- Email: [email protected]
Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis
original articles
Annals of Oncology Annals of Oncology 24: 2850–2854, 2013 doi:10.1093/annonc/mdt351 Published online 13 August 2013
Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis H. S. Kim1,†, H. J. Kim2,†, S. Y. Kim3, T. Y. Kim4, K. W. Lee5, S. K. Baek3, T. Y. Kim4, M. H. Ryu6, B. H. Nam7 & D. Y. Zang1* 1
Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang; 2Department of Preventive Medicine, Korea University, College of Medicine, Seoul; 3Department of Internal Medicine, Kyung Hee University Hospital, Seoul; 4Department of Internal Medicine, Seoul National University Hospital, Seoul; 5Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si; 6Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul; 7Biometric Research Branch, National Cancer Center, Goyang, Korea
Background: Many patients with refractory or relapsed gastric cancer after first-line chemotherapy have received salvage chemotherapy in routine clinical practice. However, there was no evidence to support this treatment until recent phase III trials demonstrated substantial prolongation of overall survival. Therefore, we conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than best supportive care. Patients and methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980–2013, week 13). In addition, we searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013. Results: The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. A significant reduction in the risk of death [HR = 0.64, 95% confidence interval (CI) 0.52–0.79, P < 0.0001] was observed with salvage chemotherapy.When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (95% CI 0.40–0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56–0.90, P = 0.004) for docetaxel. Conclusion: This meta-analysis demonstrated evidence to support second-line chemotherapy in advanced gastric cancer. Key words: advanced gastric cancer, second-line chemotherapy, best supportive care, meta-analysis
introduction Gastric cancer is the fourth most frequent malignant disease and the second most common cause of cancer-related death in the world [1]; it is also the second most frequent malignancy in Korea [2]. Although patients with early gastric cancer can be cured by surgical resection with perioperative or adjuvant chemotherapy, a large majority of patients experience a relapse after initial surgery or are diagnosed with unresectable, locally advanced or metastatic disease. Systemic chemotherapy with combination of fluoropyrimidine and platinum is now regarded as the standard treatment of these patients [3]. However, the efficacy of first-line treatment is modest, and most patients are nonresponders or eventually experience disease progression. *Correspondence to: Prof. Dae Young Zang, Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, 896 Pyeongchon-dong, Dongan-gu, Anyang 431-070, Korea. Tel: +82-31-380-3871; Fax: +82-31-386-2269; E-mail: [email protected] †
H.S.K. and H.J.K. were equally contributed to this study.
Even though patients with refractory gastric cancer have received salvage chemotherapy in routine clinical practice, especially in Asia, there was no evidence to support salvage chemotherapy until recent phase III trials demonstrated substantial prolongation of overall survival. Results of three randomized, controlled trials (RCT) were published as articles [4, 5] or abstract [6] and showed overall survival benefit from treatments with irinotecan or docetaxel compared with best supportive care (BSC) alone in patients for whom one or two prior treatments failed. We conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than BSC.
methods search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980–2013, week 13) for articles that included the following search terms in their tiles, abstracts, or keyword lists: ‘gastric or gastroesophageal or
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Grand Valley State Univ on November 3, 2013
Received 27 May 2013; revised 9 July 2013; accepted 10 July 2013
original articles
Annals of Oncology gastroesophagus or esophagogastric or stomach’, ‘cancer or neoplasm or carcinoma or malignant or malignancy’, ‘second-line or salvage or supportive care’, ‘chemotherapy or chemotherapeutic or antineoplastic agent’, and ‘randomized or randomized, controlled trial or randomised’. In addition, we searched the reference lists of relevant articles/reviews and used the ‘related articles’ feature in PubMed to identify additional articles. We searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013 and sought expert opinion to identify relevant but unpublished studies. We assessed all potentially eligible studies identified by the above search strategy. Clinical trials that met the following criteria were included in the meta-analysis: (i) trials comparing second-line or salvage treatment chemotherapy with BSC and (ii) prospective phase III randomized trials. Two review authors extracted data from each included study using an agreed-upon form and assessed the risk of bias. We resolved discrepancies through discussion.
