A Retrospective Study of Survival and Patterns of Failure in Gastric Cancer after Adjuvant Chemoradiation

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1 Med. J. Cairo Univ., Vol. 82, No. 2, December: , A Retrospective Study of Survival and Patterns of Failure in Gastric Cancer after Adjuvant Chemoradiation ALIA M.A. ATTIA, M.D.*; MOHAMED I. EL-SAYED, M.D.*; MONA M. SAYED, M.D.*; HUSSEIN F. HOZAYEN, M.D.**; HESHAM M. HAMZA, M.D.** and MOSTAFA E. ABDEL-WANIS, M.D.* The Departments of Radiation Oncology* and Surgical Oncology**, South Egypt Cancer Institute, Assiut University, Egypt Abstract Background: Even after curative resection, 38-94% of gastric cancer patients develop locoregional recurrence denoting the importance of adjuvant therapy and its refinement. The aim of this study was to assess survival and pattern of failure and factors affecting them in non-metastatic gastric cancer. Patients and Methods: Medical records of 43 nonmetastatic gastric cancer patients, who received adjuvant concurrent chemoradiotherapy of 5-FU/Leucovorin after curative resection, were analyzed. Results: After a median follow-up of 45 months (6-81 months), the 4-year Overall survival (OAS) and disease free survival (DFS) rates were 51.3% and 46.4% respectively. Multivariate analysis for OAS revealed that stage is the only significant prognostic factor (HR: 4.25; 95% CI: ). Patterns of recurrence were iisolated locoregional recurrence (LRR), isolated hematogenous and mixed recurrences seen in 6 patients (14.0%), 11 patients (25.6%) and 5 patients (11.6%) respectively. Conclusion: Postoperative chemoradiation was promising, with acceptable toxicity, decreasing locoregional failure with less pronounced benefit on peritoneal and distant failure, suggesting the need for more effective systemic chemotherapy for adjuvant treatment especially for locally advanced gastric cancer (pt3 and PT4), which predicts worse OAS. Key Words: Treatment results Postoperative chemoradiation Stomach cancer. Introduction GASTRIC cancer remains the 2 nd leading cause of cancer related deaths worldwide [1]. Complete removal of the tumor with an adequate safety margin plus at least D 1 dissection is considered to be the only curative treatment for localized gastric cancer [2]. Despite this treatment, 38-94% of the patients develop locoregional recurrence [3-6], Correspondence to: Dr. Alia M.A. Attia, The Department of Radiation Oncology, South Egypt Cancer Institute, Assiut University, Egypt which accounted for 33-69% of all recurrences [4, 6-8] with median survival time of only 24 months and 5-year survival rate of 30% [9]. In patients with resectable >T2N0 gastric cancer, surgery is no longer the sole treatment [10], because of the survrvival advantage demonstrated with postoperative chemoradiotherapy [11,12] and perioperative chemotherapy [13]. The United States Intergroup study (INT 0116) and MAGIC/UK Medical Research Council (MRC) were large randomized studies that showed a significant improvement in survival with adjuvant therapy in patients after curative surgical resection of gastric cancer. Patients in SWOG tria [11,12] received postoperative chemoradiotherapy, while patients in MAGIC trial received perioperative ECF [13]. Both trials suggested the need for both chemotherapy and radiotherapy in the perioperative setting in patients with localized gastric cancer. To refine adjuvant treatment, patterns of failure should be well understood. The aim of the present study was to: Describe the clinicopathological pattern of gastric cancer. Determine the pattern of failure, disease-free survival, and overall survival rates in patients with completely resected gastric adenocrcinoma. Detection of possible prognostic factors and correlating them with overall survival. Patients and Methods This retrospective study was carried out by analyzing the medical records of patients with histologically confirmed non metastatic adenocarcinoma of the stomach and gastroesophageal junction seen at South Egypt Cancer Institute (SECI), Assiut University during the period of January 2004 and January Informed consent was 131

