Journal of Surgical Oncology 2015;111:277–284
Adjuvant Chemoradiotherapy Versus Chemotherapy for Gastric Cancer: A Meta-Analysis of Randomized Controlled Trials QIANG DAI, MM,1 LEI JIANG, MD,2 RUI-JIANG LIN, MM,1 KONG-KONG WEI, MM,1 LIANG-LIANG GAN, MM,1 CHENG-HUI DENG, MM,1 AND QUAN-LIN GUAN, MD2* 1
The First Clinical Medical College of Lanzhou University, Lanzhou, China 2 The First Hospital of Lanzhou University, Lanzhou, China
Objective: The aim of this study was to evaluate the efficacy and safety of adjuvant chemoradiotherapy (CRT) versus chemotherapy (CT) for patients with gastric cancer. Methods: Electronic databases including PUBMED, EMBASE, and Cochrane Library were retrieved for original studies from their inception to April 2014. Two reviewers independently evaluated the quality of the included studies and extracted the data. All Statistical analyses were performed using RevMan Version 5.2 software. Results: Six randomized controlled trials involving 1,171 patients were included. The meta‐analysis showed that there were statistical significances between chemoradiotherapy group and chemotherapy group in 5‐year disease free survival rate (OR ¼ 1.56, 95% CI: 1.09–2.24), local‐regional recurrence rate (OR ¼ 0.46, 95% CI: 0.32–0.67) and neutropenia (OR ¼ 1.47, 95% CI: 1.11–1.96). While treatment efficacy did not differ significantly by the 5‐year overall survival rate (OR ¼ 1.32, 95% CI: 0.92–1.88), 3‐year disease free survival rate (OR ¼ 1.28, 95% CI: 0.92–1.80), and new metastases (OR ¼ 0.76, 95% CI: 0.57–1.03). Toxicities were not significantly different between two groups for nausea/vomiting, diarrhea, anemia, and thrombocytopenia. Conclusions: For patients with gastric cancer, adjuvant chemoradiotherapy could significantly improve 5‐year disease free survival rate and reduce local‐regional recurrence rate compared with chemotherapy and, can be well accepted and tolerated.
J. Surg. Oncol. 2015;111:277–284. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: gastric cancer; chemoradiotherapy; surgery; meta‐analysis
INTRODUCTION In recent years, the incidence and mortality rates of gastric cancer have continued to decrease in most countries worldwide [1]. However, it still remains the fourth most common cancer and the second most common cause of death from cancer with a total of 989,600 new gastric cancer cases and 738,000 deaths estimated to have occurred in 2008 [2]. There are several treatment options for gastric cancer such as surgery, chemotherapy, and radiotherapy [3]. And curative resection has been accepted as the foremost and effective treatment among them. Although the concept and experience of surgical treatment keep being improved during these years, the efficacy of surgical treatment alone appears to have reached the vertex since loco‐regional and distant recurrence rates still remain high levels [4,5]. In some developing areas, approximately 80% of patients with a diagnosis of gastric cancer are in advanced disease stages, which results in a poor prognosis that 5‐year survival rate is only 30–50% after surgical resection [6]. In order to improve survival outcomes after surgical resection for these gastric cancer patients, several studies have been conducted to compare adjuvant therapies including chemotherapy, radiotherapy and chemoradiotherapy with surgery alone [5,7,8]. In 2001, the results of the famous INT‐0116 trial demonstrated that adjuvant chemoradiotherapy significantly improved the overall survival and relapse‐free survival compared with surgery alone [7]. Likewise, a statistically‐significant 3‐ year overall survival benefit was found in patients who accepted adjuvant chemotherapy in another randomized trial [8]. This result has also been supported by a recent meta‐analysis [9]. Based on the above report data, we can deduce that both adjuvant chemoradiotherapy and chemotherapy are effective therapies to improve the survival of gastric cancer patients. But receiving chemotherapy might suffer higher toxicity and cost more than chemoradiotherapy. As
ß 2014 Wiley Periodicals, Inc.
the efficiency of the two therapies still remain unclear, it is necessary to carry out a meta‐analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐analyses Statement (PRISMA) by pooling data from all of the available RCTs published to date [10]. Thus, we could evaluate the efficacy and safety of these two therapies and offer an appropriate treatment option for the patients diagnosed with gastric cancer.
