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Prolonged adjuvant capecitabine chemotherapy improved survival of stage IIIA gastric cancer after D2 gastrectomy
Biomedicine & Pharmacotherapy 72 (2015) 140–143
Available online at
ScienceDirect www.sciencedirect.com
Original article
Prolonged adjuvant capecitabine chemotherapy improved survival of stage IIIA gastric cancer after D2 gastrectomy Wen Ming Feng, Cheng Wu Tang *, Hui Hui Guo, Ying Bao, Mao Yun Fei Department of General Surgery and Molecular Surgery, First People’s Hospital Affiliated to Huzhou University Medical College, Huzhou, Zhejiang Province, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 November 2014 Accepted 25 March 2015
Goals: This study aims to investigate the safety and efficacy of prolonged adjuvant capecitabine chemotherapy on survival of gastric cancer after D2 gastrectomy. Background: Inadequate evidence is available on optimal duration of chemotherapy and the number of administered cycles is generally based on patient responsiveness and individual tolerability as well as physician preferences. Study: We randomly assigned 307 gastric cancer patients after D2 gastrectomy between January 2006 and December 2010 to XELOX group and Prolonged group. XELOX consisted of a 2-h intravenous infusion of oxaliplatin 130 mg/mg on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles in half a year. In Prolonged group, patients underwent extra oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles after eight cycles of XELOX. The disease-free survival and overall survival were compared. Results: Significant differences were found in 3-year disease-free survival (Prolonged group 56.6%, XELOX group 48.4%, P = 0.0357). Subgroup analysis by TNM staging showed that patients with stage IIIA gastric cancer in the Prolonged group had significantly higher DFS (50.00% vs 40.96, P = 0.0178) and OS (71.95% vs 57.83, P = 0.0230) than that of patients in the XELOX group. No grade 4 adverse effects or treatmentrelated deaths were reported. More patients in the Prolonged group experienced hand-foot syndrome than in the XELOX group. Conclusions: Prolonged capecitabine chemotherapy prevents improves the prognosis of patients with stage IIIA gastric cancer after D2 gastrectomy. ß 2015 Published by Elsevier Masson SAS.
Keywords: Gastric cancer D2 gastrectomy Recurrence Chemotherapy
1. Introduction Gastric cancer is the fourth prevalent cancer and second most common cause of cancer-related deaths worldwide, with half of all patients in East Asia [1]. Although the results of many randomized, controlled studies conducted to verify the effectiveness of postoperative adjuvant chemotherapy for gastric cancer were negative on an individual study basis [2,3]. Meta-analyses of these results have suggested that postoperative adjuvant chemotherapy is therapeutically useful in patients with gastric cancer [4–6]. The National Comprehensive Cancer Network (NCCN) has suggested that postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3–T4 tumors and node-positive T1–T2 tumors [7]. Data from population-based studies and analysis of clinical trials demonstrate that the survival * Corresponding author. Tel.: +86 0572 2039346; fax: +86 0572 2023728. E-mail address: [email protected] (C.W. Tang). http://dx.doi.org/10.1016/j.biopha.2015.03.003 0753-3322/ß 2015 Published by Elsevier Masson SAS.
