Med Oncol (2015) 32:127 DOI 10.1007/s12032-015-0521-2
REVIEW ARTICLE
Cetuximab in patients with esophageal cancer: a systematic review and meta-analysis of randomized controlled trials Xu Tian • Jian-Guo Zhou • Zi Zeng • Ting Shuai • Li-Juan Yi • Li Ma • Yan Wang Hong Cao • Guo-Min Song
•
Received: 18 December 2014 / Accepted: 13 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Esophageal cancer is one cause of the most common cancer death and diagnosed in approximately half a million people annually worldwide, as well as has resulted in worse status, which is responsible for an estimated 482,300 new cases and 406,800 deaths in 2008, and is the fifth highest in the mortality rate among tumor sites. Esophageal cancer mainly occurred in southern and eastern Africa, eastern Asia and some areas of China. The results of meta-analysis suggested that survival rate can be improved [relative risk (RR) 1.6; 95 % confidence interval (CI) 1.17–2.18]; objective response rate (RR 1.47; 95 % CI 1.05–2.06) and disease control rate (RR 1.21; 95 % CI 1.03–1.43) in combination group are superior to that of the
control group; however, the higher incidence of acne-like rash was caused (RR 9.03; 95 % CI 1.64–49.63). Moreover, collated differences in overall survival rate and progression-free survival remained the most common grade 3/4/5 toxicities, and quality of life after intervention revealed no evidence of a difference between the two groups. With the present evidence, there is no role for cetuximab combined with standard approaches for esophageal cancer. Keywords Cetuximab Epidermal growth factor receptor Esophageal cancer
Introduction Xu Tian, Jian-Guo Zhou and Zi Zeng have equally contributed to this work X. Tian Z. Zeng T. Shuai L.-J. Yi L. Ma Graduate College, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People’s Republic of China J.-G. Zhou Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, People’s Republic of China Y. Wang (&) School of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People’s Republic of China e-mail: [email protected] H. Cao Department of Internal Orthopedics, Tianjin Hospital, Tianjin 300211, People’s Republic of China G.-M. Song (&) Department of Nursing, Tianjin Hospital, Tianjin 300211, People’s Republic of China e-mail: [email protected]
Esophageal cancer is diagnosed in approximately half a million people annually and has been listed as the eighth most common cancer worldwide [1, 2]; moreover, it caused yearly more than 400,000 cancer deaths in the whole world [3]. Issued evidence demonstrated that the esophageal carcinoma brought about more than 15,000 cancer deaths, in the USA in 2012 [4], and this condition is the sixth most common cause resulted in cancer death, as well as it is noted that in the UK, it caused approximately 5 % of all cancer deaths [5]. Published results suggested that the esophageal cancer is one of the most contributors to an estimated 482,300 new cancer cases and 406,800 deaths in 2008 and is the fifth highest in the mortality rate among tumor sites [1]. Esophageal cancer seriously occurred in the southern and eastern Africa and eastern Asia [6]. Issued data illustrated that in some areas of China, the incidence of esophageal cancer is 10- to 100-fold more than that of America [7]. Prognosis of esophageal cancer is greatly poor, and the grave status was characterized by a high
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mortality-to-incidence rate ratio of 0.83 [8]. The 5-year survival rate of patients who contracted the esophageal cancer has been only modestly improved over the past decade though various advanced medical alternatives developed [9]. Routine treatment regimes for esophageal cancer included standard surgery, chemotherapy based on the cisplatin and 5-fluorouracil (5-FU), and chemoradiotherapy (CRT) was adopted to treat the advanced esophageal carcinoma. Surgery has been preferentially selected to doctor the esophageal cancer over the past 50 years, whereas the corresponding survival rate after the operation ranging from 6 to 26 % is reported in these published studies [10– 12]. At the beginning of the 1990s, radiation therapy is part of the foremost, effective and safe intervention alternatives, but \10 % clients who have undergone esophageal carcinoma will achieve level of 5-year survival rate after radiotherapy. Systemic chemotherapy based on cisplatin and 5-FU is the most commonly adopted first-line regimen for advanced esophageal cancer; however, response rate and median survival rate are poor [13]. Most patients who relapse do so within the previously irradiated and chemotherapy-only area; CRT was established to improve various clinical outcomes [14–16]. But the local failure rate of patients treated with CRT reported in these recent evidences is 45–58 %, and the definitive CRT in patients with a poor outlook can be caused using long-term disease control. A large number of clients with esophageal cancer still succumb to the condition [17]. Epidermal growth factor receptor (EGFR) is over-expressed in up to 55 % of gastroesophageal cancers and is the most important contributor to the poor prognosis of various cancers [18]. Cetuximab, a monoclonal EGFR antagonist, improved outcomes when given in combination with chemotherapy in other tumors [19, 20]. Published studies have proved the potential of cetuximab in combination with conventional definitive chemotherapy or CRT, but these results remain controversial. So we undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to systematically evaluate the effect and safety of cetuximab combined with conventional approaches for patients with esophageal cancer.