METHODS Literature SEARCH Electronic databases (PUBMED, EMBASE, Cochrane Controlled Trials Register) were searched from inception till April 2014 to identify relevant studies. Combination of Free text terms and Medical Subject Headings (MeSH) terms were used for the subject search. Search terms included: “gastric cancer ,” “stomach cancer ,” “gastric neoplasm ,”“stomach neoplasm ,” “chemoradiotherapy,” “chemotherapy.” The search was
*The purpose of adding an asterisk symbol after the Mesh term was to prevent the miss detection of literatures. Conflict of interest: All the authors indicated no potential conflicts of interest. *Correspondence to: Quan‐Lin Guan, MD, Surgical Oncology Department, The First Hospital of Lanzhou University, 1 Dong gang Road, Cheng Guan District, Lanzhou, Gansu 730000, China. Fax: þ86‐931‐8625200. E‐mail: [email protected] Received 12 June 2014; Accepted 29 August 2014 DOI 10.1002/jso.23795 Published online 1 October 2014 in Wiley Online Library (wileyonlinelibrary.com).
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limited to RCTs published in English. Additionally, references of included studies and related reviews were manually reviewed to further identify other potentially eligible studies.
Data Selection Two reviewers (Qiang Dai and Lei Jiang) independently assessed every retrieved study for inclusion. The inclusion criteria were as follows: (1) Included study papers were published in English. (2) Included studies were randomized controlled trials that conducted on the treatment of gastric cancer with adjuvant chemoradiotherapy and chemotherapy. (3) The participants included must be 318 years and histologically or cytologically confirmed gastric cancer. (4) The participants included should have adequate function of major organs (including cardiac, hepatic, bone marrow, and renal function); and not previously treated for disease with any regimen of chemotherapy or radiotherapy.
Statistical Analysis We anticipated heterogeneity between studies due to different methods of analysis, different lag exposures, and population differences. In this meta‐analysis, RevMan 5.2 software, developed by the Cochrane Collaboration, was used to analyze the data. Enumeration data and measurement data were carried out for statistical efficacy analysis using odds ratio (OR), mean and standard deviation (SMD) respectively. Statistical heterogeneity between studies was examined using the x2 test and the I2 statistic. The heterogeneity was considered minimal when I2 < 25%; moderate, when 25% < I2< 50%; and substantial, when I2 50%. If there was no statistically significant heterogeneity in a given set of data, the fixed effects model was used for meta‐analysis. If the results of trials showed heterogeneity, the random effects model was used. If heterogeneity among the groups is too large, the descriptive analysis was used. P values 0.05 were considered statistically significant. A funnel plot was applied for detecting publication bias in the meta‐analysis.
Data Extraction Data collection and analysis were performed according to a standard Cochrane protocol [11]. The same two reviewers independently reviewed eligible studies for study characteristics and clinical relevance. All disagreements were resolved by an independent third reviewer (Quan‐lin Guan). If feasible, the data were extracted. The following information were extracted onto standardized data collection forms: author, trial title and year of publication, study design, length of follow‐up, number of participants and their basic characteristics.
Outcome Definition OS was measured from the date of randomization until death from any cause and surviving patients were censored at the date of last contact. DFS was defined as the time from the date of randomization to the date of relapse or the last contact for patients who did not experience a relapse. Loco‐regional recurrence was defined as a relapse in the anastomosis site, tumor bed, or remnant stomach or in the regional lymph nodes within the radiation field. Distant metastasis was defined as lymph node recurrence outside the radiation field, peritoneal seeding, liver metastasis, or metastasis of other extra‐abdominal sites. Grade 3–4 toxicity was defined as severe, life‐threatening or disabling adverse events according to NCI Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) [12] with the severity of nausea/vomiting and diarrhea are upper separate 6 and 7 episodes in 24 hr or have the life‐threatening consequences; the severity degree of anemia as hemoglobin are ranged from 65 to 80 g/L for grade 3 or lower for grade 4, while the severity of thrombocytopenia as plate are ranged from 25 to 50 109/L for grade 3 or lower for grade 4; the severity of neutropenia is counted as the absolute neutrophil count 60, (31.8%)
Korea
34 (73.9) 12 (26.1) >60, (19.6%)
46
CRT
Kim et al. [17]
(21.3) (36.5) (30.8) (11.3)
50 86 65 27
(21.9) (37.7) (28.6) (11.8)
130 (57.0) 88 (38.6) 10 (4.4) XP 1 (0.4)
45
53.2 (36.9–77.3)
188 (81.7) 172 (75.4) Negative 3‐year DFS
144 (62.6) 75 (32.6) 11 (4.8) XPþ3D‐CRT 1 (0.4)
D2 40 (12–84) 40 (13–142) Adenocarcinoma
49 84 71 26
228
CT
153 (67.1) 75 (32.9) 56 (22–77)
Korea
143 (62.2) 87 (37.8) 56 (28–76)
230
CRT
Lee et al. [18]
D2
15 (9.1) 30 (18.2) 96 (58.2) 24 (14.5)
FL 0
45
186 (100.0) 165 (100.0) Negative 5‐year DFS 5‐year OS 42.5
FLþIMRT 0
Adenocarcinoma
20 (10.8) 36 (19.4) 103 (55.4) 27 (14.5)
165
CT
126 (76.4) 39 (23.6) 59 (42–75)
China
135 (72.9) 51 (27.1) 56 (38–73)
186
CRT
Zhu et al. [19]
CRT, chemoradiotherapy; CT, chemotherapy; RT, radiotherapy; FP, 5‐FUþ cisplatin; DC, docetaxel þ Cisplatin; LV, leucovorin FL, fluorouracil þ leucovorin; XP, capecitabine þ cisplatin. Data not available; 3D‐CRT, 3D conformal radiotherapy; IMRT, intensity modulated radiotherapy; LN, lymph node.
