studied cases was 12 months with a cumulative overall survival at 3 and 5 years were 16 and 10% respectively (Fig. 1). On univariate analysis, age more than 60 years, performance status (PS) of 3–4, upper tumor location, high grade, diffuse type, T4 lesions, nodal status N2 and N3, and the presence of metastasis were associated with significantly predicted poor overall survival (OS). High CEA levels were associated with worse OS of borderline significance. On multivariate analysis, age more than 60 years, PS 3–4, high grade, diffuse type, T4 lesions, N2 and N3, and the presence of metastasis were independently associated with worse OS.
Table 1.
Patients’ and disease characteristics
| Age | Median | Range |
|---|---|---|
| 43 | 24–74 | |
| Other parameters | Number | Percentage |
| Gender | ||
| Male | 200 | 66.7 |
| Female | 100 | 33.3 |
| Smoking history (males) | 120/200 | 60 |
| Diabetes history | 10 | 3.3 |
| Family history | 2 | 0.7 |
| Presenting symptom | ||
| Weight loss | 14 | 4.7 |
| Dyspepsia | 62 | 20.7 |
| Dysphagia | 36 | 12.0 |
| Hematemesis | 16 | 5.3 |
| Pain | 108 | 36.0 |
| Vomiting | 64 | 21.3 |
| ECOG performance status | ||
| 0 | 4 | 1.3 |
| 1 | 102 | 34.0 |
| 2 | 124 | 41.3 |
| 3 | 56 | 18.7 |
| 4 | 14 | 4.7 |
Table 2.
Tumor characteristics
| No | Percentage | |
|---|---|---|
| Location | ||
| Cardia | 42 | 14.0 |
| Fundus | 36 | 12.0 |
| Body | 158 | 52.7 |
| Pyloric antrum | 56 | 18.7 |
| Multiple | 8 | 2.7 |
| Grade (Broder’s) | ||
| 1 | 48 | 16.0 |
| 2 | 89 | 29.7 |
| 3 | 98 | 32.7 |
| 4 | 65 | 21.7 |
| Pathology | ||
| Intestinal | 178 | 59.3 |
| Diffuse | 122 | 40.7 |
| PT | ||
| 2 | 19 | 6.3 |
| 3 | 244 | 81.3 |
| 4 | 37 | 12.3 |
| PNa | ||
| 0 | 53 | 17.7 |
| 1 | 52 | 17.3 |
| 2 | 117 | 39.0 |
| 3 | 78 | 26.0 |
| Total positive LN | 247/300 | 83.3 |
| M | ||
| 0 | 174 | 58.0 |
| 1 | 126 | 42.0 |
| TNM stage | ||
| IB | 10 | 3.3 |
| IIA | 34 | 11.3 |
| IIB | 34 | 11.3 |
| IIIA | 26 | 8.7 |
| IIIB | 58 | 19.3 |
| IIIC | 12 | 4.0 |
| IV | 126 | 42.0 |
| Metastatic sites | ||
| Brain | 0 | 0.0 |
| Lung | 14 | 4.7 |
| Liver | 42 | 14.0 |
| Bone | 1 | 0.3 |
| Peritoneal | 56 | 18.7 |
| Othersb | 13 | 4.3 |
| High CEA | 145 | 48.3 |
| High CA19.9 | 111 | 37 |
aNodal positivity as assessed by biopsy either with resection or without
bOther metastatic sites suprarenal, splenic, and supraclavicular lymph node metastases
Table 3.
Treatment of the studied cases
| No | Percentage | |
|---|---|---|
| Surgery | ||
| Total gastrectomy | 70 | 23.3 |
| Subtotal and distal gastrectomy | 77 | 25.7 |
| No resection | 121 | 40.3 |
| Bypass | 32 | 10.7 |
| Margin | ||
| Negative | 106 | 72.1 |
| Positive | 41 | 27.9 |
| Total resected cases | 147 | 100 |
| Neoadjuvant chemotherapy | 156 | 52 |
| Adjuvant chemotherapy | 196 | 65.3 |
| Palliative chemotherapy | ||
| Cisplatin-5FU | 28 | 9.3 |
| DCF | 14 | 4.6 |
| FOLFERI | 10 | 3.3 |
| ECX | 42 | 14 |
| Total | 94/300 | 31.3% |
| Postoperative radiotherapy | 128 | 42.7 |
Cisplatin-5FU cisplatin/5 fluorouracil, DCF (modified) docetaxel/leucovorin/fluorouraci/cisplatin, FOLFERI irinotecan/leucovorin/fluorouracil, ECX epirubicin/cisplatin/capecitabine
Table 4.