of patients with gastric cancer has improved with the use of newer chemotherapeutic agents [8]. In particular, inadequate evidence is available on optimal duration of chemotherapy and the number of administered cycles is generally based on patient responsiveness and individual tolerability as well as physician preferences. In this regard, the NCCN guidelines state that ‘‘Due to the lack of overall survival differences, the use of prolonged versus shorter chemotherapy needs to be weighted against the detrimental effects of continuous chemotherapy on overall quality of life.’’ In this study, we investigate the safety and efficacy of prolonged adjuvant capecitabine chemotherapy on survival of gastric cancer after D2 gastrectomy. 2. Patients and methods 2.1. Patient eligibility Patients with histopathologically confirmed diagnosis of stage II, IIIA, or IIIB gastric cancer were eligible. Further criteria were as
W.M. Feng et al. / Biomedicine & Pharmacotherapy 72 (2015) 140–143
follows: age more than 18 years; Karnofsky performance status of 70% or more; adequate renal function, hepatic function and haematologic function; no prior chemotherapy, immunotherapy or radiotherapy for gastric cancer; R0 resection with D2 or more extensive lymph node dissection. Patients were excluded from the study if they had hypersensitivity to oxaliplatin, or died from nongastric cancer during follow-up. All patients signed an informed consent. The study was conducted in accordance with the World Medical Association Declaration of Helsinki. This protocol was approved by the Ethical Review Committee of the First Affiliated Hospital of Huzhou University. 2.2. Treatment Eligible patients were randomly assigned to XELOX group and Prolonged group. XELOX consisted of a 2-h intravenous infusion of oxaliplatin 130 mg/mg on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles in half a year. In Prolonged group, patients underwent extra oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles after eight cycles of XELOX. Antiemetic prophylaxis with 5-HT3-receptor antagonist granisetron (8 mg) i.v. and dexamethasone (5 mg) i.a. prior to the application of oxaliplatin were administered. All patients had curative D2 gastrectomy within 3 weeks before chemotherapy. 2.3. Toxicity assessment Toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria (NCI-CTC) for Adverse Events (version 3.0). Adverse events were documents during chemotherapy and for 28 days after the last dose of study medication. In cases of grade 3 or 4 toxicity, treatment was delayed by up to 3 weeks until the patient recovered from various adverse effects. Dose reductions were based on the worst adverse effects observed during the previous cycle. 2.4. Evaluation of efficacy outcomes All patients were followed up in the same manner from the date of random assignment. The results of KPS score, blood tests and clinical findings were assessed at 3-week intervals during treatment. Prespecified tumor assessments to assess whether patients were disease free were done by abdominal CT or MRI every 6 months during the follow-up and by chest radiograph every 3 months for the first 2 years, every 6 months for the subsequent year. Relapse was confirmed by imaging studies, including ultrasonography, computed tomography, and GI radiography, as well as endoscopy. There was no loss to follow-up. The primary endpoint was disease-free survival (DFS), defined as the time from randomization to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. Secondary endpoints were overall survival (OS), defined as the time from the date of randomization to date of death from any reason. 2.5. Statistical analysis All statistical analyses were done with SPSS 20.0 software (SPSS, Inc., Chicago, IL, United States). The primary endpoint of the study was disease-free survival after three years of follow-up, and the secondary endpoints were overall survival by intent-totreat. All time-related parameters were analyzed using the Kaplan–Meier method. Data were expressed as means or medians with ranges. P value less than 0.05 were considered statistically significant.