Median follow up (months) Total RT does (Gy)
Characteristics Population Total number Sex No. (%) Male Female Age (years) Tumor stage no. (%) IB II III IV (M0) Lymphadenectomy No. of dissected LNs Pathological type Lauren classification No. (%) Diffuse Intestinal Mixed/unclassified Treatment regimens Treatment‐related death No. (%) Treatment completion No. (%) Surgical margins Primary endpoints
Refs
Kwon et al. [14]
TABLE I. Characteristics of the Included Studies
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Fig. 2. Risk of bias summary.
with positive tumors was 63.2 months (HR ¼ 0.51, 95% CI: 0.26–1.00, P ¼ 0.046) [15]. Generally, OS would be increased as the local‐regional recurrence rate reduces. In our analysis, however, a better local‐regional recurrence rate was observed in the CRT group, while OS in the two groups was similar. It may be because patients at stage of III_IV (M0) took a big proportion no less than 60%. For those patients at early stages,
Fig. 3. Journal of Surgical Oncology
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OS increased as loco‐regional control improved, but the prognosis was still poor for patients at an advanced stage even if loco‐regional recurrence was controlled since the lymph node metastasis occurred more frequently and the nutritional station was worse. Therefore we can still not learn about the relationship among OS, DFS, and TNM stage clearly. But the ongoing CRITICS trial (Chemoradiotherapy After Induction Chemotherapy of Cancer in the Stomach) (NCT00407186), which compared perioperative chemotherapy treatment with epirubicin, cisplatin, and capecitabine chemotherapy versus epirubicin, cisplatin, and capecitabine chemotherapy followed by CRT (45 Gy with 5 fractions with weekly cisplatin and daily capecitabine) in patients with gastric cancer after D1 or greater resection, might bring a better outcome as expected when it ended. On the other hand, operation types of lymphadenectomy differed in the included studies. Gastrectomy with D2 lymph node dissection was the standard treatment for resectable gastric cancer in eastern Asia while D2 lymph node dissection was considered as a recommended but not an indispensable procedure in the west [28]. Besides, only three of the involved studies reported the median number of dissected lymph nodes ranged from 14 to 47. Obviously, the more lymph nodes dissected, the better prognosis would be. Thus, a potential bias may exist and influence the result. The severity of toxicity may have a serious influence on the life of quality and treatment tolerance in patients, however, our results demonstrated that there was no significant difference of hematologic and gastrointestinal toxicities (except lower neutropenia in the chemoradiotherapy group (OR ¼ 1.47, 95% CI: 1.11–1.96; P ¼ 0.008), which could increase the risk of infection and weakness) [29]. Katakami et al. [30] recruited non‐small cell lung cancer patients at stage IIIA for a phase III study and it showed that preoperative adjuvant chemoradiotherapy conferred better local control without significant adverse events. In addition, some potential sources of limitations needed to be pointed out: (1) Different chemotherapy regimens and drugs as well as radiotherapy patterns and target volumes were used, which might lead an inherent difference. (2) Although the basic characteristics of the two groups were well balanced, potential confounding factors could not be all taken into our consideration such as the nutritional status and postoperative surgical complications which were not mentioned in any included studies. (3) Although no evidence of publication bias was found in this meta‐analysis using Begg’s funnel plot, the bias remains a main concern for all meta‐analysis [31]. To our knowledge, positive outcomes are inclined to be accepted by journals, whereas those negative ones are often reported in a briefer way or even rejected. (4) Our meta‐ analysis was restricted to full publications in English language, which probably missed some potential eligible studies in other languages. (5) The results of this meta‐analysis were based on studies with relatively small sample sizes so that they should be interpreted cautiously. More well‐designed and large scale RCTs for the comparison of adjuvant
Forest plot of 5‐year OS comparing CRT with CT.