Outcome of cases who received neoadjuvant treatment (total 156)
| Number = 156 cases | No | Percentage |
|---|---|---|
| Response (RECIST) | ||
| Complete response (CR) | 14/156 | 9.0 |
| Partial response (PR) | 49/156 | 31.4 |
| Stable disease (SD) | 53/156 | 34.0 |
| Progressive disease (PD) | 40/156 | 25.6 |
RECIST response evaluation criteria in solid tumors
Fig. 1.
a Disease-free survival. b Overall survival of the studied
Discussion
The median age in this study was 43 years. This is a decade earlier than that recorded in most of the literature [13]. In view of the very low incidence of positive family history, this warrants the attention to an environmental etiology. The male to female ratio was around the international records [14]. The predominance of body adenocarcinoma raises the etiologic relation to an association with Helicobacter pylori which induces chronic gastritis. The high incidence of infection by such organism in this region is well known [15]. As reported in many publications [16, 17] and as declared by the International Agency for Research on Cancer, this organism was categorized as a definite class 1 carcinogen [18]. Smoking was positive in 60% of the affected males; studies were unable to find a direct link while others found no association with gastric cancer. There was an acceptance about the causal role of tobacco smoking in pathogenesis of gastric cancer [19, 20]. Although some studies claim that 10–15% of cases with gastric cancer show a positive family history [21], in our study, only 0.7% showed a positive family history denoting the predominance of the sporadic tendency and environmental factors in causation. Pain was the leading presenting symptom in our study; this reflects a lack of screening programs and explains the more advanced stage (Table 2) and poorer prognosis. It is reported that 5-year survival in the USA is around 29% [22] and in Europe, it is around 20% [9, 23]. In our study, it is around 10%. We report a high rate of nodal positivity, 83.3% (as assessed by biopsy either with resection or without), and a high rate of metastatic disease (42.0%). It is to be mentioned that most of the local failure after surgery is noticed in the first postoperative year and this reflects the great importance of close surveillance in this critical period. Most of the cases showed poor response to neoadjuvant therapy (34.0% showed a stable disease and 25.6% expressed progressive condition); this may be due to an aggressive biology that calls for further studies that entails biologic highlighting of this tumor in this locality. In view of both univariate and multivariate analyses (Tables 5 and 6), we can conclude that elder age, poor performance status at diagnosis, upper tumor location, advanced stage, high grade, and diffuse type are the worst prognostic factors.
Table 5.
Univariate analysis of prognostic factors of overall survival
| Variable | No (%) | HR | 95% CI | *P value | |
|---|---|---|---|---|---|
| Age | < 60 years | 220 (73.3) | |||
| ≥ 60 years | 80 (26.7) | 1.9 | 1.4–3.6 | 0.001 | |
| Gender | Female | 100 (33.3) | |||
| Male | 200 (66.7) | 1.55 | 0.93–2.79 | 0.2 | |
| PS | 0–2 | 230 (76.6) | |||
| 3–4 | 70 (23.4) | 3.9 | 2.2–8.5 | < 0.001 | |
| Location | Lower | 214 (71.3) | |||
| Upper | 86 (28.7) | 1.8 | 1.03–4.2 | 0.045 | |
| Grade | Low grade | 137 (45.6) | |||
| High grade | 163 (54.4) | 2.1 | 1.4–4.3 | 0.008 | |
| Pathology | Intestinal | 178 (59.3) | |||
| Diffuse | 122 (40.7) | 4.7 | 2.1–8.2 | < 0.001 | |
| T | 2 | 19 (6.3) | |||
| 3 | 244 (81.3) | 1.6 | 0.9–4.8 | 0.09 | |
| 4 | 37 (12.3) | 3.5 | 1.6–5.9 | 0.001 | |
| N | 0 | 53 (17.7) | |||
| 1 | 52 (17.3) | 1.3 | 0.7–4.2 | 0.1 | |
| 2 | 117 (39.0) | 1.4 | 1.1–2.8 | 0.004 | |
| 3 | 78 (26.0) | 3.479 | 2.5–4.6 | 0.009 | |
| M | 0 | 174 (58.0) | |||
| 1 | 126 (42.0) | 4.82 | 3.5–8.6 | < 0.001 | |
| CEA | Normal | 155 (51.7) | |||
| High | 145 (48.3) | 1.4 | 0.9–1.7 | 0.09 | |
| CA19.9 | Normal | 189 (63) | |||
| High | 111 (37) | 1.8 | 0.7–2.1 | 0.3 | |
HR hazard ratio
*P value is significant below 0.05
Table 6.