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3. Results 3.1. Patients 307 patients in whom advanced gastric cancer (TNM stage II, IIIA, or IIIB) was diagnosed and were treated with D2 gastrectomy between January 2006 and December 2010 were enrolled. 152 were randomly assigned to receive extra oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles after eight cycles of XELOX (Prolonged group), and 155 were assigned to receive eight cycles of XELOX chemotherapy (XELOX group). The clinicopathological characteristics of the 307 patients are shown in Table 1. The two groups were well balanced for pretreatment characteristics. There were 80 patients with stage II, 165 patients with stage IIIA and 62 patients with stage IIIB disease according to TNM staging (2010 edition). 3.2. Disease-free survival The recurrence rate at three years was 43.4% (66/152) in Prolonged group and 51.6% (80/155) in XELOX group. The 3-year DFS was statistically higher in Prolonged group compared with XELOX group (56.6% vs 48.4%, HR = 0.7109, 95%CI: 0.5135–0.9842, P = 0.0357). The effect of treatment on the DFS of the subgroups of patients with diffuse stages of tumors was also analyzed. Patients with stage IIIA gastric cancer in the Prolonged group had significantly higher DFS than that of patients in the XELOX group (50.00% vs 40.96, HR: 0.6180, 95%CI: 0.4069–0.9387, P = 0.0178) (Fig. 1). However, prolonged capecitabine chemotherapy had no significant effect on DFS in patients with stage II and IIIB gastric cancer. 3.3. Overall survival The 3-year overall survival probability was 71.1% for the Prolonged group and 62.6% for the XELOX group. The differences between them were not statistically significant (HR: 0.7026, 95%CI: 0.4764–1.0360, P = 0.0722) (Fig. 2). Subgroup analysis by TNM staging showed that prolonged capecitabine chemotherapy improved the 3-year overall survival of patients with stage IIIA gastric cancer in comparison with XELOX group (71.95% vs 57.83, HR: 0.5565, 95%CI: 0.3320–0.9328, P = 0.0230) (Fig. 2). 3.4. Toxicity and complication No grade 4 adverse effects or treatment-related deaths were reported. The incidence of the main toxicities is summarized in
Table 1 Baseline patient characteristics. Prolonged group (n = 152) Men Age (years) Histological type Well differentiated Moderately differentiated Poor differentiated Signet ring Tumor location Proximal gastric Remote gastric Whole gastric TNM stage II IIIA IIIB
104 (67.1%) 61.37 10.50
XELOX group (n = 155)
P value
99 (65.1%) 60.43 10.17
0.716 0.426
1 36 73 42
(0.7%) (23.7%) (48.0%) (27.6%)
0.262
14 (9.0%) 26 (16.8%) 115 (74.2%)
16 (10.5%) 20 (13.2%) 116 (76.3%)
0.641
39 (25.2%) 83 (53.5%) 33 (21.3%)
41 (27.0%) 82 (53.9%) 29 (19.1%)
0 26 88 41
(0.0%) (16.7%) (56.8%) (26.5%)
0.867
W.M. Feng et al. / Biomedicine & Pharmacotherapy 72 (2015) 140–143
142
Fig. 1. Kaplan–Meier curves for disease-free survival assessed in the entire population (a), patients with grade IIIA gastric cancer (b).
Fig. 2. Kaplan–Meier curves for overall survival assessed in the entire population (a), patients with grade IIIA gastric cancer (b).
Table 2 Toxicity and complication. Adverse event
Paresthesia Neutropenia Thrombocytopenia Anemia Nausea/vomiting Diarrhea Hepatic toxicity Stomatitis Hand-foot syndrome
Prolonged group
XELOX group
Grade
Grade
P value
1
2
3
4
1
2
3
4
73 62 41 76 80 39 26 7 18
20 20 12 12 14 17 11 10 10
4 5 11 9 10 8 4 0 8
0 0 0 0 0 0 0 0 0
77 57 38 68 75 35 20 8 11
19 17 10 10 13 13 8 7 3
6 7 5 7 6 9 2 0 3
0 0 0 0 0 0 0 0 0
Table 2. In general, toxicity mainly consisted of paresthesia (97/152 vs 102/155, P = 0.7307), neutropenia (87/152 vs 91/155, P = 4611), thrombocytopenia (64/152 vs 53/155, P = 0.1056), anemia (97/152 vs 85/155, P = 0.1109), nausea/vomiting (104/ 152 vs 94/155, P = 0.1268), diarrhea (64/152 vs 57/155, P = 0.3674), hepatic toxicity (41/152 vs 30/155, P = 0.1071), stomatitis (17/152 vs 15/155, P = 0.6396) and hand-foot syndrome (36/152 vs 17/155, P = 0.0334). More patients in the Prolonged group experienced hand-foot syndrome than in the XELOX group.