Materials and methods This article was performed based on the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [21] and Cochrane Handbook for Systematic Reviews of Interventions [22]. All pooled analyses are based on previously published studies, and thus, no ethical approval and informed consent are required.
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Literature search PubMed, Web of Science, EMbase, CNKI, VIP, Chinese Wanfang Data, Clinicaltrials.gov and abstracts presented at ASCO and ESMO meeting were searched for relevant studies until September 21, 2014. The following search terms were used: ‘Esophageal Neoplasms,’ ‘Neoplasm*, Esophageal,’ ‘Esophagus Neoplasm*,’ ‘Neoplasms, Esophag*,’ ‘Cancer of Esophagus,’ ‘Cancer of the Esophagus,’ ‘Esophagus Cancer,’ ‘Cancer*, Esophagus,’ ‘Esophageal Cancer*,’ ‘cetuximab,’ ‘C225,’ and ‘Erbitux.’ The reference lists of eligible studies and relevant reviews were also manually searched to include any relevant articles. Conference abstracts meeting the inclusion criteria were also covered. Selection criteria According to the PICOS acronym (population, intervention, comparison and outcome), we define inclusion criteria: (1) Population (P): All the patients diagnosed with esophageal cancer with pathology and cytology were included in the systematic review and meta-analysis. (2) Interventions (I) and comparisons (C): comparing the efficacy and safety of cetuximab in combination with chemotherapy or radiotherapy or CRT versus chemotherapy or radiotherapy or CRT-alone. (3) Outcomes (O): The following measured outcomes were included: overall survival, survival rate, progression-free rate, objective response rate, disease control rate and most common grade 3/4/5 toxicities. (4) Study Design (S): RCTs and case–control study. The following references will be excluded: (1) animal study and cell experiment; (2) the essential information was not complete to extract the data and cannot acquire primary data from authors; (3) the duplicate data reported by the same author or the same medical center, the article with the most strict methodology and most complete data was chosen to incorporate into the article; (4) non-original research, such as review, letter and specialist comments. Data extraction Two authors (Xu Tian and Jian-Guo Zhou) extracted independently the following information according to redesign form: first author, publication year, country, sample size, baseline characteristics of patients, diagnosis criteria, length of illness, study setting and intervention. Continuous or binary data reported on specific outcomes were also extracted from original studies. The author would be contacted to acquire the complete data when necessary. Any divergences between authors concerning the eligibility of a study were resolved by consulting a third author (Yan Wang and Guo-Min Song) or consensus.
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Quality assessment Assessment of risk of bias of the eligible studies was conducted by each author (Xu Tian and Zi Zeng) according to the Cochrane Handbook for Systematic Reviews of Intervention [22]. Evaluation index included randomization sequence generation, allocation concealment, blinding of participants and study personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other biases. Based on the information extracted from primary studies, each domain was rated as ‘high risk,’ ‘unclear risk’ or ‘low risk’ [22].
Statistical analysis All extracted data were entered into RevMan 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2013) for statistical analysis (Xu Tian and LiJuan Yi). For dichotomous outcomes, we calculated the relative risk (RR), and corresponding 95 % confidence interval (CI) due to hazard ratios (HR) can only be obtained from two of all studies included in this meta-analysis [one directly presented the outcome measures with the HR, and one study presented the Kaplan–Meier (K–M) curve]. Heterogeneity in the included studies was evaluated using the Cochran’s Q, corresponding P value, and substantial level of heterogeneity was evaluated by I2 statistic. If I2 was C50 %, the eligible studies were considered to be heterogeneity; in contrast, if I2 was \50 %, the studies were considered to be homogeneous. The meta-analysis was performed via a random effects model or a fixed effects model based on Mantel–Haenszel (MH) or inverse variance (IV) statistical approach according to the clinical characteristic and methodology of eligible studies pooled. Subgroup analysis was conducted according to survival time. A qualitative analysis will be used to describe the studies, in which data are incomplete; heterogeneity can affect the pooled results or lack of a number of studies to pool. Owing to the limited number (below 10) of studies included in each analysis, publication bias was not assessed.