Multivariate analysis of prognostic factors of overall survival
| Variable | No (%) | HR | 95% CI | P value | |
|---|---|---|---|---|---|
| Age | < 60 years | 220 (73.3) | |||
| ≥ 60 years | 80 (26.7) | 1.7 | 1.3–2.96 | 0.005 | |
| PS | 0–2 | 230 (76.6) | |||
| 3–4 | 70 (23.4) | 3.5 | 2.1–9.5 | 0.001 | |
| Location | Lower | 214 (71.3) | |||
| Upper | 86 (28.7) | 1.1 | 0.8–3.1 | 0.2 | |
| Grade | Low grade | 137 (45.6) | |||
| High grade | 163 (54.4) | 1.9 | 1.5–3.9 | 0.009 | |
| Pathology | Intestinal | 178 (59.3) | |||
| Diffuse | 122 (40.7) | 2.6 | 1.7–7.3 | < 0.001 | |
| T | 2 | 19 (6.3) | |||
| 3 | 244 (81.3) | 1.8 | 0.9–4.8 | 0.1 | |
| 4 | 37 (12.3) | 2.1 | 1.9–6.5 | 0.001 | |
| N | 0 | 53 (17.7) | |||
| 1 | 52 (17.3) | 1.2 | 0.7–4.1 | 0.1 | |
| 2 | 117 (39.0) | 1.2 | 1.2–2.9 | 0.004 | |
| 3 | 78 (26.0) | 3.8 | 2.2–4.7 | 0.007 | |
| M | 0 | 174 (58.0) | |||
| 1 | 126 (42.0) | 4.3 | 2.5–7.7 | < 0.001 | |
Conclusion
We report a clinic-epidemiologic study of gastric carcinoma in the Egyptian delta; the age at presentation was a decade earlier than that recorded in the USA and Europe, most of the cases were sporadic, located mostly at the body. Most of the cases were presented at stage IV with poor response to neoadjuvant therapy with a poorer overall survival than that recorded in the USA and Europe.
Compliance with Ethical Standards
This work was carried out in the period from January 2010 until June 2016 according to the guidelines of the Declaration of Helsinki and it was approved by the local institutional ethical committee review board (Code: R/17.07.51).
Conflict of Interest
The authors declare that they have no conflict of interest.