0.7307 0.4611 0.1056 0.1109 0.1268 0.3674 0.1071 0.6396 0.0334
4. Discussion Despite improvements in various treatment modalities, gastric cancer has a poor prognosis. Surgical resection of the tumor with the dissection of regional lymph nodes is regarded as the only curative treatment [9]. However, approximately 80% of patients with adequate negative margins still have recurrences and most patients ultimately die from their disease [10,11]. As residual cancer cells are thought to be responsible for
W.M. Feng et al. / Biomedicine & Pharmacotherapy 72 (2015) 140–143
the disease relapse, postsurgical adjuvant chemotherapy has been implemented to prevent recurrence. Various combinations of drugs have been used for adjuvant treatment. There is no clearly recommended protocol for the standard treatment of patients with gastric cancer after complete resection, and adjuvant capecitabine and oxaliplatin (XELOX) has been widely used. Data from our study suggested a significantly improvement in 3-year disease-free survival and a reduction in the relative risk of recurrence with prolonged capecitabine chemotherapy after XELOX chemotherapy compared with XELOX chemotherapy, especially for those with stage IIIA gastric cancer. Though the relative risk of death was not significantly improved in Prolonged group, the subgroup analysis revealed that prolonged capecitabine chemotherapy improved the OS of patients with stage IIIA gastric cancer comparing with XELOX group. The frequency, severity, and type of adverse events documents with capecitabine and oxaliplatin in our study were consistent with the safety profile reported with capecitabine and oxaliplatin [12,13]. The toxicity and complication of Prolonged group were similar to XELOX group, though more hand-foot syndrome were found in the Prolonged group. Most of the symptoms were not severe and manageable by the administration of supportive drugs in both groups [14,15]. Moreover, there were not any new safety signals revealed and the treatment was generally well tolerated in the present study. In conclusion, extra eight 3-week cycles of oral capecitabine chemotherapy after eight 3-week cycles of XELOX chemotherapy is an effective procedure for improving the prognosis of patients with stage IIIA gastric cancer after D2 gastrectomy, and this protocol we used in this study can be safely employed in a prospective randomized study.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
143
Author contributions Wen Ming Feng and Cheng Wu Tang designed the study and wrote the manuscript; Hui Hui Guo, Mao Yun Fei did the follow-up work; Ying Bao provided the collection of all the human material in addition to providing financial support for this work. References [1] A. Jemal, F. Bray, M.M. Center, et al., Global cancer statistics, CA Cancer J. Clin. 61 (2011) 69–90. [2] A. Ohtsu, M. Sasako, Overview of adjuvant therapy for resected gastric cancer: differences in Japan and the United States, Semin. Oncol. 32 (2005) S101–S104. [3] A. Ohtsu, S. Yoshida, N. Saijo, Disparities in gastric cancer chemotherapy between the East and West, J. Clin. Oncol. 24 (2006) 2188–2196. [4] X. Paoletti, K. Oba, T. Burzykowski, et al., Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis, JAMA 303 (2010) 1729–1737. [5] Y.J. Bang, Y.W. Kim, H.K. Yang, et al., Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial, Lancet 379 (2012) 315–321. [6] M. Sasako, S. Sakuramoto, H. Katai, et al., Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer, J. Clin. Oncol. 29 (2011) 4387–4393. [7] J.A. Ajani, D.J. Bentrem, S. Besh, et al., Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines, J. Natl. Compr. Cancer Netw.: JNCCN 11 (2013) 531–546. [8] K. Fujitani, S. Tamura, Y. Kimura, et al., Three-year outcomes of a phase II study of adjuvant chemotherapy with S-1 plus docetaxel for stage III gastric cancer after curative D2 gastrectomy, Gastric Cancer 17 (2014) 348–353. [9] S.R. Alberts, A. Cervantes, C.J. van de Velde, Gastric cancer: epidemiology, pathology and treatment, Ann. Oncol. 14 (Suppl. 2) (2003) ii31–ii36. [10] L.L. Gunderson, Gastric cancer – patterns of relapse after surgical resection, Semin. Radiat. Oncol. 12 (2002) 150–161. [11] A. Gallo, C. Cha, Updates on esophageal and gastric cancers, World J. Gastroenterol.: WJG 12 (2006) 3237–3242. [12] H.J. Schmoll, T. Cartwright, J. Tabernero, et al., Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients, J. Clin. Oncol. 25 (2007) 102–109. [13] D.G. Haller, J. Tabernero, J. Maroun, et al., Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer, J. Clin. Oncol. 29 (2011) 1465–1471. [14] S.E. Al-Batran, J.T. Hartmann, S. Probst, et al., Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie, J. Clin. Oncol. 26 (2008) 1435–1442. [15] K. Oba, S. Morita, A. Tsuburaya, et al., Efficacy of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials in Japan, J. Chemother. 18 (2006) 311–317.