statistical analysis The primary outcome measure of this meta-analysis was overall survival, defined as the time from the date of random assignment to date of death as a result of any cause. Survival analysis was conducted using the intention-totreat population. A fixed effect model was used to calculate the pooled hazard ratio (HR) estimate. HRs for death were combined using an inverse variance method based on a logarithmic conversion; 95% confidence intervals (95% CIs) were used to determine the standard error (SE) using the formula SE = 95% CI/1.96. The traditional Q-test and the I 2 statistic were used to evaluate heterogeneity. Significant heterogeneity was considered to be present for P < 0.05 in the Q test or for I 2 > 30%. The Z-test for overall
Figure 1. Flowchart of search process.
effect and its two-sided P-value were also assessed. RevMan v5.2 software was used to report outcomes.
results The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis. Figure 1 shows the search process. Finally, three randomized phase III trials that compared irinotecan or docetaxel with BSC were selected. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. The characteristics of studies are described in Table 1. The trials by Thuss-Patience et al. and Cook et al. were conducted in Europe, and the trial by Kang et al. took place in Asia. Enrolled patients were diagnosed with esophagogastric cancer. Most had an ECOG performance status of 0 or 1 and progressed within 3 months of a previous chemotherapy (Table 2). Overall survival was compared for 238 patients who were assigned to irinotecan or docetaxel as salvage chemotherapy with 172 patients who received supportive care. A significant reduction in the risk of death (HR = 0.64, 95% CI 0.52–0.79, P < 0.0001) was observed with salvage chemotherapy, as shown in Figure 2. Heterogeneity was not detected. When the analysis was restricted to irinotecan or docetaxel, there was still a significant reduction in the risk of death associated with each chemotherapeutic agent, as shown in Figure 3 and 4. The HR was 0.55 (95% CI 0.40–0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56–0.90, P = 0.004) for docetaxel. There were no significant differences in treatment effect according to the chemotherapeutic agent. Meta-analysis of the two trials in Europe also demonstrated that second-line chemotherapy reduced the risk of death by 37% compared with BSC (HR = 0.63, 95% CI 0.47–0.84; Figure 5).
Table 1. Main characteristics of the studies included in the meta-analysis Study Thuss-Patience et al. (2011) Kang et al. (2012)
Cook et al. (2013)
Patients (n) 21 19 133
69 84 84
Treatments a
Irinotecan 250 mg/m2, every 3 weeks Best supportive care Docetaxel 60 mg/m2, every 3 weeks Irinotecan 150 mg/m2, every 2 weeks Best supportive care Docetaxel 75 mg/m2,every 3 weeks Best supportive care
Objective response rate (%)
Disease control rate (%)
Median overall survival (months)
Hazard ratio (95% CI)
0
53
4.0
0.48 (0.25–0.92) P = 0.012
– 11
– 38
2.4 5.3
8
43
– 7
– 46
3.8 5.2
–
–
3.6
0.657 (0.485–0.891) P = 0.007
0.67 (0.49–0.92) P = 0.01
a
Dose of irinotecan could be escalated to 350 mg/m2 in subsequent cycles according to the protocol
Volume 24 | No. 11 | November 2013
doi:10.1093/annonc/mdt351 |
original articles
Annals of Oncology
Table 2. Brief characteristics of patients Characteristics
Thuss-Patience et al. Irinotecan No. (%)
No. of patients 21 Age, years Median 58 Range 43–73 Sex Male 18 (86) Female 3 (14) ECOG performance status 0 17 (81) 1 2 4 (19) Response to prior chemotherapy CR/PR 7 (33) SD/PD 14 (67) No. of metastatic sites 1 6 (29) ≥2 15 (71) Interval from last chemotherapy, months <3 18 (86) ≥3 3 (14)
BSC No. (%)
Kang et al. SLC No. (%)
BSC No. (%)
Cook et al. Docetaxel %
ASC %
19
133
69
84
84
55 35–72
56 31–83
56 32–74
65 25–84
66 35–84
11 (58) 8 (42)
93 (70) 40 (30)
44 (64) 25 (36)
82 18
80 20
14 (74) 5 (26)
72 (54) 61 (46) –
36 (52) 33 (48) –
28 55 17
28 55 17
4 (21) 15 (79)
54 (41) 79 (59)
29 (42) 40 (58)
– –
11 (58) 8 (42)
42 (32) 91 (68)
28 (41) 41 (59)
– –
17 (89) 2 (11)
101 (76) 32 (24)
48 (70) 21 (30)
75 25
69 31
ASC, active symptom control; BSC, best supportive care; CR, complete response; ECOG, eastern Cooperative Oncology Group; PD, progressive disease; PR, partial response; SD, stable disease; SLC, salvage chemotherapy.