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(five met quantitative synthesis, and one was qualitatively analyzed) trials were summarized in Table 1. Assessing risk of bias A total of five eligible studies which met the quantitative synthesis were incorporated into the meta-analysis. Three of the trials were RCTs [23, 24, 27]. There was no allocation concealment or blinding of participants and personnel; however, all outcomes were objective indicators, and thus, measurement will not be negatively affected. Only one trial adopted intention-to-treat (ITT) analysis to deal with data, and other potential biases did not exist in all trials. The remaining two trials were case–control studies [25, 26]. Additionally, subtype of carcinoma and interventions was inconsistent for all studies included. The assessing risk of bias outcome is summarized in Fig. 2a, b. Subgroup meta-analysis Outcomes We performed a subgroup meta-analysis according to survival rate of various years. Two studies [25, 26], including 66 patients, reported 1-year survival rate, and all were pooled to examine the effect of cetuximab in combination with routing regime in patients with esophageal cancer. The meta-analysis revealed that there were significant differences that were not detected between the two groups (RR 1.42; 95 % CI 1.02–.98). No significant differences in clinical characteristic and methodology were identified for these studies included, as well as no statistical heterogeneity was verified for all studies (v2 = 0.79, P = 0.78, I2 = 0 %); therefore, a fixed-effect model was adopted in order to pool effect size (Fig. 3a). The 2-year survival rate is reported in two studies [23, 26], which included 57 and 55 patients between groups, respectively. Differences of clinical characteristics and methodology were not obvious, and there was no statistical heterogeneity (v2 = 0.08, P = 0.78, I2 = 0 %), and thus, a fixed-effect model was adopted in order to pool the results. The result indicated a significant difference between groups (RR 1.87; 95 % CI 1.04–3.34) (Fig. 3a).
Results
Meta-analysis outcomes
Study selection and trial characteristics
Four trials [23, 25–27] reported the objective response rate between groups. Clinical characteristics and methodology of all eligible trials were deemed to be homogeneity. Moreover, to establish the homogeneity, statistical heterogeneity was not detected based on testing for included studies (v2 = 1.33, P = 0.72, I2 = 0 %) and then a fixedeffect model was selected to summarize effect size. Metaanalysis showed that objective response rate in the
A total of 296 citations were identified at initial literature search stage, and five [23–27] eligible studies, which included 401 patients, and a study [28] that was qualitatively analyzed remained eligible according to the present study’s inclusion criteria. A flow diagram of literature retrieval and selection is shown in Fig. 1. The basic characteristics of six
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Fig. 1 Flow diagram of literature retrieval and screening
combination group was higher than that of control, with statistically significant difference (RR 1.47; 95 % CI 1.05–2.06) (Fig. 3b). Disease control rate was presented in three eligible trials [23, 26, 27], which included 66 and 66 patients between groups, respectively. The three studies were deemed to be homogeneous according to depth analysis on clinical characteristics and methodology. In addition, we adopted Chi-square test and I2 statistic to verify the statistical heterogeneity (v2 = 2.98, P = 0.23, I2 = 33 %). A fixedeffect model was adopted according to comprehensive analysis to examine the results. The pooled result suggested that the addition of cetuximab to CRT or chemotherapy or radiotherapy can effectively control disease, with statistically significant difference (RR 1.21; 95 % CI 1.03–1.43) (Fig. 3c). Two included studies reported the overall survival rate (OS), and progression-free survival (PFS) was presented in three eligible trials. Obvious difference in basic clinical characteristics and methodology of eligible studies was considered. Then, we selected Cochran’s Q and I2 statistic to verify the level of heterogeneity. Based on these
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analyses, a random-effect model was conducted to summarize the OS and PFS, respectively. Meta-analysis indicated that the pooled results were all not significantly different between groups (Fig. 3d, e). In addition, Mohan Suntharalingam’s phase III trial 28 revealed that the addition of cetuximab to concurrent chemoradiation did not improve OS, and the 12- and 24-month OS (95 % CI) for cetuximab plus CRT group is 64 and 44 % versus 65 and 42 % for CRT-alone (P = 0.70). Common terminology criteria for adverse events (CTCAE) was used to assess adverse events between groups during the treatment. Most common CTCAE grade 3 or 4 or 5 toxicities, including neutropenia, diarrhea, acnelike rash, etc., were listed in the three included trials. Heterogeneity was identified between groups, and thus, the random-effect model was selected. Meta-analysis shows that cetuximab in combination with standard therapy can cause serious acne-like rash (RR, 9.03; 95 % CI, 1.6449.63) (Fig. 4). Results from Mohan Suntharalingam [28] showed that the incidence of grade 3/4/5 treatment-related adverse events was 45, 22, 4 % in cefuroxime plus CRT group, and 49, 17, 1 % in CRT-alone.