Available online at
ScienceDirect www.sciencedirect.com
Original article
Prolonged adjuvant capecitabine chemotherapy improved survival of stage IIIA gastric cancer after D2 gastrectomy Wen Ming Feng, Cheng Wu Tang *, Hui Hui Guo, Ying Bao, Mao Yun Fei Department of General Surgery and Molecular Surgery, First People’s Hospital Affiliated to Huzhou University Medical College, Huzhou, Zhejiang Province, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 November 2014 Accepted 25 March 2015
Goals: This study aims to investigate the safety and efficacy of prolonged adjuvant capecitabine chemotherapy on survival of gastric cancer after D2 gastrectomy. Background: Inadequate evidence is available on optimal duration of chemotherapy and the number of administered cycles is generally based on patient responsiveness and individual tolerability as well as physician preferences. Study: We randomly assigned 307 gastric cancer patients after D2 gastrectomy between January 2006 and December 2010 to XELOX group and Prolonged group. XELOX consisted of a 2-h intravenous infusion of oxaliplatin 130 mg/mg on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles in half a year. In Prolonged group, patients underwent extra oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles after eight cycles of XELOX. The disease-free survival and overall survival were compared. Results: Significant differences were found in 3-year disease-free survival (Prolonged group 56.6%, XELOX group 48.4%, P = 0.0357). Subgroup analysis by TNM staging showed that patients with stage IIIA gastric cancer in the Prolonged group had significantly higher DFS (50.00% vs 40.96, P = 0.0178) and OS (71.95% vs 57.83, P = 0.0230) than that of patients in the XELOX group. No grade 4 adverse effects or treatmentrelated deaths were reported. More patients in the Prolonged group experienced hand-foot syndrome than in the XELOX group. Conclusions: Prolonged capecitabine chemotherapy prevents improves the prognosis of patients with stage IIIA gastric cancer after D2 gastrectomy. ß 2015 Published by Elsevier Masson SAS.
Keywords: Gastric cancer D2 gastrectomy Recurrence Chemotherapy
1. Introduction Gastric cancer is the fourth prevalent cancer and second most common cause of cancer-related deaths worldwide, with half of all patients in East Asia [1]. Although the results of many randomized, controlled studies conducted to verify the effectiveness of postoperative adjuvant chemotherapy for gastric cancer were negative on an individual study basis [2,3]. Meta-analyses of these results have suggested that postoperative adjuvant chemotherapy is therapeutically useful in patients with gastric cancer [4–6]. The National Comprehensive Cancer Network (NCCN) has suggested that postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3–T4 tumors and node-positive T1–T2 tumors [7]. Data from population-based studies and analysis of clinical trials demonstrate that the survival * Corresponding author. Tel.: +86 0572 2039346; fax: +86 0572 2023728. E-mail address: [email protected] (C.W. Tang). http://dx.doi.org/10.1016/j.biopha.2015.03.003 0753-3322/ß 2015 Published by Elsevier Masson SAS.