Figure 2. Standard forest plot of the hazard ratio (HR) for death comparing second-line chemotherapy with best supportive care.
discussion Many patients with advanced gastric cancer are refractory to first-line chemotherapy or experience disease progression after a short response to treatment. Despite lack of evidence for salvage chemotherapy in advanced gastric cancer it is common practice to offer further chemotherapy after first-line failure. Recently, three trials have demonstrated the prolongation of survival with second-line chemotherapy over BSC. The Korean trial by Kang et al. [5] is the largest complete randomized trial involving 202 patients. The trial by Thuss-Patience et al. in Europe was prematurely closed after only 40 patients enrolled due to enrollment difficulties and the trial by Cook et al. enrolled 168 European patients in a trial presented as an abstract [4, 6]. This meta-analysis demonstrated that there exists a clear clinical benefit from the use of second-line chemotherapy in patients with advanced gastric cancer with 36% reduction in the risk of death. These results were observed consistently regardless
| Kim et al.
of the administered drugs, and the magnitude of the clinical benefit was similar between European and Asian populations in terms of survival (HR = 0.63 and 0.657, respectively). The results of randomized clinical trials including a BSC arm can be affected seriously by the lack of standardization of BSC delivery. Considering the descriptions of BSC in articles, the authors were aware of the risk of bias and tried to provide consistent and preplanned BSC intervention. Kang et al. [5] attempted to describe the administration of BSC intervention in detail and to provide explicit guidance. Thuss-Patience et al. had patients in the BSC arm examined and evaluated at the same frequency and by the same methods as in the irinotecan arm [4]. Therefore, it is unlikely that the lack of standardization of BSC may be a source of bias. If the patients in the BSC arm received chemotherapy during the study period or after progression, it could be an important factor reducing the power of the findings of these trials. In trials by Thuss-Patience et al. and Kang et al., only four patients (4.5%) among 88 patients enrolled in BSC arm received
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Annals of Oncology
original articles
Figure 3. Standard forest plot of the hazard ratio (HR) for death comparing second-line irinotecan with best supportive care.
Figure 4. Standard forest plot of the hazard ratio (HR) for death comparing second-line docetaxel with best supportive care.
Figure 5. Standard forest plot of the hazard ratio (HR) for death comparing second-line chemotherapy with best supportive care in European patients.