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Fig. 4. Forest plot of 3‐year DFS comparing CRT with CT.
Fig. 5. Forest plot of 5‐year DFS comparing CRT with CT.
Fig. 6. Forest plot of local‐regional recurrence rate comparing CRT with CT.
Fig. 7. Journal of Surgical Oncology
Forest plot of new metastases comparing CRT with CT.
Meta‐Analysis for Gastric Cancer
Fig. 8.
Forest plot of grade 3–4 toxicity comparing CRT with CT.
chemoradiotherapy with chemotherapy in gastric cancer should be conducted for further studies. In conclusion, our meta‐analysis suggested that chemoradiotherapy could be well tolerated and might have an advantage in Journal of Surgical Oncology
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local‐regional recurrence rate and 5‐year disease but no advantage was observed in overall with positive lymph nodes and ERCC1 positive a potential prognosis benefit. However, further
free survival rate, survival; patients tumors may have larger prospective
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Fig. 9. Funnel plot. CRT, chemoradiotherapy; CT, chemotherapy.
studies with different adjuvant approaches are needed to strengthen our findings.
REFERENCES 1. Ferro A, Peleteiro B, Malvezzi M, et al.: Worldwide trends in gastric cancer mortality (1980–2011), with predictions to 2015, and incidence by subtype. Eur J Cancer 2014;50:1330–1344. 2. Jemal A, Bray F, Center MM, et al.: Global cancer statistics. CA Cancer J Clin 2011;61:69–90. 3. Orditura M, Galizia G, Sforza V, et al.: Treatment of gastric cancer. World J Gastroenterol 2014;20:1635–1649. 4. Yamamoto M, Sakaguchi Y, Matsuyama A, et al.: Surgery after preoperative chemotherapy for patients with unresectable advanced gastric cancer. Oncology 2013;85:241–247. 5. Kim S, Lim DH, Lee J, et al.: An observational study suggesting clinical benefit for adjuvant postoperative chemoradiation in a population of over 500 cases after gastric resection with D2 nodal dissection for adenocarcinoma of the stomach. Int J Radiat Oncol Biol Phys 2005;63:1279–1285. 6. Persiani R, D’Ugo D, Rausei S, et al.: Prognostic indicators in locally advanced gastric cancer (LAGC) treated with preoperative chemotherapy and D2‐gastrectomy. J Surg Oncol 2005;89: 227–236; discussion 237–228. 7. Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345:725–730. 8. Sakuramoto S, Sasako M, Yamaguchi T, et al.: Adjuvant chemotherapy for gastric cancer with S‐1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–1820. 9. Paoletti X, Oba K, Burzykowski T, et al.: Benefit of adjuvant chemotherapy for resectable gastric cancer: A meta‐analysis. JAMA 2010;303:1729–1737. 10. Moher D, Liberati A, Tetzlaff J, et al.: PRISMA Group Preferred reporting items for systematic reviews and metaanalyses: The PRISMA statement. Ann Intern Med 2009;151:264–269. 11. Furlan AD, Pennick V, Bombardier C, et al.: 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine 2009;34:1929–1941. 12. Trotti A, Colevas AD, Setser A, et al.: CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176–181. 13. Higgins JPT, Green S: Cochrane handbook for systematic reviews of interventions, version 5.1.0.2011, http://handbook.cochrane.org/ .