2 132 A Retrospective Study of Survival & Patterns of Failure obtained for all patients and treatment decision was approved by the institutional review board at SECI. Eligible patients had histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction with no distant metastasis, and were untreated previous to attending SECI. For each patient evaluations consisted of history and physical examinations, routine laboratory investigations, imaging studies in form of CT chest for GEJ tumors, and CT abdomen and pelvis to assess the extent of the disease. Other investigations in the form of barium meal and endoscopy were done to assess the location and extent of gastric tumor. Histologic diagnosis was obtained from gastric mass by endoscopy and biopsy. Histopathologic criteria of the surgical specimen was recorded and staging of the disease was done according to AJCC 2002 [14]. Between January 2004 and January 2012, there were 89 gastric cancer patients treated at SECI. Out of those patients there were 19 metastatic cases and 27 patients presented with unresectable disease and they were excluded from the current study. The remaining 43 cases received postoperative chemoradiation, and were analyzed in the present study for clinicopathological characteristics, patterns of failure and survival rates. To evaluate acute toxicities, patients were monitored weekly during radiotherapy (RT), and one week after completion of RT. After that, patients were followed up regularly at 3 months intervals by examination, and tumor markers (CEA, and CA19-9). Computerized tomography (CT) of abdomen and pelvis, or CT chest for GEJ, were requested every 6 months. Bone scan was done when indicated. Patients with locoregional recurrence, or distant metastasis were referred for salvage therapy according to the status of each patient. Statistical method: Disease free survival (DFS) was defined as the interval from enrollment of patients to the date of relapse or death from any cause or last follow-up. Overall survival (OAS) was defined as the interval from enrollment to the date of death from any cause or last follow-up. DFS and OAS rates were estimated by the Kaplan-Meier method [15] and the differences were compared using the log-rank test. To determine relationships between the patterns of failure, clinicopathological, and treatment related factors, the chi-square test was used. All p-values.05 considered to be significant. All analyses were performed using the Statistical Package for Social Sciences software (version 18.0, SPSS, Chicago, IL). Results Patients and tumor characteristics: The age of the patients ranged from years with a median age of 53 years. There were 25 males (58.1%) and 18 females (41.9%) with male to female ratio of 1.4:1. According to Eastern Cooperation Oncology Group (ECOG) performance status [16], 76.7% and 23.3% of the patients had performance status of 1, and 2 respectively. Most patients presented with pt3 tumors (60.5%), 65.1% of the patients had pathologically involved lymph nodes and 60.5% of the patients had poorly differentiated tumors. According to TNM stage classification, 48.8% of the patients had stage III disease. Twenty one patients (48.8%) had their tumor located in the distal third of the stomach Table (1). Table (1): Patients and tumor characteristics in all patients. Variables Number (%) Age: <40 8 (18.8) (51.2) >60 13 (30.2) Sex: Male 25 (58.1) Female 18 (41.9) Performance status: 1 33 (76.7) 2 10 (23.3) Site of the disease: Cardia 11 (25.6) Fundus 2 (4.7) Body 7 (16.3) Pylorus 21 (48.8) Diffuse infilteration 2 (4.7) Laurens type: Diffuse 23 (53.5) Intestinal Mixed 13 (30.2) 7 (16.3) Histopathological type: Adenocarcinoma 34 (79.1) Signet ring carcinoma 9 (20.9) Grade: Well differentiated 4 (9.3) Moderately differentiated Poorly differentiated 13 (30.2) 26 (60.5) Stage: IB 3 (7.0) II 11 (25.6) IIIA 12 (27.9) III 9 (20.9) IV 8 (18.6) Type of surgery: Subtotal gastrectomy 26 (60.5) Total gastrectomy 17 (39.5)

