|Year : 2015 | Volume
| Issue : 2 | Page : 369-374
Adjuvant chemoradiation versus chemotherapy for stage III gastric cancer after surgery with curative intent
Sevim Turanli, Can Atalay, Ugur Berberoglu, Kaptan Gulben
Department of General Surgery, Ankara Oncology Education and Research Hospital, Demetevler, Ankara, Turkey
|Date of Web Publication||7-Jul-2015|
Department of General Surgery, Ankara Oncology Education and Research Hospital, Demetevler-06200, Ankara
Source of Support: None, Conflict of Interest: None
Objective: Gastric cancer is often diagnosed at an advanced stage and surgery alone cannot guarantee satisfactory results. Both chemoradiotherapy (CRT) and chemotherapy (CT) are used in postoperative therapy. However, it is controversial whether CRT or CT is better after D2 lymphadenectomy. In this study we investigated the efficacy of adjuvant CRT versus CT in stage III gastric cancer patients treated with R0 gastrectomy and D2 lymph node dissection.
Patients and Methods: Data from 92 patients diagnosed with gastric adenocarcinoma and treated with surgery followed by adjuvant treatment were retrospectively analyzed. Patients were classified into two groups depending on type of adjuvant treatment such as CT (Arm A) and CRT (Arm B).
Results: Twenty-one patients in Arm A and 71 patients in Arm B were included. Median age at diagnosis was 60 years. The median follow-up time was 30 months. No difference in local recurrence (14.3 vs 15.7%, P = 0.89), peritoneal recurrence (29.4 vs 23.5%, P = 0.62), and distant metastases rates (57.1 vs 45.1%, P = 0.42) were observed between the arms. Disease-free survival (DFS) rates did not differ between Arms A and B (26 and 22 months, P = 0.80) respectively. Median overall survival (OS) in Arm A was 29 months and it was 32 months for Arm B. There was no difference in 5-year OS and DFS between Arms A and B (23.8 vs 34.4%, P = 0.74; and 24.1 vs 32.9%, P = 0.80).
Conclusions: Adjuvant CRT does not appear to improve clinical outcomes compared to adjuvant CT in this study and prospective studies are required to confirm these results.
Keywords: Adjuvant treatment, chemoradiotherapy, chemotherapy, gastric carcinoma, survival
|How to cite this article:|
Turanli S, Atalay C, Berberoglu U, Gulben K. Adjuvant chemoradiation versus chemotherapy for stage III gastric cancer after surgery with curative intent. J Can Res Ther 2015;11:369-74
|How to cite this URL:|
Turanli S, Atalay C, Berberoglu U, Gulben K. Adjuvant chemoradiation versus chemotherapy for stage III gastric cancer after surgery with curative intent. J Can Res Ther [serial online] 2015 [cited 2019 Sep 18];11:369-74. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/369/160050
| > Introduction|| |
Gastric carcinoma still represents one of the main causes of death due to cancer in the world. Surgery is the only potentially curative treatment for localized gastric cancer. Complete tumor removal with a sufficient resection margin plus extended lymph node dissection is considered to be the most important factor in terms of reduced locoregional recurrence and improved survival.  However, surgery cannot detect and remove satellite micrometastases around the primary tumor and the tumor cells disseminated during operative maneuvers. Surgery alone cannot guarantee satisfactory results for patients with advanced disease.  Overall survival (OS) of patients who undergo surgery progressively diminishes as stage increases, ranging from 75% for stage I to 35% or less for stage II and beyond.  The use of multimodal therapies (chemotherapy (CT) and radiotherapy (RT), alone or combined, used in the neoadjuvant, intraoperative, or adjuvant setting) could improve the outcomes by acting on the remaining tumor.  Despite the benefit of adjuvant therapy has been clearly demonstrated, no general consensus has been still reached on the best treatment option. Treatment choices vary widely based on the different geographic areas, with CT alone more often preferred in Europe or Asia and chemoradiotherapy (CRT) in the United States. The reason for different approaches is mainly due to the fact that less than D2 lymph node dissection is routinely used in the United States, whereas D2 dissection is the standard treatment in Europe. Thus, optimal local control may be obtained by adding RT to D0-D1 dissection.  In countries where D2 lymph node dissection is performed, the effect of RT on locoregional recurrence is controversial. Therefore, it is necessary to investigate whether radiation added to adjuvant CT further improves survival.