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14. Kwon HC, Kim MC, Kim KH, et al.: Adjuvant chemoradiation versus chemotherapy in completely resected advanced gastric cancer with D2 nodal dissection. Asia Pac J Clin Oncol 2010;6: 278–285. 15. Bamias A, Karina M, Papakostas P, et al.: A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol 2010;65:1009–1021. 16. Yu C, Yu R, Zhu W, et al.: Intensity‐modulated radiotherapy combined with chemotherapy for the treatment of gastric cancer patients after standard D1/D2 surgery. J Cancer Res Clin Oncol 2012;138:255–259. 17. Kim TH, Park SR, Ryu KW, et al.: Phase 3 trial of postoperative chemotherapy alone versus chemoradiation therapy in stage III–IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. Int J Radiat Oncol Biol Phys 2012;84:e585–e592. 18. Lee J, Lim do H, Kim S, et al.: Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: The ARTIST trial. J Clin Oncol 2012;30:268–273. 19. Zhu WG, Xua DF, Pu J, et al.: A randomized, controlled, multicenter study comparing intensity‐modulated radiotherapy plus concurrent chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection. Radiother Oncol 2012;104: 361–366. 20. Roukos DH, Kappas AM: Perspectives in the treatment of gastric cancer. Nat Clin Pract Oncol 2005;2:98–107. 21. Smalley SR, Benedetti JK, Haller DG, et al.: Updated analysis of SWOG‐directed intergroup study 0116: A phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol 2012;30:2327–2333. 22. Stessin AM, Sison C, Schwartz A, et al.: Does adjuvant radiotherapy benefit patients with diffuse‐type gastric cancer? Results from the surveillance, epidemiology, and end results database. Cancer 2014; DOI: 10.1002/cncr.28913 23. Zhang ZX, Gu XZ, Yin WB, et al.: Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)—Report on 370 patients. Int J Radiat Oncol Biol Phys 1998;42:929–934. 24. Valentini V, Cellini F, Minsky BD, et al.: Survival after radiotherapy in gastric cancer: Systematic review and meta‐ analysis. Radiother Oncol 2009;92:176–183. 25. Tsujitani S, Oka S, Suzuki K, et al.: Prognostic factors in patients with advanced gastric cancer treated by noncurative resection: A multivariate analysis. Hepatogastroenterology 2001;48:1504–1508. 26. Chau I, Norman AR, Cunningham D, et al.: Multivariate prognostic factor analysis in locally advanced and metastatic esophago‐gastric cancer—Pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004; 22:2395–2403. 27. Rivera F, Gravalos C, Garcia‐Carbonero R: SEOM clinical guidelines for the diagnosis and treatment of gastric adenocarcinoma. Clin Transl Oncol 2012;14:528–535.2012. 28. Ajani JA, Bentrem DJ, Besh S, et al.: Gastric cancer, version 2. 2013 featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2013;11:531–546. 29. Smalley SR, Benedetti JK, Haller DG, et al.: Neutropenia and invasive fungal infection in patients with hematological malignancies treated with chemotherapy: A multicenter, prospective, non‐ interventional study in China. Tumour Biol 2014;35:5869–5876. 30. Katakami N, Tada H, Mitsudomi T, et al.: A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer 2012;118:6126–6135. 31. Begg CB, Berlin JA: 1988;Publication bias: A problem in interpreting medical data. J R Stat Soc 1998:419–463.
Adjuvant Chemoradiotherapy Versus Chemotherapy for Gastric Cancer: A Meta-Analysis of Randomized Controlled Trials QIANG DAI, MM,1 LEI JIANG, MD,2 RUI-JIANG LIN, MM,1 KONG-KONG WEI, MM,1 LIANG-LIANG GAN, MM,1 CHENG-HUI DENG, MM,1 AND QUAN-LIN GUAN, MD2* 1
The First Clinical Medical College of Lanzhou University, Lanzhou, China 2 The First Hospital of Lanzhou University, Lanzhou, China
Objective: The aim of this study was to evaluate the efficacy and safety of adjuvant chemoradiotherapy (CRT) versus chemotherapy (CT) for patients with gastric cancer. Methods: Electronic databases including PUBMED, EMBASE, and Cochrane Library were retrieved for original studies from their inception to April 2014. Two reviewers independently evaluated the quality of the included studies and extracted the data. All Statistical analyses were performed using RevMan Version 5.2 software. Results: Six randomized controlled trials involving 1,171 patients were included. The meta‐analysis showed that there were statistical significances between chemoradiotherapy group and chemotherapy group in 5‐year disease free survival rate (OR ¼ 1.56, 95% CI: 1.09–2.24), local‐regional recurrence rate (OR ¼ 0.46, 95% CI: 0.32–0.67) and neutropenia (OR ¼ 1.47, 95% CI: 1.11–1.96). While treatment efficacy did not differ significantly by the 5‐year overall survival rate (OR ¼ 1.32, 95% CI: 0.92–1.88), 3‐year disease free survival rate (OR ¼ 1.28, 95% CI: 0.92–1.80), and new metastases (OR ¼ 0.76, 95% CI: 0.57–1.03). Toxicities were not significantly different between two groups for nausea/vomiting, diarrhea, anemia, and thrombocytopenia. Conclusions: For patients with gastric cancer, adjuvant chemoradiotherapy could significantly improve 5‐year disease free survival rate and reduce local‐regional recurrence rate compared with chemotherapy and, can be well accepted and tolerated.