3 Alia M.A. Attia, et al. 133 Treatment: Surgery: All patients underwent curative surgical resection with lymph node dissection; subtotal gastrectomy was performed in 26 patients (60.5%), while total gastrectomy was performed in 17 patients (39.5%). D0, D1, D2 of lymph nodes dissection was performed in 7 patients (16.3%), 27 (62.8%) patients and 9 patients (20.9%) respectively. Adjuvant treatment: Following curative surgical resection, chemoradiotherapy was given to 43 patients. Postoperative chemotherapy, started within 4-6 weeks except for 5 patients (11.6%) who had delayed wound healing and so started their postoperative chemotherapy within 8 weeks. Chemotherapy consisted of one cycle of 5-fluorouracil, 425mg/m 2 IV bolus, and Leucovorin, 20mg/m 2 IV bolus, immediately before fluorouracil, for 5 days. Chemoradiation, started within 4 weeks after the start of initial cycle of chemotherapy. It consisted of: Radiation therapy, 4500cGy (180cGy per day), 5 days per week for 5 weeks, given concurrently with: 5- Fluorouracil: 400mg/m 2 IV bolus on days 1-4 and on the last 3 days of radiation therapy and Leucovorin: 20mg/m 2 IV bolus on days 1-4 and on the last 3 days of radiation therapy. One month after completion of radiotherapy, two five-day cycles of 5-Fluorouracil (425mg/m 2 IV bolus, and Leucovorin (20mg/m 2 IV bolus) were given one month apart. Radiation target volume included the tumor bed (preoperative CT), anastomosis, remnant stomach and regional lymphatics (perigastric, splenic, portahepatis, celiac, pancreaticoduodenal, and lower paraesophageal nodes for gastroesophageal junction tumors) with 2cm margins. We used the definition of Japanese Research Society for Gastric Cancer for delineation of regional node areas [17]. Pretreatment diagnostic studies were used to determine the extent of disease and these included esophagogastroscopy, barium swallow radiographs, CT on chest and abdomen. Series of scans were taken every 0.5cm throughout the target volume. Multiple fields technique were used. All fields were treated isocentrically. Radiation was delivered with 15 MV photons. Doses were limited so that < 3000cGy of radiation of hepatic volume, and the equivalent of at least 2/3 of one kidney was spared from the radiation field. The dose was 45Gy in 25 fractions (1.8 Gy/fraction), five days per week for 5 weeks. Of the 43 patients assigned to the treatment protocol, 31 (71.1%) patients completed treatment as planned. Treatment was interrupted in 11 (25.6%) patients, because of toxic effects. Death was recorded in 1 patient (2.3%) during chemoradiation. All patients were analyzed in the present study including those who stopped treatment and the dead case. Toxicities were graded as 1-5 based on National Cancer Institute Common Terminology Criteria for Adverse Events v3 (NCICTCAE) [18], most toxicities occurred during concurrent chemoradiotherapy Table (2). Table (2): Toxic effects that occurred in the 43 patients. Toxicity Grade 1 Grade 2 Grade 3 No % No % No % Hematologic: Neutropenia Anaemia Thrombocytopenia Gastrointestinal: Nausea & vomiting Diarrhea Mucositis Patterns of failure: After a median follow-up period of 45 months, recurrence occurred in 22 patients (51.2%), and the median time to its occurrence from the date of surgery was 35 months (ranged 6-81 months). The pattern of treatment failure of the study group (43 patients) was isolated locoregional recurrence (LRR) in 6 (14.0%) patients, isolated distant metastasis (DM) in 11 (25.6%) and mixed recurrence in 5 (11.6%) patients as shown in Table (3). Table (3): Pattern of treatment failure in all patients. Relapse status No (%) No relapse 21 (48.8) Relapse 22 (51.2) Total 43 (100) Isolated LRR: 6 (14.0) Anastomosis site 2 (4.7) Remnant stomach 3 (7.0) Isolated DM: 11 (25.6) Peritoneal seeding 9 (20.9) Distant organs 11 (25.6) Site Liver 7 (16.3) Lung 1 (2.3) Bone 3 (7.0) Mixed 5 (11.6)