chemotherapy. Therefore, chemotherapy in the BSC arm may not affect the findings of the trials evaluated in this metaanalysis. The efficacy of second-line chemotherapy was comparable among trials. The objective response rate (ORR) was about 10% and the disease control rate was above 40%. Different chemotherapy regimens such as docetaxel or irinotecan and administration schedule did not have any influence on the outcome. Several recent trials support these results. Ueda et al. [7] conducted a phase III study comparing second-line chemotherapy regimens in 223 patients with advanced gastric cancer. Patients received either weekly paclitaxel (80 mg/m2, days 1, 8, 15, every 4 weeks) or irinotecan (150 mg/m2, every 2 weeks). There were no differences between treatment groups in terms of ORR, median overall survival, and toxic effect. Roy et al. [8] conducted a phase II study to evaluate the efficacy and safety of single-agent PEP02 with irinotecan or docetaxel in the second-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma. Patients received either PEP02 (120 mg/m2, every 3 weeks), docetaxel (75 mg/m2, every 3 weeks), or irinotecan (300 mg/m2, every 3 weeks). The ORR, the primary end point, was similar between treatment groups. Although the benefit of second-line chemotherapy is evident, the disease control rate is just above 40%. In other words, almost half of patients do not benefit from second-line chemotherapy and suffer from chemotherapy toxic effect. Therefore, it is
Volume 24 | No. 11 | November 2013
important to predict whether patients can benefit from secondline chemotherapy. Considering the results of univariate analysis for survival in two trials [4, 5], a good performance status and long chemotherapy-free interval (≥3 months) could be important positive prognostic indicators that could help physicians to make a decision regarding treatment. Several retrospective studies conducted to identify optimal prognostic factors have also suggested prognostic factors such as performance status, hemoglobin level, and time to progression of first-line chemotherapy [9–12]. Several limitations of this meta-analysis should be noted. Clinical and pathological factors were not analyzed thoroughly to identify prognostic factors, since the details about these factors were not available. The impact of second-line chemotherapy on quality of life was not analyzed due to lack of data. The trial by Cook et al. [6] addressed in the abstract that similar global health-related quality of life was observed in each arm. The other two trials did not report any assessment of quality of life. In conclusion, this meta-analysis demonstrated evidence to support the efficacy of second-line chemotherapy in the treatment of advanced gastric cancer. Several agents are available, and physicians can choose a regimen depending on toxic effect profiles and previous chemotherapy agents. Clinical prognostic factors derived from previous trials may guide physicians in deciding on the best treatment plan to improve outcomes.
doi:10.1093/annonc/mdt351 |
original articles funding This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065).
disclosure The authors have declared no conflicts of interest.
references 1. Ferlay J, Shin HR, Bray F et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893–2917. 2. Jung KW, Won YJ, Kong HJ et al. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat 2013; 45: 1–14. 3. Wagner AD, Unverzagt S, Grothe W et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010; CD004064. 4. Thuss-Patience PC, Kretzschmar A, Bichev D et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer—a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011; 47: 2306–2314.
Annals of Oncology 5. Kang JH, Lee SI, Lim do H et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 2012; 30: 1513–1518. 6. Cook N, Marshall A, Blazeby JM et al. COUGAR-02: a randomized phase III study of docetaxel versus active symptom control in patients with relapsed esophagogastric adenocarcinoma. J Clin Oncol 2013; 31 (suppl): abstract 4023. 7. Ueda S, Hironaka S, Yasui H et al. Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial. J Clin Oncol 2012; 30 (suppl): abstract 4002. 8. Roy AC, Park SR, Cunningham D et al. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol 2013; 24: 1567–1573. 9. Catalano V, Graziano F, Santini D et al. Second-line chemotherapy for patients with advanced gastric cancer: who may benefit? Br J Cancer 2008; 99: 1402–1407. 10. Ji SH, Lim do H, Yi SY et al. A retrospective analysis of second-line chemotherapy in patients with advanced gastric cancer. BMC Cancer 2009; 9: 110–115. 11. Kanagavel D, Pokataev IA, Fedyanin MY et al. A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy. Ann Oncol 2010; 21: 1779–1785. 12. Hasegawa H, Fujitani K, Nakazuru S et al. Optimal indications for second-line chemotherapy in advanced gastric cancer. Anticancer Drugs 2012; 23: 465–470.