J. Surg. Oncol. 2015;111:277–284. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: gastric cancer; chemoradiotherapy; surgery; meta‐analysis
INTRODUCTION In recent years, the incidence and mortality rates of gastric cancer have continued to decrease in most countries worldwide [1]. However, it still remains the fourth most common cancer and the second most common cause of death from cancer with a total of 989,600 new gastric cancer cases and 738,000 deaths estimated to have occurred in 2008 [2]. There are several treatment options for gastric cancer such as surgery, chemotherapy, and radiotherapy [3]. And curative resection has been accepted as the foremost and effective treatment among them. Although the concept and experience of surgical treatment keep being improved during these years, the efficacy of surgical treatment alone appears to have reached the vertex since loco‐regional and distant recurrence rates still remain high levels [4,5]. In some developing areas, approximately 80% of patients with a diagnosis of gastric cancer are in advanced disease stages, which results in a poor prognosis that 5‐year survival rate is only 30–50% after surgical resection [6]. In order to improve survival outcomes after surgical resection for these gastric cancer patients, several studies have been conducted to compare adjuvant therapies including chemotherapy, radiotherapy and chemoradiotherapy with surgery alone [5,7,8]. In 2001, the results of the famous INT‐0116 trial demonstrated that adjuvant chemoradiotherapy significantly improved the overall survival and relapse‐free survival compared with surgery alone [7]. Likewise, a statistically‐significant 3‐ year overall survival benefit was found in patients who accepted adjuvant chemotherapy in another randomized trial [8]. This result has also been supported by a recent meta‐analysis [9]. Based on the above report data, we can deduce that both adjuvant chemoradiotherapy and chemotherapy are effective therapies to improve the survival of gastric cancer patients. But receiving chemotherapy might suffer higher toxicity and cost more than chemoradiotherapy. As
ß 2014 Wiley Periodicals, Inc.
the efficiency of the two therapies still remain unclear, it is necessary to carry out a meta‐analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐analyses Statement (PRISMA) by pooling data from all of the available RCTs published to date [10]. Thus, we could evaluate the efficacy and safety of these two therapies and offer an appropriate treatment option for the patients diagnosed with gastric cancer.
METHODS Literature SEARCH Electronic databases (PUBMED, EMBASE, Cochrane Controlled Trials Register) were searched from inception till April 2014 to identify relevant studies. Combination of Free text terms and Medical Subject Headings (MeSH) terms were used for the subject search. Search terms included: “gastric cancer ,” “stomach cancer ,” “gastric neoplasm ,”“stomach neoplasm ,” “chemoradiotherapy,” “chemotherapy.” The search was
*The purpose of adding an asterisk symbol after the Mesh term was to prevent the miss detection of literatures. Conflict of interest: All the authors indicated no potential conflicts of interest. *Correspondence to: Quan‐Lin Guan, MD, Surgical Oncology Department, The First Hospital of Lanzhou University, 1 Dong gang Road, Cheng Guan District, Lanzhou, Gansu 730000, China. Fax: þ86‐931‐8625200. E‐mail: [email protected] Received 12 June 2014; Accepted 29 August 2014 DOI 10.1002/jso.23795 Published online 1 October 2014 in Wiley Online Library (wileyonlinelibrary.com).
278
Dai et al.
limited to RCTs published in English. Additionally, references of included studies and related reviews were manually reviewed to further identify other potentially eligible studies.
Data Selection Two reviewers (Qiang Dai and Lei Jiang) independently assessed every retrieved study for inclusion. The inclusion criteria were as follows: (1) Included study papers were published in English. (2) Included studies were randomized controlled trials that conducted on the treatment of gastric cancer with adjuvant chemoradiotherapy and chemotherapy. (3) The participants included must be 318 years and histologically or cytologically confirmed gastric cancer. (4) The participants included should have adequate function of major organs (including cardiac, hepatic, bone marrow, and renal function); and not previously treated for disease with any regimen of chemotherapy or radiotherapy.