of patients with gastric cancer has improved with the use of newer chemotherapeutic agents [8]. In particular, inadequate evidence is available on optimal duration of chemotherapy and the number of administered cycles is generally based on patient responsiveness and individual tolerability as well as physician preferences. In this regard, the NCCN guidelines state that ‘‘Due to the lack of overall survival differences, the use of prolonged versus shorter chemotherapy needs to be weighted against the detrimental effects of continuous chemotherapy on overall quality of life.’’ In this study, we investigate the safety and efficacy of prolonged adjuvant capecitabine chemotherapy on survival of gastric cancer after D2 gastrectomy. 2. Patients and methods 2.1. Patient eligibility Patients with histopathologically confirmed diagnosis of stage II, IIIA, or IIIB gastric cancer were eligible. Further criteria were as
W.M. Feng et al. / Biomedicine & Pharmacotherapy 72 (2015) 140–143
follows: age more than 18 years; Karnofsky performance status of 70% or more; adequate renal function, hepatic function and haematologic function; no prior chemotherapy, immunotherapy or radiotherapy for gastric cancer; R0 resection with D2 or more extensive lymph node dissection. Patients were excluded from the study if they had hypersensitivity to oxaliplatin, or died from nongastric cancer during follow-up. All patients signed an informed consent. The study was conducted in accordance with the World Medical Association Declaration of Helsinki. This protocol was approved by the Ethical Review Committee of the First Affiliated Hospital of Huzhou University. 2.2. Treatment Eligible patients were randomly assigned to XELOX group and Prolonged group. XELOX consisted of a 2-h intravenous infusion of oxaliplatin 130 mg/mg on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles in half a year. In Prolonged group, patients underwent extra oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles after eight cycles of XELOX. Antiemetic prophylaxis with 5-HT3-receptor antagonist granisetron (8 mg) i.v. and dexamethasone (5 mg) i.a. prior to the application of oxaliplatin were administered. All patients had curative D2 gastrectomy within 3 weeks before chemotherapy. 2.3. Toxicity assessment Toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria (NCI-CTC) for Adverse Events (version 3.0). Adverse events were documents during chemotherapy and for 28 days after the last dose of study medication. In cases of grade 3 or 4 toxicity, treatment was delayed by up to 3 weeks until the patient recovered from various adverse effects. Dose reductions were based on the worst adverse effects observed during the previous cycle. 2.4. Evaluation of efficacy outcomes All patients were followed up in the same manner from the date of random assignment. The results of KPS score, blood tests and clinical findings were assessed at 3-week intervals during treatment. Prespecified tumor assessments to assess whether patients were disease free were done by abdominal CT or MRI every 6 months during the follow-up and by chest radiograph every 3 months for the first 2 years, every 6 months for the subsequent year. Relapse was confirmed by imaging studies, including ultrasonography, computed tomography, and GI radiography, as well as endoscopy. There was no loss to follow-up. The primary endpoint was disease-free survival (DFS), defined as the time from randomization to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. Secondary endpoints were overall survival (OS), defined as the time from the date of randomization to date of death from any reason. 2.5. Statistical analysis All statistical analyses were done with SPSS 20.0 software (SPSS, Inc., Chicago, IL, United States). The primary endpoint of the study was disease-free survival after three years of follow-up, and the secondary endpoints were overall survival by intent-totreat. All time-related parameters were analyzed using the Kaplan–Meier method. Data were expressed as means or medians with ranges. P value less than 0.05 were considered statistically significant.