China
China
Germany
UK
Germany
UK
Feng [25]
Liu [26]
Lorenzen [23]
Thomas [24]
Rades [25]
Mohan [28]
Esophageal carcinoma
Localized esophageal squamous cell cancer or adenocarcinomas
Localized esophageal squamous cell cancer and adenocarcinomas
Advanced esophageal squamous cell carcinoma
Advanced Esophageal carcinoma
Squamous cell carcinoma
Diagnosis
T treatment group, C control group
Country
Study ID
Unclear
18-75
44.9-84.1/ 35.7-81.9
40-76/40-74
unclear
unclear
Participants’ age (years)
unclear
9/11
129/129
32/30
25/25
8/8
Number of patients (T/C)
Progression-free Survival, Objective response rate, Disease control rate
Overall survival, Complete release rate, Most common grade 3/4/5 toxicities
Cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions
Cisplatin 60 mg/m2 on day 1 and capecitabine 625 mg/m2 twice daily on days 1 through 21 for 4 cycles with radiation therapy (RT) delivered to 50 Gy at 2 Gy per fraction given during cycles 3 and 4. RT was given with 3-dimensional conformal technique to the primary tumor plus a 2-cm mucosal margin and a 1-cm radial margin
Cisplatin 60 mg/m2 on day 1 and capecitabine 625 mg/m2 twice daily on days 1 through 21 for 4 cycles with radiation therapy (RT) delivered to 50 Gy at 2 Gy per fraction given during cycles 3 and 4. RT was given with 3-dimensional conformal technique to the primary tumor plus a 2-cm mucosal margin and a 1-cm radial margin. Cetuximab 400 mg/m2 on day 1 followed by 250 mg/m2 weekly for 12 weeks Cetuximab: Initial doses 400 mg/m2 (day 1), followed by weekly doses of 250 mg/m2 for 14 weeks in total, IV 5-FU: 1000 mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750 mg/m2/day as continuous infusion on day 71-74 and 99-102; Cisplatin 20 mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102); Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.57 weeks (5 9 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery Cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions plus weekly cetuximab (400 mg/m2 day 1 then weekly 250 mg/m2).
Survival rate, Objective response rate, Disease control rate, Progressionfree survival, Grade 3/4/5 toxicities, Quality of life Objective response rate, Disease control rate, Progression-free survival, Overall survival, Survival rate, Grade 3/4 toxicities Progression-free survival, Overall survival, Survival rate, Grade 3/4 toxicities
Survival rate, Objective response rate
Reported outcomes
5-FU: 1000 mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750 mg/ m2/day as continuous infusion on day 64-67 and 92-95; Cisplatin 20 mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95); Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 9 1.8 Gy per week) on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery
Cisplatin 100 mg/m2, day 1, plus 5-FU 1000 mg/m2, days 1-5
Standard concurrent chemoradiotherapy which based on cisplatin and 5-fluorouracil (5-FU) and radiotherapy with intensity-modulated radiotherapy (IMRT) Standard radiotherapy-alone
Interventions in Control group
Cisplatin 100 mg/m2, day 1, plus 5-FU 1000 mg/m2, days 1-5, plus cetuximab (400 mg/m2 initial dose followed by 250 mg/m2 weekly thereafter)
Cetuximab plus concurrent chemoradiotherapy which based on cisplatin and 5-fluorouracil (5-FU) and radiotherapy with intensitymodulated radiotherapy (IMRT) Radiotherapy plus Erbitux
Interventions in Treatment group
Table 1 | Basic characteristics of 6 studies included in this systematic review and meta-analysis
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Fig. 2 Risk of bias graph (a), Risk of bias summary (b)
Quality of life was analyzed as a primary outcome in two included studies; however, data cannot be derived from one trial, and thus, descriptive analysis was performed. One [24] at the combination therapy can effectively improve dysphagia, feed and eating restriction conditions in patients with esophageal cancer (P \ 0.05). In contrast, remaining one trial revealed that the change in the physical function, role function, fatigue, dysphagia and eating restriction scores from baseline to week 13 did not differ significantly between groups (P [ 0.05).