Statistical Analysis We anticipated heterogeneity between studies due to different methods of analysis, different lag exposures, and population differences. In this meta‐analysis, RevMan 5.2 software, developed by the Cochrane Collaboration, was used to analyze the data. Enumeration data and measurement data were carried out for statistical efficacy analysis using odds ratio (OR), mean and standard deviation (SMD) respectively. Statistical heterogeneity between studies was examined using the x2 test and the I2 statistic. The heterogeneity was considered minimal when I2 < 25%; moderate, when 25% < I2< 50%; and substantial, when I2 50%. If there was no statistically significant heterogeneity in a given set of data, the fixed effects model was used for meta‐analysis. If the results of trials showed heterogeneity, the random effects model was used. If heterogeneity among the groups is too large, the descriptive analysis was used. P values 0.05 were considered statistically significant. A funnel plot was applied for detecting publication bias in the meta‐analysis.
Data Extraction Data collection and analysis were performed according to a standard Cochrane protocol [11]. The same two reviewers independently reviewed eligible studies for study characteristics and clinical relevance. All disagreements were resolved by an independent third reviewer (Quan‐lin Guan). If feasible, the data were extracted. The following information were extracted onto standardized data collection forms: author, trial title and year of publication, study design, length of follow‐up, number of participants and their basic characteristics.
Outcome Definition OS was measured from the date of randomization until death from any cause and surviving patients were censored at the date of last contact. DFS was defined as the time from the date of randomization to the date of relapse or the last contact for patients who did not experience a relapse. Loco‐regional recurrence was defined as a relapse in the anastomosis site, tumor bed, or remnant stomach or in the regional lymph nodes within the radiation field. Distant metastasis was defined as lymph node recurrence outside the radiation field, peritoneal seeding, liver metastasis, or metastasis of other extra‐abdominal sites. Grade 3–4 toxicity was defined as severe, life‐threatening or disabling adverse events according to NCI Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) [12] with the severity of nausea/vomiting and diarrhea are upper separate 6 and 7 episodes in 24 hr or have the life‐threatening consequences; the severity degree of anemia as hemoglobin are ranged from 65 to 80 g/L for grade 3 or lower for grade 4, while the severity of thrombocytopenia as plate are ranged from 25 to 50 109/L for grade 3 or lower for grade 4; the severity of neutropenia is counted as the absolute neutrophil count 60, (31.8%)
Korea
34 (73.9) 12 (26.1) >60, (19.6%)
46
CRT
Kim et al. [17]
(21.3) (36.5) (30.8) (11.3)
50 86 65 27
(21.9) (37.7) (28.6) (11.8)
130 (57.0) 88 (38.6) 10 (4.4) XP 1 (0.4)
45
53.2 (36.9–77.3)
188 (81.7) 172 (75.4) Negative 3‐year DFS
144 (62.6) 75 (32.6) 11 (4.8) XPþ3D‐CRT 1 (0.4)
D2 40 (12–84) 40 (13–142) Adenocarcinoma
49 84 71 26
228
CT
153 (67.1) 75 (32.9) 56 (22–77)
Korea
143 (62.2) 87 (37.8) 56 (28–76)
230
CRT
Lee et al. [18]
D2
15 (9.1) 30 (18.2) 96 (58.2) 24 (14.5)
FL 0
45
186 (100.0) 165 (100.0) Negative 5‐year DFS 5‐year OS 42.5
FLþIMRT 0
Adenocarcinoma
20 (10.8) 36 (19.4) 103 (55.4) 27 (14.5)
165
CT
126 (76.4) 39 (23.6) 59 (42–75)
China
135 (72.9) 51 (27.1) 56 (38–73)
186
CRT
Zhu et al. [19]
CRT, chemoradiotherapy; CT, chemotherapy; RT, radiotherapy; FP, 5‐FUþ cisplatin; DC, docetaxel þ Cisplatin; LV, leucovorin FL, fluorouracil þ leucovorin; XP, capecitabine þ cisplatin. Data not available; 3D‐CRT, 3D conformal radiotherapy; IMRT, intensity modulated radiotherapy; LN, lymph node.