141
3. Results 3.1. Patients 307 patients in whom advanced gastric cancer (TNM stage II, IIIA, or IIIB) was diagnosed and were treated with D2 gastrectomy between January 2006 and December 2010 were enrolled. 152 were randomly assigned to receive extra oral capecitabine 1000 mg/m2 twice daily on days 1–14 of a 3-week cycle for eight cycles after eight cycles of XELOX (Prolonged group), and 155 were assigned to receive eight cycles of XELOX chemotherapy (XELOX group). The clinicopathological characteristics of the 307 patients are shown in Table 1. The two groups were well balanced for pretreatment characteristics. There were 80 patients with stage II, 165 patients with stage IIIA and 62 patients with stage IIIB disease according to TNM staging (2010 edition). 3.2. Disease-free survival The recurrence rate at three years was 43.4% (66/152) in Prolonged group and 51.6% (80/155) in XELOX group. The 3-year DFS was statistically higher in Prolonged group compared with XELOX group (56.6% vs 48.4%, HR = 0.7109, 95%CI: 0.5135–0.9842, P = 0.0357). The effect of treatment on the DFS of the subgroups of patients with diffuse stages of tumors was also analyzed. Patients with stage IIIA gastric cancer in the Prolonged group had significantly higher DFS than that of patients in the XELOX group (50.00% vs 40.96, HR: 0.6180, 95%CI: 0.4069–0.9387, P = 0.0178) (Fig. 1). However, prolonged capecitabine chemotherapy had no significant effect on DFS in patients with stage II and IIIB gastric cancer. 3.3. Overall survival The 3-year overall survival probability was 71.1% for the Prolonged group and 62.6% for the XELOX group. The differences between them were not statistically significant (HR: 0.7026, 95%CI: 0.4764–1.0360, P = 0.0722) (Fig. 2). Subgroup analysis by TNM staging showed that prolonged capecitabine chemotherapy improved the 3-year overall survival of patients with stage IIIA gastric cancer in comparison with XELOX group (71.95% vs 57.83, HR: 0.5565, 95%CI: 0.3320–0.9328, P = 0.0230) (Fig. 2). 3.4. Toxicity and complication No grade 4 adverse effects or treatment-related deaths were reported. The incidence of the main toxicities is summarized in
Table 1 Baseline patient characteristics. Prolonged group (n = 152) Men Age (years) Histological type Well differentiated Moderately differentiated Poor differentiated Signet ring Tumor location Proximal gastric Remote gastric Whole gastric TNM stage II IIIA IIIB
104 (67.1%) 61.37 10.50
XELOX group (n = 155)
P value
99 (65.1%) 60.43 10.17
0.716 0.426
1 36 73 42
(0.7%) (23.7%) (48.0%) (27.6%)
0.262
14 (9.0%) 26 (16.8%) 115 (74.2%)
16 (10.5%) 20 (13.2%) 116 (76.3%)
0.641
39 (25.2%) 83 (53.5%) 33 (21.3%)
41 (27.0%) 82 (53.9%) 29 (19.1%)
0 26 88 41
(0.0%) (16.7%) (56.8%) (26.5%)
0.867
W.M. Feng et al. / Biomedicine & Pharmacotherapy 72 (2015) 140–143
142
Fig. 1. Kaplan–Meier curves for disease-free survival assessed in the entire population (a), patients with grade IIIA gastric cancer (b).
Fig. 2. Kaplan–Meier curves for overall survival assessed in the entire population (a), patients with grade IIIA gastric cancer (b).
Table 2 Toxicity and complication. Adverse event
Paresthesia Neutropenia Thrombocytopenia Anemia Nausea/vomiting Diarrhea Hepatic toxicity Stomatitis Hand-foot syndrome
Prolonged group
XELOX group
Grade
Grade
P value
1
2
3
4
1
2
3
4
73 62 41 76 80 39 26 7 18
20 20 12 12 14 17 11 10 10
4 5 11 9 10 8 4 0 8
0 0 0 0 0 0 0 0 0
77 57 38 68 75 35 20 8 11
19 17 10 10 13 13 8 7 3
6 7 5 7 6 9 2 0 3
0 0 0 0 0 0 0 0 0
Table 2. In general, toxicity mainly consisted of paresthesia (97/152 vs 102/155, P = 0.7307), neutropenia (87/152 vs 91/155, P = 4611), thrombocytopenia (64/152 vs 53/155, P = 0.1056), anemia (97/152 vs 85/155, P = 0.1109), nausea/vomiting (104/ 152 vs 94/155, P = 0.1268), diarrhea (64/152 vs 57/155, P = 0.3674), hepatic toxicity (41/152 vs 30/155, P = 0.1071), stomatitis (17/152 vs 15/155, P = 0.6396) and hand-foot syndrome (36/152 vs 17/155, P = 0.0334). More patients in the Prolonged group experienced hand-foot syndrome than in the XELOX group.