Annals of Oncology 24: 2854–2859, 2013 doi:10.1093/annonc/mdt340 Published online 29 August 2013
Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation A. Suzuki1, L. Xiao2, T. Taketa1, K. Sudo1, R. Wadhwa1, M. A. Blum1, H. Skinner3, R. Komaki3, B. Weston4, J. H. Lee4, M. S. Bhutani4, D. C. Rice5, D. M. Maru6, J. Erasmus7, S. G. Swisher5, W. L. Hofstetter5 & J. A. Ajani1* Departments of 1Gastrointestinal Medical Oncology; 2Biostatistics; 3Radiation Oncology; 4Gastroenterology, Hepatology, and Nutrition; 5Thoracic and Cardiovascular Surgery; 6Pathology; 7Radiology, University of Texas M.D. Anderson Cancer Center, Houston, USA
Received 24 March 2013; revised 21 May 2013 & 17 June 2013; accepted 9 July 2013
Background: Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a
*Correspondence to: Dr Jaffar A. Ajani, Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel: +1-713-792-2828; Fax: +1-713-563-0540; E-mail: jajani@ mdanderson.org
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Annals of Oncology Annals of Oncology 24: 2850–2854, 2013 doi:10.1093/annonc/mdt351 Published online 13 August 2013
Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis H. S. Kim1,†, H. J. Kim2,†, S. Y. Kim3, T. Y. Kim4, K. W. Lee5, S. K. Baek3, T. Y. Kim4, M. H. Ryu6, B. H. Nam7 & D. Y. Zang1* 1
Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang; 2Department of Preventive Medicine, Korea University, College of Medicine, Seoul; 3Department of Internal Medicine, Kyung Hee University Hospital, Seoul; 4Department of Internal Medicine, Seoul National University Hospital, Seoul; 5Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si; 6Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul; 7Biometric Research Branch, National Cancer Center, Goyang, Korea
Background: Many patients with refractory or relapsed gastric cancer after first-line chemotherapy have received salvage chemotherapy in routine clinical practice. However, there was no evidence to support this treatment until recent phase III trials demonstrated substantial prolongation of overall survival. Therefore, we conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than best supportive care. Patients and methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980–2013, week 13). In addition, we searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013. Results: The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. A significant reduction in the risk of death [HR = 0.64, 95% confidence interval (CI) 0.52–0.79, P < 0.0001] was observed with salvage chemotherapy.When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (95% CI 0.40–0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56–0.90, P = 0.004) for docetaxel. Conclusion: This meta-analysis demonstrated evidence to support second-line chemotherapy in advanced gastric cancer. Key words: advanced gastric cancer, second-line chemotherapy, best supportive care, meta-analysis
introduction Gastric cancer is the fourth most frequent malignant disease and the second most common cause of cancer-related death in the world [1]; it is also the second most frequent malignancy in Korea [2]. Although patients with early gastric cancer can be cured by surgical resection with perioperative or adjuvant chemotherapy, a large majority of patients experience a relapse after initial surgery or are diagnosed with unresectable, locally advanced or metastatic disease. Systemic chemotherapy with combination of fluoropyrimidine and platinum is now regarded as the standard treatment of these patients [3]. However, the efficacy of first-line treatment is modest, and most patients are nonresponders or eventually experience disease progression. *Correspondence to: Prof. Dae Young Zang, Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, 896 Pyeongchon-dong, Dongan-gu, Anyang 431-070, Korea. Tel: +82-31-380-3871; Fax: +82-31-386-2269; E-mail: [email protected] †
H.S.K. and H.J.K. were equally contributed to this study.
Even though patients with refractory gastric cancer have received salvage chemotherapy in routine clinical practice, especially in Asia, there was no evidence to support salvage chemotherapy until recent phase III trials demonstrated substantial prolongation of overall survival. Results of three randomized, controlled trials (RCT) were published as articles [4, 5] or abstract [6] and showed overall survival benefit from treatments with irinotecan or docetaxel compared with best supportive care (BSC) alone in patients for whom one or two prior treatments failed. We conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than BSC.
methods search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980–2013, week 13) for articles that included the following search terms in their tiles, abstracts, or keyword lists: ‘gastric or gastroesophageal or
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Grand Valley State Univ on November 3, 2013
Received 27 May 2013; revised 9 July 2013; accepted 10 July 2013
original articles
Annals of Oncology gastroesophagus or esophagogastric or stomach’, ‘cancer or neoplasm or carcinoma or malignant or malignancy’, ‘second-line or salvage or supportive care’, ‘chemotherapy or chemotherapeutic or antineoplastic agent’, and ‘randomized or randomized, controlled trial or randomised’. In addition, we searched the reference lists of relevant articles/reviews and used the ‘related articles’ feature in PubMed to identify additional articles. We searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013 and sought expert opinion to identify relevant but unpublished studies. We assessed all potentially eligible studies identified by the above search strategy. Clinical trials that met the following criteria were included in the meta-analysis: (i) trials comparing second-line or salvage treatment chemotherapy with BSC and (ii) prospective phase III randomized trials. Two review authors extracted data from each included study using an agreed-upon form and assessed the risk of bias. We resolved discrepancies through discussion.