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Discussion Esophageal cancer is a malignant disease characterized by poor prognosis. About 50 % of clients who suffered from esophageal cancer have been progressed into the terminal stage when diagnosis was identified, and most patients only survive the 8- to 10-month overall survival (OS) time, as well as 5–17 % patients can survive 5 years [29].The esophageal cancer recurrence rate and metastasis rate were noted in more than 65 % of patients after 5 years though
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Fig. 3 Meta-analyses result of survival rate (a), objective response rate (b), disease control rate (c), overall survival rate (d) and progression-free survival (e)
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Fig. 4 Meta-analyses result of most common CTCAE grade 3/4/5 toxicities
some curative surgical treatments were conducted [30]. Response rates in systemic chemotherapy based on cisplatin and 5-FU are low at 15–45 %, and median survival time is usually shorter than 8 months [31], as well as the published failure rate is 45–58 % of patients treated with radiotherapy [32]. In addition, the clinical effect can be enhanced by using the CRT; however, a majority of adverse events have occurred, which limited the use of the approach. A series of studies were expected to be
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completed to identify novel therapies, in which the esophageal cancer will be effectively treated. Results from a large number of trials suggested that EGFR is over-expressed in up to 50–70 % of gastroesophageal cancers [33– 35] and have been correlated with prognosis [34–36]. Cetuximab, a monoclonal EGFR antagonist that specifically targets the EGFR, has shown efficacy in the treatment of advanced colorectal adenocarcinomas [19], squamous cell head and neck cancer [20] and non-small cell lung cancer (NSCLC)
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[37]. In addition, preclinical studies revealed that cetuximab can overcome an important mechanism of radioresistance [32], and results of a phase 3 trial by Bonner and colleagues [38] in squamous cell carcinoma of the head and neck show that cetuximab plus standard radiotherapy can improve local control and overall survival versus radiotherapy only. To our knowledge, this is the first systematic review and meta-analysis to evaluate the effect and safety of cetuximab in combination with standard approaches for treating esophageal cancer. The findings of this meta-analysis suggest that cetuximab in combination with other standard approaches may be more effective than standard treatment interventions alone, increasing the survival rate for esophageal cancer; however, there was no evidence that the cetuximab addition into the standard interventions enhances the objective response rate, disease control rate, progression-free survival and overall survival compared with standard care only. More importantly, cetuximab plus other standard therapeutic methods can increase the incidence of acne-like rash. Moreover, the results on quality of life between the two included studies were inconsistent. There are a number of limitations in this systematic review and meta-analysis that need to be acknowledged. Firstly, and perhaps most notably, only a small number of studies met the inclusion criteria, thus reducing the power of the analyses. Only studies in English and Chinese language literature were eligible for the article, so it is possible that additional relevant studies may have been identified, if the search had been extended to literature in other languages. Seven databases and conference abstracts were electronically searched; however, Sciencedirect, SpringerLink, EBSCOhost and China Biomedical Literature Database (CBM) were included; therefore, the risk of incompletely retrieved information exists in the current study. In all of the trials included in the meta-analysis, methodological and clinical heterogeneity was not excluded. In addition, the test on publication bias for studies was not conducted due to the small number of eligible studies, and thus, it may have a negative effect on the pooled results of current meta-analysis. Finally, some unpublished and missing data might lead bias to the pooled effect. In two studies, treatment approach of cetuximab concurrent with chemotherapy [25] or radiotherapy [24] used was different from the remaining three studies in which cetuximab in combination with chemoradiotherapy was used [22, 26, 27], and the difference may induce heterogeneity to negatively affect the power of pooled results. The Feng study was a conference article, but detailed data were obtained via email to the authors. The small sample and the differences in intervention methods, classification of participants and study methods among the trials included may have hit the outcomes of the meta-analyses. For example, some of the studies involved esophageal
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adenocarcinomas [26, 27]. Differences in race and methodological heterogeneity could have resulted in some bias in the meta-analysis. There is insufficient high-quality evidence available in the current literature regarding the effectiveness and safety of cetuximab plus standard approaches for the treatment of patients with esophageal cancer. Hence, the findings from this systematic and meta-analysis are by no means definitive. Nevertheless, the findings suggest that the addition of cetuximab to standard approaches may be more effective in increasing the survival rate, improving the objective response rate and disease control rate, but other outcomes were not significantly different compared with control interventions. More importantly, cetuximab addition to the standard methods can cause serious grade 3 or 4 toxicities, particularly acne-like rash. Currently, there is no role for cetuximab combined with standard approaches for esophageal cancer. Acknowledgments We would like to appreciate the work of editors and anonymous reviewers. The authors have declared that no competing interests exist. The study was not supported by any sources. Conflict of interest
No conflict of interest to declare.