4 134 A Retrospective Study of Survival & Patterns of Failure Prognostic factors for recurrence: Univariate analysis revealed that age, sex, performance status, site of the disease, Lauren type, histology and grade were not statistically significant prognostic factors for any type of recurrence. However, increased depth of tumor invasion was associated with statistically significant increase in isolated locoregional recurrence (p=0.040) and mixed recurrence (p=0.012). Increased number of involved lymph nodes (p=0.035) and advanced stage of the disease (p=0.012) were associated with statistically significant increase in isolated hematogenous recurrence Table (4). Survival: After a median follow-up period of 45 months (13-81), the 4-year OAS and DFS were 51.3% and 46.4% respectively. Table (4): Pattern of treatment failure according to clinicopathological factors. Variables Isolated locoregional recurrence No (%) Isolated distant metastasis No (%) Multiple recurrence sites No (%) Age <40 (n=8) 1 (12.5) 3 (37.5) 2 (25) (n=22) 2 (9.1) 4 (18.2) 2 (9.1) >60 (n=13) 3 (23.1) 4 (30.8) 1(7.7) p-value Sex Male (n=25) 3 (12) 6 (24) 4 (16) Female (n=18) 3 (16.7) 5 (27.8) 1 (5.6) p-value Performance Status 1 (n=33) 4 (12.1) 9 (27.3) 3 (9.1) 2 (n=10) 2 (20) 2 (20) 2 (20) p-value Site of tumor Cardia (n=11) 1 (9.1) 5 (45.5) 3 (27.3) Fundus (n=2) Body (n=7) 2 (28.6) 2 (28.6) 1 (14.3) Pylorus (n=21) 2 (9.5) 3 (14.3) 1 (4.8) Diffuse infilteration (n=2) 1(50) 1 (50) 0 p-value Lauren histotype Diffuse (n=23) 1 (4.3) 8 (34.8) 3 (13) Intestinal (n=13) 4 (30.8) 2 (15.4) 2 (15.4) Mixed (n=7) 1 (14.3) 1 (14.3) 0 p-value Histologic types Adenocarcinoma (n=34) 5 (14.7) 8 (23.5) 5 (14.7) Signet ring carcinoma (n=9) 1 (11.1) 3 (33.3) 0 p-value Grading G1 (n=4) 0 1 (25) 1 (25) G2 (n=13) 0 2 (15.4) 1 (7.7) G3 (n=26) 6 (23.1) 8 (30.8) 3 (11.5) p-value Stage IB (n=3) II (n=11) IIIA (n=12) 2 (16.7) 3 (25.0) 1 (8.3) IIIB (n=9) 1 (11.1) 6 (66.7) 1 (11.1) VI (n=8) 3 (37.5) 2 (25.0) 3 (37.5) p-value

5 Alia M.A. Attia, et al. 135 Prognostic factors for survival: Univariate analysis of survival revealed that, age, sex, performance status, Lauren type, histology and grade were not statistically significant prognostic factors for disease free survival or overall survival. On the other hand, locally advanced disease, increased number of involved lymph nodes, advanced stage, proximal location and diffuse infil- Table (5): Association between clinicopathological variables and survival. tration of the stomach were significantly associated with poor disease free and overall survival with variable levels of statistical significance Table (5). Multivariate analysis for overall surviva, however, revealed that stage is the only significant prognostic factor (p=0.001; HR:4.248; 95% CI: ) Fig. (3). Variables DFS 4 year (%) OAS 4 year (%) Age <40 (n=8) (n=22) >60 (n=13) p-value Sex Male (n=25) Female (n=18) p-value Performance Status 1 (n=33) (n=10) p-value Site of tumor Cardia (n=11) Fundus (n=2) Body (n=7) Pylorus (n=21) Diffuse infiltration (n=2) 0 0 p-value Lauren histotype Diffuse (n=23) Intestinal (n=13) Mixed (n=7) p-value Histologic types Adenocarcinoma (n=34) Singnet ring carcinoma (n=9) p-value Grading Well differentiated (n=4) Moderately differentiated (n=13) Poorly differentiated (n=26) p-value Stage IB (n=3) II (n=11) IIIA (n=12) IIIB (n=9) VI (n=8) p-value Survival Survival Survival function + Censored Months Fig. (1): 4-year overall suvival of 43 patients with gastric carcinoma Survival function + Censored Months Fig. (2): 4-year DFS of 43 patients with gastric carcinoma.