statistical analysis The primary outcome measure of this meta-analysis was overall survival, defined as the time from the date of random assignment to date of death as a result of any cause. Survival analysis was conducted using the intention-totreat population. A fixed effect model was used to calculate the pooled hazard ratio (HR) estimate. HRs for death were combined using an inverse variance method based on a logarithmic conversion; 95% confidence intervals (95% CIs) were used to determine the standard error (SE) using the formula SE = 95% CI/1.96. The traditional Q-test and the I 2 statistic were used to evaluate heterogeneity. Significant heterogeneity was considered to be present for P < 0.05 in the Q test or for I 2 > 30%. The Z-test for overall
Figure 1. Flowchart of search process.
effect and its two-sided P-value were also assessed. RevMan v5.2 software was used to report outcomes.
results The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis. Figure 1 shows the search process. Finally, three randomized phase III trials that compared irinotecan or docetaxel with BSC were selected. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. The characteristics of studies are described in Table 1. The trials by Thuss-Patience et al. and Cook et al. were conducted in Europe, and the trial by Kang et al. took place in Asia. Enrolled patients were diagnosed with esophagogastric cancer. Most had an ECOG performance status of 0 or 1 and progressed within 3 months of a previous chemotherapy (Table 2). Overall survival was compared for 238 patients who were assigned to irinotecan or docetaxel as salvage chemotherapy with 172 patients who received supportive care. A significant reduction in the risk of death (HR = 0.64, 95% CI 0.52–0.79, P < 0.0001) was observed with salvage chemotherapy, as shown in Figure 2. Heterogeneity was not detected. When the analysis was restricted to irinotecan or docetaxel, there was still a significant reduction in the risk of death associated with each chemotherapeutic agent, as shown in Figure 3 and 4. The HR was 0.55 (95% CI 0.40–0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56–0.90, P = 0.004) for docetaxel. There were no significant differences in treatment effect according to the chemotherapeutic agent. Meta-analysis of the two trials in Europe also demonstrated that second-line chemotherapy reduced the risk of death by 37% compared with BSC (HR = 0.63, 95% CI 0.47–0.84; Figure 5).
Table 1. Main characteristics of the studies included in the meta-analysis Study Thuss-Patience et al. (2011) Kang et al. (2012)
Cook et al. (2013)
Patients (n) 21 19 133
69 84 84
Treatments a
Irinotecan 250 mg/m2, every 3 weeks Best supportive care Docetaxel 60 mg/m2, every 3 weeks Irinotecan 150 mg/m2, every 2 weeks Best supportive care Docetaxel 75 mg/m2,every 3 weeks Best supportive care
Objective response rate (%)
Disease control rate (%)
Median overall survival (months)
Hazard ratio (95% CI)
0
53
4.0
0.48 (0.25–0.92) P = 0.012
– 11
– 38
2.4 5.3
8
43
– 7
– 46
3.8 5.2
–
–
3.6
0.657 (0.485–0.891) P = 0.007
0.67 (0.49–0.92) P = 0.01
a
Dose of irinotecan could be escalated to 350 mg/m2 in subsequent cycles according to the protocol
Volume 24 | No. 11 | November 2013
doi:10.1093/annonc/mdt351 |
original articles
Annals of Oncology
Table 2. Brief characteristics of patients Characteristics
Thuss-Patience et al. Irinotecan No. (%)
No. of patients 21 Age, years Median 58 Range 43–73 Sex Male 18 (86) Female 3 (14) ECOG performance status 0 17 (81) 1 2 4 (19) Response to prior chemotherapy CR/PR 7 (33) SD/PD 14 (67) No. of metastatic sites 1 6 (29) ≥2 15 (71) Interval from last chemotherapy, months <3 18 (86) ≥3 3 (14)
BSC No. (%)
Kang et al. SLC No. (%)
BSC No. (%)
Cook et al. Docetaxel %
ASC %
19
133
69
84
84
55 35–72
56 31–83
56 32–74
65 25–84
66 35–84
11 (58) 8 (42)
93 (70) 40 (30)
44 (64) 25 (36)
82 18
80 20
14 (74) 5 (26)
72 (54) 61 (46) –
36 (52) 33 (48) –
28 55 17
28 55 17
4 (21) 15 (79)
54 (41) 79 (59)
29 (42) 40 (58)
– –
11 (58) 8 (42)
42 (32) 91 (68)
28 (41) 41 (59)
– –
17 (89) 2 (11)
101 (76) 32 (24)
48 (70) 21 (30)
75 25
69 31
ASC, active symptom control; BSC, best supportive care; CR, complete response; ECOG, eastern Cooperative Oncology Group; PD, progressive disease; PR, partial response; SD, stable disease; SLC, salvage chemotherapy.