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REVIEW ARTICLE
Cetuximab in patients with esophageal cancer: a systematic review and meta-analysis of randomized controlled trials Xu Tian • Jian-Guo Zhou • Zi Zeng • Ting Shuai • Li-Juan Yi • Li Ma • Yan Wang Hong Cao • Guo-Min Song
•
Received: 18 December 2014 / Accepted: 13 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Esophageal cancer is one cause of the most common cancer death and diagnosed in approximately half a million people annually worldwide, as well as has resulted in worse status, which is responsible for an estimated 482,300 new cases and 406,800 deaths in 2008, and is the fifth highest in the mortality rate among tumor sites. Esophageal cancer mainly occurred in southern and eastern Africa, eastern Asia and some areas of China. The results of meta-analysis suggested that survival rate can be improved [relative risk (RR) 1.6; 95 % confidence interval (CI) 1.17–2.18]; objective response rate (RR 1.47; 95 % CI 1.05–2.06) and disease control rate (RR 1.21; 95 % CI 1.03–1.43) in combination group are superior to that of the
control group; however, the higher incidence of acne-like rash was caused (RR 9.03; 95 % CI 1.64–49.63). Moreover, collated differences in overall survival rate and progression-free survival remained the most common grade 3/4/5 toxicities, and quality of life after intervention revealed no evidence of a difference between the two groups. With the present evidence, there is no role for cetuximab combined with standard approaches for esophageal cancer. Keywords Cetuximab Epidermal growth factor receptor Esophageal cancer
Introduction Xu Tian, Jian-Guo Zhou and Zi Zeng have equally contributed to this work X. Tian Z. Zeng T. Shuai L.-J. Yi L. Ma Graduate College, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People’s Republic of China J.-G. Zhou Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, People’s Republic of China Y. Wang (&) School of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People’s Republic of China e-mail: [email protected] H. Cao Department of Internal Orthopedics, Tianjin Hospital, Tianjin 300211, People’s Republic of China G.-M. Song (&) Department of Nursing, Tianjin Hospital, Tianjin 300211, People’s Republic of China e-mail: [email protected]
Esophageal cancer is diagnosed in approximately half a million people annually and has been listed as the eighth most common cancer worldwide [1, 2]; moreover, it caused yearly more than 400,000 cancer deaths in the whole world [3]. Issued evidence demonstrated that the esophageal carcinoma brought about more than 15,000 cancer deaths, in the USA in 2012 [4], and this condition is the sixth most common cause resulted in cancer death, as well as it is noted that in the UK, it caused approximately 5 % of all cancer deaths [5]. Published results suggested that the esophageal cancer is one of the most contributors to an estimated 482,300 new cancer cases and 406,800 deaths in 2008 and is the fifth highest in the mortality rate among tumor sites [1]. Esophageal cancer seriously occurred in the southern and eastern Africa and eastern Asia [6]. Issued data illustrated that in some areas of China, the incidence of esophageal cancer is 10- to 100-fold more than that of America [7]. Prognosis of esophageal cancer is greatly poor, and the grave status was characterized by a high
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mortality-to-incidence rate ratio of 0.83 [8]. The 5-year survival rate of patients who contracted the esophageal cancer has been only modestly improved over the past decade though various advanced medical alternatives developed [9]. Routine treatment regimes for esophageal cancer included standard surgery, chemotherapy based on the cisplatin and 5-fluorouracil (5-FU), and chemoradiotherapy (CRT) was adopted to treat the advanced esophageal carcinoma. Surgery has been preferentially selected to doctor the esophageal cancer over the past 50 years, whereas the corresponding survival rate after the operation ranging from 6 to 26 % is reported in these published studies [10– 12]. At the beginning of the 1990s, radiation therapy is part of the foremost, effective and safe intervention alternatives, but \10 % clients who have undergone esophageal carcinoma will achieve level of 5-year survival rate after radiotherapy. Systemic chemotherapy based on cisplatin and 5-FU is the most commonly adopted first-line regimen for advanced esophageal cancer; however, response rate and median survival rate are poor [13]. Most patients who relapse do so within the previously irradiated and chemotherapy-only area; CRT was established to improve various clinical outcomes [14–16]. But the local failure rate of patients treated with CRT reported in these recent evidences is 45–58 %, and the definitive CRT in patients with a poor outlook can be caused using long-term disease control. A large number of clients with esophageal cancer still succumb to the condition [17]. Epidermal growth factor receptor (EGFR) is over-expressed in up to 55 % of gastroesophageal cancers and is the most important contributor to the poor prognosis of various cancers [18]. Cetuximab, a monoclonal EGFR antagonist, improved outcomes when given in combination with chemotherapy in other tumors [19, 20]. Published studies have proved the potential of cetuximab in combination with conventional definitive chemotherapy or CRT, but these results remain controversial. So we undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to systematically evaluate the effect and safety of cetuximab combined with conventional approaches for patients with esophageal cancer.
Materials and methods This article was performed based on the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [21] and Cochrane Handbook for Systematic Reviews of Interventions [22]. All pooled analyses are based on previously published studies, and thus, no ethical approval and informed consent are required.