Both CRT and CT are used in postoperative adjuvant therapy for resected gastric cancer. However, it is controversial whether CRT or CT is the optimal strategy for patients with gastric cancer after D2 lymphadenectomy. The aim of the study is to evaluate the efficacy of adjuvant CRT versus CT in stage III gastric cancer patients treated with R0 gastrectomy and D2 lymph node dissection on disease-free survival (DFS), OS, and patterns of failure.
| > Patients and methods|| |
The data were collected retrospectively and approved by our institutional ethics committee.
Between June 2004 and December 2009, the data from patients who were diagnosed with gastric carcinoma (including Siewert type II and III adenocarcinoma of the gastroesophageal junction) and treated with surgery followed by CT or CRT at tertiary oncology referral center were retrospectively analyzed. The inclusion criteria of the patients are as follows: (i) Patients with histologically confirmed adenocarcinoma of the stomach, (ii) all cases classified as stage III, according to the staging criteria established by the American Joint Committee on Cancer (AJCC, 7 th edition),  and (iii) patients with no history of any other cancer or previous RT or CT. The exclusion criteria of the patients are as follows: (i) Patients who developed secondary malignancy during the follow-up period, (ii) patients who were unable to tolerate CT or CRT because of other systemic illnesses or any other reason. Patients included in the study were classified into two groups depending on the type of adjuvant treatment. Patients assigned to Arm A received CT regimens and to Arm B received CRT.
All patients underwent surgical resection of tumor with negative margins without residual disease (R0 gastrectomy) and D2 lymph node dissection. This procedure entails the resection of the involved proximal or distal part of the stomach or the entire stomach including the greater and lesser omental lymph nodes, the removal of the anterior leaf of the transverse mesocolon, and all the nodes along the corresponding arteries depending on the location of the tumor. Postoperative adjuvant treatment was planned according to patient's city of residence, and patient's and surgeon's preferences. Arm A patients received six cycles of 5-fluorouracil (FU) 425 mg/m 2 and leucovorin (LV) 20 mg/m 2 for 5 days, q 28 days (in nine patients) or six cycles of FU, cisplatin, and epirubicin (ECF; epirubicin 50 mg/m 2 , cisplatin 60 mg/m 2 on day 1, and continuous infusion of FU 200 mg/m 2 through days 1-21, q 21 days; in 12 patients). Arm B patients were subjected to CT 4-6 weeks after the operation. After one cycle of FU and LV CT (CT regimen consisted of 425 mg/m 2 of FU per day plus 20 mg/m 2 of LV per day for 5 days), 45 Gy of regional RT (1.8 Gy/day 5 days/week) for 5 weeks, with FU and LV on the first 4 and the last 3 days of RT was given. RT was given 28 days after the beginning of the initial cycle of CT. Four weeks after the completion of RT, the patients received two additional cycles of FU and LV given every 28 days. RT was delivered with linear accelerators with nominal energy of 6 and/or 18 MV, through parallel-opposed anteroposterior-posteroanterior (AP-PA) fields. Target volume included the tumor bed identified on the preoperative computed tomography, the anastomoses, the stomach remnant, as well as the regional lymphatics. In cases of proximal T3 lesions, the medial left hemidiaphragm was also included in the radiation fields. The regional lymph nodes irradiated were the perigastric, celiac, local paraortic, pancreaticoduodenal, portal, hepatic, and splenic nodes. In patients with lesions of the antrum, the splenic nodes could be excluded. In patients with proximal lesions, exclusion of the pancreaticoduodenal nodes was allowed.
Follow-up and definition of recurrence
After the completion of planned adjuvant treatment, regular follow-up including a physical examination, complete blood counts, biochemical examination, carcinoembryonic antigen and carbohydrate antigen 19.9, and chest radiography was conducted. All patients in both groups had ultrasonography and/or abdominopelvic tomography and gastroscopy at 6-month intervals and annually thereafter. After treatment was completed, patients were seen every 3 months during the 1 st year, follow-up was every 6 months in the 2 nd year, and then annually until 5 years. Disease local recurrence, metastasis, and deaths were documented.
The sites of recurrence were classified as follows: Locoregional, peritoneal, and distant metastases. Locoregional recurrence was defined as recurrence at the anastomotic site, duodenal stump, tumor bed, or remnant stomach or at the regional lymph nodes within the radiation field; as peritoneal, if the tumor was detected within the peritoneal cavity; and as distant, if the metastases were diagnosed outside the peritoneal cavity or lymph node recurrence outside the radiation field, liver metastasis, or metastasis of other extra-abdominal sites. If two or more failure sites developed simultaneously, they were counted separately.