6 136 A Retrospective Study of Survival & Patterns of Failure Survival TNM stage Months IB II IIIA IIIB IV + + IB-censored II-censored IIIA-censored IIIB-censored + IV-censored Fig. (3): 4-year OAS according to the stage of 43 patients with gastric carcinoma. Discussion The use of adjuvant radiation therapy in the treatment of gastric cancer has been investigated as a result of high rates of local and regional failure after primary curative surgical resection reaching 80% [19]. The survival benefit associated with postoperative chemoradiotherapy in INT-0116 trial [11,12] and the apparent trends reported in the ART- IST trial [20] make postoperative chemoradiotherapy a standard adjuvant treatment in patients with gastric cancer. Our study demonstrated that 72.1 % of patients (31/43) completed the treatment as planned. This figure is higher than that reported by intergroup trial; only 64% of patients could complete the treatment as planned [11] and comparable to that reported by the ARTIST trial (75%) [20]. Grade 3 acute toxicity occurred in 48.8% of patients. Such a toxicity profile compared favorably with those of other series [21,22] where grade 3 acute toxicity rate of 33-73% has been reported. The reason for low toxicity profile reported by our study was that high proportion of patients had performance status of one allowing them to tolerate chemoradiation protocol. In the present study local recurrence occurred in 5 patients (11.6%) and regional recurrence occurred in 11 patients (25.6%). MacDonald et al., reported higher local (19%) and regional (65%) recurrence rates for chemoradiotherapy group [11]. The reason might be that in the Intergroup 0116 study, peritoneal and hepatic metastasis were coded as regional relapse in addition to regional lymph node involvement. Another reason is that most of our patients underwent D 1 dissection compared to patients in the Intergroup 0116 study; most of them (54%) underwent D0 dissection. A study conducted by Lim et al., [22], evaluating the effect of adjuvant chemoradiation after extended lymphadenectomy also reported low rate of local (7%) and regional (12%) recurrences. These figures are lower than that reported by our study, the reason for that might be due to that all patients in this study underwent D2 lymphadenectomy. Landry et al., [6], found that anastomosis was the most common site of local failure (25%), while Papachreistou and Fortner (1981) [24], reported that remnant stomach was the most common site of local recurrence (22%). Our study found that remnant stomach was the commonest site of local failure constituted 7% of the patients, with lower recurrence rate compared with that reported by the previous two series, the reason for that might be attributed to adjuvant chemoradiotherapy. In the present study peritoneum and distant organs failure constituted 20.9% and 25.6% of all treated patients respectively. This result was comparable to that reported by Lim et al., [23] who analyzed the pattern of failure among 291 patients received chemoradiation after extended lymphadenectomy and found that peritoneum and distant relapse constituted 27.8% and 16.8% respectively. On the other hand Hyng-Silk et al., [25] reported lower rate of distant (9.7%) and peritoneal (6.4%) relapse than our study, suggesting that they used more effective chemotherapy regimens (one cycle of 5-FU and cisplatin followed by 4500cGy with capecitabine, then two additional cycles of 5-FU/Cisplatin). In the present study, age, sex, performance status, histology, Lauren type, grade and site of tumor were not statistically significant prognostic factor for any type of recurrence. Advanced stage of the disease and increase depth of tumor invasion were associated with statistically significant increase in isolated locoregional recurrence ( p=0.040) and mixed recurrence (p=0.012) respectively. Increase number of involved lymph nodes (p= 0.035) and advanced stage of the disease ( p=0.012) were associated with statistically significant increase in isolated hematogenous recurrence. A retrospective review of 367 patients who underwent an R0 resection found that advanced T stage, distal

7 Alia M.A. Attia, et al. 137 location, diffuse Lauren s subtype, and female gender were significantly associated with peritoneal metastases. Proximal location and male gender were associated with locoregional recurrence. Proximal location, early T stage, and intestinal Lauren s subtype were associated with distal recurrence. Extensive stage and nodal involvement, affect all pattern of recurrence [26]. The 4-year OAS rates were 51.3% and 4-year DFS rates were 46.4%, in our study. McDonald et al., reported comparable 4-year DFS and OAS rates in the adjuvant chemoradiotherapy group (45% and 48% respectively) [11]. An update of this study showed maintained significant improvements in DFS (HR 1.52) and OS (HR 1.31) in the chemoradiotherapy arm after a median follow up of more than 10 years [12]. Lim et al., [23] showed higher DFS (64%) and OAS (67%) rates which could be explained by the fact that the reported study, in contrast to our study, included more favorable stages (pt1 and pt2). A detailed review published in 1995 by Hermanek and Wittekind [27] concluded that, all large multivariate studies in gastric cancer found tumour stage and nodal status to have a significant prognostic influence on survival, but the role of other variables is less clear. The current study showed that by multivariate analysis, disease stage was the only statistically significant prognostic factor affecting OAS, (HR: 4.248; 95% CI: ). The potential limitation of this study is the fact that information about some patients was incomplete in view of the retrospective nature of the study; this required omission of these patients leading to small number of patients included in the current study. This study included only patients who were evaluated and treated at (SECI), which may not reflect the whole population in Egypt. However, despite this limitation, the study has provided local data that can help in the management of patients with gastric cancer. 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