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Literature search PubMed, Web of Science, EMbase, CNKI, VIP, Chinese Wanfang Data, Clinicaltrials.gov and abstracts presented at ASCO and ESMO meeting were searched for relevant studies until September 21, 2014. The following search terms were used: ‘Esophageal Neoplasms,’ ‘Neoplasm*, Esophageal,’ ‘Esophagus Neoplasm*,’ ‘Neoplasms, Esophag*,’ ‘Cancer of Esophagus,’ ‘Cancer of the Esophagus,’ ‘Esophagus Cancer,’ ‘Cancer*, Esophagus,’ ‘Esophageal Cancer*,’ ‘cetuximab,’ ‘C225,’ and ‘Erbitux.’ The reference lists of eligible studies and relevant reviews were also manually searched to include any relevant articles. Conference abstracts meeting the inclusion criteria were also covered. Selection criteria According to the PICOS acronym (population, intervention, comparison and outcome), we define inclusion criteria: (1) Population (P): All the patients diagnosed with esophageal cancer with pathology and cytology were included in the systematic review and meta-analysis. (2) Interventions (I) and comparisons (C): comparing the efficacy and safety of cetuximab in combination with chemotherapy or radiotherapy or CRT versus chemotherapy or radiotherapy or CRT-alone. (3) Outcomes (O): The following measured outcomes were included: overall survival, survival rate, progression-free rate, objective response rate, disease control rate and most common grade 3/4/5 toxicities. (4) Study Design (S): RCTs and case–control study. The following references will be excluded: (1) animal study and cell experiment; (2) the essential information was not complete to extract the data and cannot acquire primary data from authors; (3) the duplicate data reported by the same author or the same medical center, the article with the most strict methodology and most complete data was chosen to incorporate into the article; (4) non-original research, such as review, letter and specialist comments. Data extraction Two authors (Xu Tian and Jian-Guo Zhou) extracted independently the following information according to redesign form: first author, publication year, country, sample size, baseline characteristics of patients, diagnosis criteria, length of illness, study setting and intervention. Continuous or binary data reported on specific outcomes were also extracted from original studies. The author would be contacted to acquire the complete data when necessary. Any divergences between authors concerning the eligibility of a study were resolved by consulting a third author (Yan Wang and Guo-Min Song) or consensus.
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Quality assessment Assessment of risk of bias of the eligible studies was conducted by each author (Xu Tian and Zi Zeng) according to the Cochrane Handbook for Systematic Reviews of Intervention [22]. Evaluation index included randomization sequence generation, allocation concealment, blinding of participants and study personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other biases. Based on the information extracted from primary studies, each domain was rated as ‘high risk,’ ‘unclear risk’ or ‘low risk’ [22].
Statistical analysis All extracted data were entered into RevMan 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2013) for statistical analysis (Xu Tian and LiJuan Yi). For dichotomous outcomes, we calculated the relative risk (RR), and corresponding 95 % confidence interval (CI) due to hazard ratios (HR) can only be obtained from two of all studies included in this meta-analysis [one directly presented the outcome measures with the HR, and one study presented the Kaplan–Meier (K–M) curve]. Heterogeneity in the included studies was evaluated using the Cochran’s Q, corresponding P value, and substantial level of heterogeneity was evaluated by I2 statistic. If I2 was C50 %, the eligible studies were considered to be heterogeneity; in contrast, if I2 was \50 %, the studies were considered to be homogeneous. The meta-analysis was performed via a random effects model or a fixed effects model based on Mantel–Haenszel (MH) or inverse variance (IV) statistical approach according to the clinical characteristic and methodology of eligible studies pooled. Subgroup analysis was conducted according to survival time. A qualitative analysis will be used to describe the studies, in which data are incomplete; heterogeneity can affect the pooled results or lack of a number of studies to pool. Owing to the limited number (below 10) of studies included in each analysis, publication bias was not assessed.
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(five met quantitative synthesis, and one was qualitatively analyzed) trials were summarized in Table 1. Assessing risk of bias A total of five eligible studies which met the quantitative synthesis were incorporated into the meta-analysis. Three of the trials were RCTs [23, 24, 27]. There was no allocation concealment or blinding of participants and personnel; however, all outcomes were objective indicators, and thus, measurement will not be negatively affected. Only one trial adopted intention-to-treat (ITT) analysis to deal with data, and other potential biases did not exist in all trials. The remaining two trials were case–control studies [25, 26]. Additionally, subtype of carcinoma and interventions was inconsistent for all studies included. The assessing risk of bias outcome is summarized in Fig. 2a, b. Subgroup meta-analysis Outcomes We performed a subgroup meta-analysis according to survival rate of various years. Two studies [25, 26], including 66 patients, reported 1-year survival rate, and all were pooled to examine the effect of cetuximab in combination with routing regime in patients with esophageal cancer. The meta-analysis revealed that there were significant differences that were not detected between the two groups (RR 1.42; 95 % CI 1.02–.98). No significant differences in clinical characteristic and methodology were identified for these studies included, as well as no statistical heterogeneity was verified for all studies (v2 = 0.79, P = 0.78, I2 = 0 %); therefore, a fixed-effect model was adopted in order to pool effect size (Fig. 3a). The 2-year survival rate is reported in two studies [23, 26], which included 57 and 55 patients between groups, respectively. Differences of clinical characteristics and methodology were not obvious, and there was no statistical heterogeneity (v2 = 0.08, P = 0.78, I2 = 0 %), and thus, a fixed-effect model was adopted in order to pool the results. The result indicated a significant difference between groups (RR 1.87; 95 % CI 1.04–3.34) (Fig. 3a).