Median follow up (months) Total RT does (Gy)
Characteristics Population Total number Sex No. (%) Male Female Age (years) Tumor stage no. (%) IB II III IV (M0) Lymphadenectomy No. of dissected LNs Pathological type Lauren classification No. (%) Diffuse Intestinal Mixed/unclassified Treatment regimens Treatment‐related death No. (%) Treatment completion No. (%) Surgical margins Primary endpoints
Refs
Kwon et al. [14]
TABLE I. Characteristics of the Included Studies
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Fig. 2. Risk of bias summary.
with positive tumors was 63.2 months (HR ¼ 0.51, 95% CI: 0.26–1.00, P ¼ 0.046) [15]. Generally, OS would be increased as the local‐regional recurrence rate reduces. In our analysis, however, a better local‐regional recurrence rate was observed in the CRT group, while OS in the two groups was similar. It may be because patients at stage of III_IV (M0) took a big proportion no less than 60%. For those patients at early stages,
Fig. 3. Journal of Surgical Oncology
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OS increased as loco‐regional control improved, but the prognosis was still poor for patients at an advanced stage even if loco‐regional recurrence was controlled since the lymph node metastasis occurred more frequently and the nutritional station was worse. Therefore we can still not learn about the relationship among OS, DFS, and TNM stage clearly. But the ongoing CRITICS trial (Chemoradiotherapy After Induction Chemotherapy of Cancer in the Stomach) (NCT00407186), which compared perioperative chemotherapy treatment with epirubicin, cisplatin, and capecitabine chemotherapy versus epirubicin, cisplatin, and capecitabine chemotherapy followed by CRT (45 Gy with 5 fractions with weekly cisplatin and daily capecitabine) in patients with gastric cancer after D1 or greater resection, might bring a better outcome as expected when it ended. On the other hand, operation types of lymphadenectomy differed in the included studies. Gastrectomy with D2 lymph node dissection was the standard treatment for resectable gastric cancer in eastern Asia while D2 lymph node dissection was considered as a recommended but not an indispensable procedure in the west [28]. Besides, only three of the involved studies reported the median number of dissected lymph nodes ranged from 14 to 47. Obviously, the more lymph nodes dissected, the better prognosis would be. Thus, a potential bias may exist and influence the result. The severity of toxicity may have a serious influence on the life of quality and treatment tolerance in patients, however, our results demonstrated that there was no significant difference of hematologic and gastrointestinal toxicities (except lower neutropenia in the chemoradiotherapy group (OR ¼ 1.47, 95% CI: 1.11–1.96; P ¼ 0.008), which could increase the risk of infection and weakness) [29]. Katakami et al. [30] recruited non‐small cell lung cancer patients at stage IIIA for a phase III study and it showed that preoperative adjuvant chemoradiotherapy conferred better local control without significant adverse events. In addition, some potential sources of limitations needed to be pointed out: (1) Different chemotherapy regimens and drugs as well as radiotherapy patterns and target volumes were used, which might lead an inherent difference. (2) Although the basic characteristics of the two groups were well balanced, potential confounding factors could not be all taken into our consideration such as the nutritional status and postoperative surgical complications which were not mentioned in any included studies. (3) Although no evidence of publication bias was found in this meta‐analysis using Begg’s funnel plot, the bias remains a main concern for all meta‐analysis [31]. To our knowledge, positive outcomes are inclined to be accepted by journals, whereas those negative ones are often reported in a briefer way or even rejected. (4) Our meta‐ analysis was restricted to full publications in English language, which probably missed some potential eligible studies in other languages. (5) The results of this meta‐analysis were based on studies with relatively small sample sizes so that they should be interpreted cautiously. More well‐designed and large scale RCTs for the comparison of adjuvant
Forest plot of 5‐year OS comparing CRT with CT.
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Fig. 4. Forest plot of 3‐year DFS comparing CRT with CT.
Fig. 5. Forest plot of 5‐year DFS comparing CRT with CT.
Fig. 6. Forest plot of local‐regional recurrence rate comparing CRT with CT.
Fig. 7. Journal of Surgical Oncology
Forest plot of new metastases comparing CRT with CT.
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Fig. 8.
Forest plot of grade 3–4 toxicity comparing CRT with CT.
chemoradiotherapy with chemotherapy in gastric cancer should be conducted for further studies. In conclusion, our meta‐analysis suggested that chemoradiotherapy could be well tolerated and might have an advantage in Journal of Surgical Oncology
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local‐regional recurrence rate and 5‐year disease but no advantage was observed in overall with positive lymph nodes and ERCC1 positive a potential prognosis benefit. However, further
free survival rate, survival; patients tumors may have larger prospective
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Fig. 9. Funnel plot. CRT, chemoradiotherapy; CT, chemotherapy.
studies with different adjuvant approaches are needed to strengthen our findings.
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