References
- 1.McGuire S. World Cancer report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015. Adv Nutr. 2016;7(2):418–419. doi: 10.3945/an.116.012211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.La Vecchia C, Negri E, Franceschi S, Gentile A. Family history and the risk of stomach and colorectal cancer. Cancer. 1992;70(1):50–55. doi: 10.1002/1097-0142(19920701)70:1<50::AID-CNCR2820700109>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
- 3.Hirohata Tomio, Kono Suminori. Diet/nutrition and stomach cancer in Japan. International Journal of Cancer. 1997;71(S10):34–36. doi: 10.1002/(SICI)1097-0215(1997)10+<34::AID-IJC9>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
- 4.Tsugane Shoichiro, Sasazuki Shizuka. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer. 2007;10(2):75–83. doi: 10.1007/s10120-007-0420-0. [DOI] [PubMed] [Google Scholar]
- 5.Ladeiras-Lopes Ricardo, Pereira Alexandre Kirchhofer, Nogueira Amanda, Pinheiro-Torres Tiago, Pinto Isabel, Santos-Pereira Ricardo, Lunet Nuno. Smoking and gastric cancer: systematic review and meta-analysis of cohort studies. Cancer Causes & Control. 2008;19(7):689–701. doi: 10.1007/s10552-008-9132-y. [DOI] [PubMed] [Google Scholar]
- 6.Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. J Am Med Assoc. 2004;291(2):187–194. doi: 10.1001/jama.291.2.187. [DOI] [PubMed] [Google Scholar]
- 7.Neumann William L., Coss Elizabeth, Rugge Massimo, Genta Robert M. Autoimmune atrophic gastritis—pathogenesis, pathology and management. Nature Reviews Gastroenterology & Hepatology. 2013;10(9):529–541. doi: 10.1038/nrgastro.2013.101. [DOI] [PubMed] [Google Scholar]
- 8.Ahmad SA, Xia BT, Bailey CE, Abbott DE, Helmink BA, Daly MC, Thota R, Schlegal C, Winer LK, Ahmad SA, al Humaidi AH, Parikh AA. An update on gastric cancer. Curr Probl Surg. 2016;53:449–490. doi: 10.1067/j.cpsurg.2016.08.001. [DOI] [PubMed] [Google Scholar]
- 9.Wanebo HJ, Kennedy BJ, Chmiel J, Steele Jr G, Winchester D, Osteen R. Cancer of the stomach. Ann Surg. 1993;218(5):583–592. doi: 10.1097/00000658-199321850-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Postlewait LM, Maithel SK. The importance of surgical margins in gastric cancer. J Surg Oncol. 2016;113(3):277–282. doi: 10.1002/jso.24110. [DOI] [PubMed] [Google Scholar]
- 11.Akagi T, Shiraishi N, Kitano S. Lymph node metastasis of gastric cancer. Cancers (Basel) 2011;3(2):2141–2159. doi: 10.3390/cancers3022141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20. doi: 10.1056/NEJMoa055531. [DOI] [PubMed] [Google Scholar]
- 13.Kelley JR, Duggan JM. Gastric cancer epidemiology and risk factors. COMMENTARY. J Clin Epidemiol. 2003;56:1–9. doi: 10.1016/S0895-4356(02)00534-6. [DOI] [PubMed] [Google Scholar]
- 14.Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107. [DOI] [PubMed] [Google Scholar]
- 15.Khalifa MM, Sharaf RR, Aziz RK. Helicobacter pylori: a poor man’s gut pathogen? Gut Pathogens. 2010;2:2. doi: 10.1186/1757-4749-2-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Eslick GD, Lim LL, Byles JE, et al. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol. 1999;94(9):2373–2379. doi: 10.1111/j.1572-0241.1999.01360.x. [DOI] [PubMed] [Google Scholar]
- 17.Xue F-B, Xu Y-Y, Wan Y, Pan B-R, Ren J, Fan D-M. Association of H. Pylori infection with gastric carcinoma: a meta-analysis. World J Gastroenterol. 2001;7(6):801–804. doi: 10.3748/wjg.v7.i6.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.IARC. Schistosomes, liver flukes and helicobacter pylori. IARC monographs of the evaluation of carcinogenic risks to humans 1994;61:177–241 [PMC free article] [PubMed]
- 19.Tobacco smoke and involuntary smoking. Lyon, France: World Health Organisation ; 2004
- 20.Sjodahl K, Lu Y, Nilsen TI, et al. Smoking and alcohol drinking in relation to risk of gastric cancer: a population-based, prospective cohort study. Int J Cancer. 2007;120:128–132. doi: 10.1002/ijc.22157. [DOI] [PubMed] [Google Scholar]
- 21.Barber M, Fitzgerald RC, Caldas C. Familial gastric cancer—aetiology and pathogenesis. Best Pract Res Clin Gastroenterol. 2006;20:721–734. doi: 10.1016/j.bpg.2006.03.014. [DOI] [PubMed] [Google Scholar]
- 22.Edge SB, Compton CC. The American joint committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–1474. doi: 10.1245/s10434-010-0985-4. [DOI] [PubMed] [Google Scholar]
- 23.Akoh JA, Macintyre IM. Improving survival in gastric cancer: review of 5-year survival rates in English language publications from 1970. Br J Surg. 1992;79:293–299. doi: 10.1002/bjs.1800790404. [DOI] [PubMed] [Google Scholar]