The primary end point of the study was OS with DFS, and patterns of failures. OS was defined as the time elapsed between the date of surgery and disease-related death or the date of last contact with the patient. DFS was calculated starting from the date of surgery to the date of recurrence detected by computed tomography and/or upper gastrointestinal endoscopy. Death without verified disease progression was considered as an event in the DFS analysis. Patterns of failure were defined as locoregional, peritoneal, and distant metastases. Chi-square test was utilized to compare patient characteristics between treatment arms for categorical variables; and continuous variables such as age and number of involved lymph nodes was evaluated by Student's t-test and tumor size, number of dissected lymph nodes, and lymph node ratio were tested by Mann-Whitney U test. Kaplan-Meier method was used for estimation of survival distribution, and differences in survival were evaluated by the log-rank statistics. P - values <0.05 were considered statistically significant. All analyses were carried out using Statistical Package for Social Sciences (SPSS) software (version 21.0; SPSS Inc, Chicago, IL).
| > Results|| |
Total of 92 patients were included in this study; 21 patients in Arm A and 71 patients in Arm B. Median age at diagnosis was 60 years (range 25-77). The tumor was located in the antrum in 50, in the corpus in 32, in the cardia in seven, and as linitis plastica in three other patients. Stage distribution was as follows; 28.2% of patients in stage IIIA, 34.8% in stage IIIB, and 37.0% in stage IIIC. All patients had undergone surgery with curative intent either with total (39 patients, 42.4%) or subtotal gastrectomy (53 patients, 57.6%).
Patients' baseline characteristics were well balanced between the treatment groups [Table 1]. The median follow-up time was 30 months (range 8-112 months). During the follow-up period, 69 patients (75.0%) developed recurrent or metastatic disease, while 68 patients (73.9%) died due to their tumor. Recurrence was observed in 16 patients (76.2%) and in 53 patients (74.6%) in CT and CRT arm, respectively. Fifteen deaths (71.4%) in Arm A and 53 deaths (74.6%) in Arm B occurred (P = 0.76). Death without verified disease progression was developed in 27 patients. Due to this reason, patterns of failure were investigated in 65 patients. No difference in local recurrence rates were observed between the two arms (14.3 vs 15.7%, P = 0.89). Peritoneal recurrence was noted in five patients (29.4%) in Arm A and 12 patients (23.5%) in Arm B (P = 0.62). Additionally, eight patients (57.1%) had evidence of distant metastases in Arm A and 23 patients (45.1%) in Arm B (P = 0.42).
|Table 1: Comparison of various clinicopathological parameters between patients in two adjuvant treatment groups|
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Median OS and DFS rates for all patients were 31 (24-38) and 26 (16-36), respectively. Median OS in CT arm was 29 months and it was 32 months for CRT arm. DFS rates did not differ statistically between the two arms (26 and 22 months for CT and CRT, respectively, P = 0.80). There was no significant difference in 5-year OS and DFS between Arms A and B [23.8 vs 34.4%, P = 0.74; [Figure 1]; and 24.1 vs 32.9%, P = 0.80; [Figure 2]].
|Figure 1: Effect of adjuvant treatment on overall survival with Kaplan-Meier curve|
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|Figure 2: Effect of adjuvant treatment on disease-free survival with Kaplan-Meier curve|
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| > Discussion|| |
Gastric cancer is often diagnosed at an advanced stage, except in countries where nationwide screening programs are enforced. Surgery with curative intent remains the main treatment of gastric cancer. However, surgery alone cannot be sufficient for patients with advanced disease and other nonsurgical treatment modalities such as CT and RT have to be taken into account, although their role is still controversial.  It is generally accepted that perioperative CT is appropriate for patients who had T1-2 N2-3 or T3-4 gastric cancer. On the other hand, adjuvant CRT is classified as appropriate for T1-2 N1-3 or T3-4 proximal gastric cancer and for T1-2 N2-3 or T3-4 distal gastric cancer.  However, treatment choices vary widely based on geographic areas.