Figure 2. Standard forest plot of the hazard ratio (HR) for death comparing second-line chemotherapy with best supportive care.
discussion Many patients with advanced gastric cancer are refractory to first-line chemotherapy or experience disease progression after a short response to treatment. Despite lack of evidence for salvage chemotherapy in advanced gastric cancer it is common practice to offer further chemotherapy after first-line failure. Recently, three trials have demonstrated the prolongation of survival with second-line chemotherapy over BSC. The Korean trial by Kang et al. [5] is the largest complete randomized trial involving 202 patients. The trial by Thuss-Patience et al. in Europe was prematurely closed after only 40 patients enrolled due to enrollment difficulties and the trial by Cook et al. enrolled 168 European patients in a trial presented as an abstract [4, 6]. This meta-analysis demonstrated that there exists a clear clinical benefit from the use of second-line chemotherapy in patients with advanced gastric cancer with 36% reduction in the risk of death. These results were observed consistently regardless
| Kim et al.
of the administered drugs, and the magnitude of the clinical benefit was similar between European and Asian populations in terms of survival (HR = 0.63 and 0.657, respectively). The results of randomized clinical trials including a BSC arm can be affected seriously by the lack of standardization of BSC delivery. Considering the descriptions of BSC in articles, the authors were aware of the risk of bias and tried to provide consistent and preplanned BSC intervention. Kang et al. [5] attempted to describe the administration of BSC intervention in detail and to provide explicit guidance. Thuss-Patience et al. had patients in the BSC arm examined and evaluated at the same frequency and by the same methods as in the irinotecan arm [4]. Therefore, it is unlikely that the lack of standardization of BSC may be a source of bias. If the patients in the BSC arm received chemotherapy during the study period or after progression, it could be an important factor reducing the power of the findings of these trials. In trials by Thuss-Patience et al. and Kang et al., only four patients (4.5%) among 88 patients enrolled in BSC arm received
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original articles
Figure 3. Standard forest plot of the hazard ratio (HR) for death comparing second-line irinotecan with best supportive care.
Figure 4. Standard forest plot of the hazard ratio (HR) for death comparing second-line docetaxel with best supportive care.
Figure 5. Standard forest plot of the hazard ratio (HR) for death comparing second-line chemotherapy with best supportive care in European patients.