0.7307 0.4611 0.1056 0.1109 0.1268 0.3674 0.1071 0.6396 0.0334
4. Discussion Despite improvements in various treatment modalities, gastric cancer has a poor prognosis. Surgical resection of the tumor with the dissection of regional lymph nodes is regarded as the only curative treatment [9]. However, approximately 80% of patients with adequate negative margins still have recurrences and most patients ultimately die from their disease [10,11]. As residual cancer cells are thought to be responsible for
W.M. Feng et al. / Biomedicine & Pharmacotherapy 72 (2015) 140–143
the disease relapse, postsurgical adjuvant chemotherapy has been implemented to prevent recurrence. Various combinations of drugs have been used for adjuvant treatment. There is no clearly recommended protocol for the standard treatment of patients with gastric cancer after complete resection, and adjuvant capecitabine and oxaliplatin (XELOX) has been widely used. Data from our study suggested a significantly improvement in 3-year disease-free survival and a reduction in the relative risk of recurrence with prolonged capecitabine chemotherapy after XELOX chemotherapy compared with XELOX chemotherapy, especially for those with stage IIIA gastric cancer. Though the relative risk of death was not significantly improved in Prolonged group, the subgroup analysis revealed that prolonged capecitabine chemotherapy improved the OS of patients with stage IIIA gastric cancer comparing with XELOX group. The frequency, severity, and type of adverse events documents with capecitabine and oxaliplatin in our study were consistent with the safety profile reported with capecitabine and oxaliplatin [12,13]. The toxicity and complication of Prolonged group were similar to XELOX group, though more hand-foot syndrome were found in the Prolonged group. Most of the symptoms were not severe and manageable by the administration of supportive drugs in both groups [14,15]. Moreover, there were not any new safety signals revealed and the treatment was generally well tolerated in the present study. In conclusion, extra eight 3-week cycles of oral capecitabine chemotherapy after eight 3-week cycles of XELOX chemotherapy is an effective procedure for improving the prognosis of patients with stage IIIA gastric cancer after D2 gastrectomy, and this protocol we used in this study can be safely employed in a prospective randomized study.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Author contributions Wen Ming Feng and Cheng Wu Tang designed the study and wrote the manuscript; Hui Hui Guo, Mao Yun Fei did the follow-up work; Ying Bao provided the collection of all the human material in addition to providing financial support for this work. References [1] A. Jemal, F. Bray, M.M. Center, et al., Global cancer statistics, CA Cancer J. Clin. 61 (2011) 69–90. [2] A. Ohtsu, M. Sasako, Overview of adjuvant therapy for resected gastric cancer: differences in Japan and the United States, Semin. Oncol. 32 (2005) S101–S104. [3] A. Ohtsu, S. Yoshida, N. Saijo, Disparities in gastric cancer chemotherapy between the East and West, J. Clin. Oncol. 24 (2006) 2188–2196. [4] X. Paoletti, K. Oba, T. Burzykowski, et al., Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis, JAMA 303 (2010) 1729–1737. [5] Y.J. Bang, Y.W. Kim, H.K. Yang, et al., Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial, Lancet 379 (2012) 315–321. [6] M. Sasako, S. Sakuramoto, H. Katai, et al., Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer, J. Clin. Oncol. 29 (2011) 4387–4393. [7] J.A. Ajani, D.J. Bentrem, S. Besh, et al., Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines, J. Natl. Compr. Cancer Netw.: JNCCN 11 (2013) 531–546. [8] K. Fujitani, S. Tamura, Y. Kimura, et al., Three-year outcomes of a phase II study of adjuvant chemotherapy with S-1 plus docetaxel for stage III gastric cancer after curative D2 gastrectomy, Gastric Cancer 17 (2014) 348–353. [9] S.R. Alberts, A. Cervantes, C.J. van de Velde, Gastric cancer: epidemiology, pathology and treatment, Ann. Oncol. 14 (Suppl. 2) (2003) ii31–ii36. [10] L.L. Gunderson, Gastric cancer – patterns of relapse after surgical resection, Semin. Radiat. Oncol. 12 (2002) 150–161. [11] A. Gallo, C. Cha, Updates on esophageal and gastric cancers, World J. Gastroenterol.: WJG 12 (2006) 3237–3242. [12] H.J. Schmoll, T. Cartwright, J. Tabernero, et al., Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients, J. Clin. Oncol. 25 (2007) 102–109. [13] D.G. Haller, J. Tabernero, J. Maroun, et al., Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer, J. Clin. Oncol. 29 (2011) 1465–1471. [14] S.E. Al-Batran, J.T. Hartmann, S. Probst, et al., Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie, J. Clin. Oncol. 26 (2008) 1435–1442. [15] K. Oba, S. Morita, A. Tsuburaya, et al., Efficacy of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials in Japan, J. Chemother. 18 (2006) 311–317.