Over the last few decades, numerous randomized controlled trials have been conducted to evaluate the benefit of adjuvant CT as compared to surgery alone. , A statistically significant survival advantage could not be demonstrated in these studies. Subsequently, study-based meta-analyses have been performed to evaluate to role of adjuvant CT and a small survival benefit was demonstrated. , In 2013, Cochrane meta-analysis reviewing randomized controlled trials of adjuvant CT vs surgery alone reported a significant improvement of OS (hazard ratio (HR) =0.85; 95% confidence interval (CI): 0.80-0.90; 34 studies) and DFS (HR = 0.79; 95% CI: 0.72-0.87; 15 studies) for adjuvant CT.  Based on these results, adjuvant CT was offered as a routine treatment following curative resection for gastric cancer. On the other hand, due to the high risk of local recurrence, different studies have been evaluating the potential benefit of RT alone or in combination with CT as adjuvant treatments for gastric cancer treated with curative D2 lymph node dissection. ,, INT0116 study randomly assigned stage IB-IV gastric cancer patients to surgery plus adjuvant CRT or surgery alone.  CT with bolus 5-FU/LV was intermingled by a "sandwich" chemoradiation phase in which 5-FU/LV was given on the first four and the last three days of RT. After more than 10 years of follow-up a persistent benefit was demonstrated for CRT group in terms of both OS and DFS.  This study can be criticized due to the fact that only 10% of patients had a D2 dissection and more than half of patients did not even have dissection of perigastric lymph nodes (D1). Furthermore, most of the patients on this study had T3/T4 disease and 85% had nodal metastases.
Since adjuvant CT and CRT demonstrated better outcomes compared to surgery, it is recommended for gastric cancer patients. CT is accepted as the standard treatment and was compared to CRT in terms of DFS and OS in the current studies.
In a retrospective study, outcomes of CT and CRT after D2 lymph node dissection in pN3 gastric cancer patients were compared.  CRT consisted of bolus 5-FU and LV before, after, and during RT; whereas, CT consisted of combination therapies involving 5-FU and cisplatin as the main drugs. OS and DFS rates did not differ statistically. In another study evaluating locally advanced gastric cancer patients (stage IIIA, IIIB, and IV (M0)), CT consisting of 5-FU and cisplatin was compared to CRT.  Three-year and 5-year DFS and OS of the patients were similar. In a similar study, patients with radically resected T3/T4 and/or N + gastric cancer were randomized to docetaxel and cisplatin CT alone or the same treatment with RT.  No statistically significant difference in OS and DFS was found between the two groups. In another study, CT alone with CRT in stage III-IV (M0) gastric cancer patients treated with R0 gastrectomy and D2 lymph node dissection were compared.  Addition of radiation therapy to CT significantly improved locoregional recurrence-free survival but not DFS. In subgroup analysis for stage III patients, CRT significantly prolonged 5-year locoregional recurrence-free survival and DFS rates compared with CT.
A meta-analysis including 895 patients in randomized controlled trials which compared postoperative CRT vs CT concluded that postoperative CRT improved local recurrence-free survival (HR = 0.53; 95% CI: 0.32-0.87) and DFS (HR = 0.72; 95% CI: 0.59-0.89), but not OS (HR = 0.79; 95% CI: 0.61-1.03).  However, the study was based only on three Asian studies and the results may not be extrapolated to Western patients. In a recent meta-analysis, overall benefit of RT in gastric cancer patients was evaluated.  Among 12 studies investigating the effect of RT in various situations, four studies testing adjuvant CRT against adjuvant CT, reported a trend towards improved OS with the use of combined modality therapy. In addition, significant DFS improvement was seen in the five trials comparing CRT to adjuvant CT.
A multicentric trial of Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) included 458 patients who received curative D2 gastrectomy for cancer and randomized to receive either CT or CRT after surgery.  Three-year DFS rates were similar in both groups. However, in patients with lymph node metastases, DFS was longer in the CRT than in CT group. In multivariate analysis, the duration of stage adjusted DFS was positively influenced by CRT in cases with lymph node metastasis. In our study although all patients had lymph node metastases, addition of RT to CT after curative surgery did not show any beneficial effect on DFS and OS.
An ongoing phase III trial (ARTIST-II) was designed to compare CT alone vs CRT in lymph node-positive gastric cancer patients treated with surgery, aiming at prospectively confirming ARTIST trial results.  Similarly, Chemoradiotherapy After Induction CT of Cancer in the Stomach (CRITICS) trial (NCT00407186) is currently investigating perioperative treatment with epirubicin, cisplatin, and capecitabine CT alone versus epirubicin, cisplatin, and capecitabine CT followed by CRT in patients with gastric cancer after D1 or greater resection. In addition, multinational prospective randomized TOPGEAR study will provide additional data regarding CRT versus CT for gastric cancer. 
| > Conclusion|| |
Our results indicate that adjuvant CRT does not appear to improve local recurrence, DFS, and OS in stage III patients with radically resected gastric cancer with D2 lymph node dissection compared to adjuvant CT. However, this study is retrospectively designed and a prospective phase III trial is required to confirm this results.
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[Figure 1], [Figure 2]