chemotherapy. Therefore, chemotherapy in the BSC arm may not affect the findings of the trials evaluated in this metaanalysis. The efficacy of second-line chemotherapy was comparable among trials. The objective response rate (ORR) was about 10% and the disease control rate was above 40%. Different chemotherapy regimens such as docetaxel or irinotecan and administration schedule did not have any influence on the outcome. Several recent trials support these results. Ueda et al. [7] conducted a phase III study comparing second-line chemotherapy regimens in 223 patients with advanced gastric cancer. Patients received either weekly paclitaxel (80 mg/m2, days 1, 8, 15, every 4 weeks) or irinotecan (150 mg/m2, every 2 weeks). There were no differences between treatment groups in terms of ORR, median overall survival, and toxic effect. Roy et al. [8] conducted a phase II study to evaluate the efficacy and safety of single-agent PEP02 with irinotecan or docetaxel in the second-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma. Patients received either PEP02 (120 mg/m2, every 3 weeks), docetaxel (75 mg/m2, every 3 weeks), or irinotecan (300 mg/m2, every 3 weeks). The ORR, the primary end point, was similar between treatment groups. Although the benefit of second-line chemotherapy is evident, the disease control rate is just above 40%. In other words, almost half of patients do not benefit from second-line chemotherapy and suffer from chemotherapy toxic effect. Therefore, it is
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important to predict whether patients can benefit from secondline chemotherapy. Considering the results of univariate analysis for survival in two trials [4, 5], a good performance status and long chemotherapy-free interval (≥3 months) could be important positive prognostic indicators that could help physicians to make a decision regarding treatment. Several retrospective studies conducted to identify optimal prognostic factors have also suggested prognostic factors such as performance status, hemoglobin level, and time to progression of first-line chemotherapy [9–12]. Several limitations of this meta-analysis should be noted. Clinical and pathological factors were not analyzed thoroughly to identify prognostic factors, since the details about these factors were not available. The impact of second-line chemotherapy on quality of life was not analyzed due to lack of data. The trial by Cook et al. [6] addressed in the abstract that similar global health-related quality of life was observed in each arm. The other two trials did not report any assessment of quality of life. In conclusion, this meta-analysis demonstrated evidence to support the efficacy of second-line chemotherapy in the treatment of advanced gastric cancer. Several agents are available, and physicians can choose a regimen depending on toxic effect profiles and previous chemotherapy agents. Clinical prognostic factors derived from previous trials may guide physicians in deciding on the best treatment plan to improve outcomes.
doi:10.1093/annonc/mdt351 |
original articles funding This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065).
disclosure The authors have declared no conflicts of interest.
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Annals of Oncology 5. Kang JH, Lee SI, Lim do H et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 2012; 30: 1513–1518. 6. Cook N, Marshall A, Blazeby JM et al. COUGAR-02: a randomized phase III study of docetaxel versus active symptom control in patients with relapsed esophagogastric adenocarcinoma. J Clin Oncol 2013; 31 (suppl): abstract 4023. 7. Ueda S, Hironaka S, Yasui H et al. Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial. J Clin Oncol 2012; 30 (suppl): abstract 4002. 8. Roy AC, Park SR, Cunningham D et al. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol 2013; 24: 1567–1573. 9. Catalano V, Graziano F, Santini D et al. Second-line chemotherapy for patients with advanced gastric cancer: who may benefit? Br J Cancer 2008; 99: 1402–1407. 10. Ji SH, Lim do H, Yi SY et al. A retrospective analysis of second-line chemotherapy in patients with advanced gastric cancer. BMC Cancer 2009; 9: 110–115. 11. Kanagavel D, Pokataev IA, Fedyanin MY et al. A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy. Ann Oncol 2010; 21: 1779–1785. 12. Hasegawa H, Fujitani K, Nakazuru S et al. Optimal indications for second-line chemotherapy in advanced gastric cancer. Anticancer Drugs 2012; 23: 465–470.
Annals of Oncology 24: 2854–2859, 2013 doi:10.1093/annonc/mdt340 Published online 29 August 2013
Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation A. Suzuki1, L. Xiao2, T. Taketa1, K. Sudo1, R. Wadhwa1, M. A. Blum1, H. Skinner3, R. Komaki3, B. Weston4, J. H. Lee4, M. S. Bhutani4, D. C. Rice5, D. M. Maru6, J. Erasmus7, S. G. Swisher5, W. L. Hofstetter5 & J. A. Ajani1* Departments of 1Gastrointestinal Medical Oncology; 2Biostatistics; 3Radiation Oncology; 4Gastroenterology, Hepatology, and Nutrition; 5Thoracic and Cardiovascular Surgery; 6Pathology; 7Radiology, University of Texas M.D. Anderson Cancer Center, Houston, USA
Received 24 March 2013; revised 21 May 2013 & 17 June 2013; accepted 9 July 2013
Background: Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a
*Correspondence to: Dr Jaffar A. Ajani, Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel: +1-713-792-2828; Fax: +1-713-563-0540; E-mail: jajani@ mdanderson.org
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