Results
Meta-analysis outcomes
Study selection and trial characteristics
Four trials [23, 25–27] reported the objective response rate between groups. Clinical characteristics and methodology of all eligible trials were deemed to be homogeneity. Moreover, to establish the homogeneity, statistical heterogeneity was not detected based on testing for included studies (v2 = 1.33, P = 0.72, I2 = 0 %) and then a fixedeffect model was selected to summarize effect size. Metaanalysis showed that objective response rate in the
A total of 296 citations were identified at initial literature search stage, and five [23–27] eligible studies, which included 401 patients, and a study [28] that was qualitatively analyzed remained eligible according to the present study’s inclusion criteria. A flow diagram of literature retrieval and selection is shown in Fig. 1. The basic characteristics of six
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Fig. 1 Flow diagram of literature retrieval and screening
combination group was higher than that of control, with statistically significant difference (RR 1.47; 95 % CI 1.05–2.06) (Fig. 3b). Disease control rate was presented in three eligible trials [23, 26, 27], which included 66 and 66 patients between groups, respectively. The three studies were deemed to be homogeneous according to depth analysis on clinical characteristics and methodology. In addition, we adopted Chi-square test and I2 statistic to verify the statistical heterogeneity (v2 = 2.98, P = 0.23, I2 = 33 %). A fixedeffect model was adopted according to comprehensive analysis to examine the results. The pooled result suggested that the addition of cetuximab to CRT or chemotherapy or radiotherapy can effectively control disease, with statistically significant difference (RR 1.21; 95 % CI 1.03–1.43) (Fig. 3c). Two included studies reported the overall survival rate (OS), and progression-free survival (PFS) was presented in three eligible trials. Obvious difference in basic clinical characteristics and methodology of eligible studies was considered. Then, we selected Cochran’s Q and I2 statistic to verify the level of heterogeneity. Based on these
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analyses, a random-effect model was conducted to summarize the OS and PFS, respectively. Meta-analysis indicated that the pooled results were all not significantly different between groups (Fig. 3d, e). In addition, Mohan Suntharalingam’s phase III trial 28 revealed that the addition of cetuximab to concurrent chemoradiation did not improve OS, and the 12- and 24-month OS (95 % CI) for cetuximab plus CRT group is 64 and 44 % versus 65 and 42 % for CRT-alone (P = 0.70). Common terminology criteria for adverse events (CTCAE) was used to assess adverse events between groups during the treatment. Most common CTCAE grade 3 or 4 or 5 toxicities, including neutropenia, diarrhea, acnelike rash, etc., were listed in the three included trials. Heterogeneity was identified between groups, and thus, the random-effect model was selected. Meta-analysis shows that cetuximab in combination with standard therapy can cause serious acne-like rash (RR, 9.03; 95 % CI, 1.6449.63) (Fig. 4). Results from Mohan Suntharalingam [28] showed that the incidence of grade 3/4/5 treatment-related adverse events was 45, 22, 4 % in cefuroxime plus CRT group, and 49, 17, 1 % in CRT-alone.
China
China
Germany
UK
Germany
UK
Feng [25]
Liu [26]
Lorenzen [23]
Thomas [24]
Rades [25]
Mohan [28]
Esophageal carcinoma
Localized esophageal squamous cell cancer or adenocarcinomas
Localized esophageal squamous cell cancer and adenocarcinomas
Advanced esophageal squamous cell carcinoma
Advanced Esophageal carcinoma
Squamous cell carcinoma
Diagnosis
T treatment group, C control group
Country
Study ID
Unclear
18-75
44.9-84.1/ 35.7-81.9
40-76/40-74
unclear
unclear
Participants’ age (years)
unclear
9/11
129/129
32/30
25/25
8/8
Number of patients (T/C)
Progression-free Survival, Objective response rate, Disease control rate
Overall survival, Complete release rate, Most common grade 3/4/5 toxicities
Cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions
Cisplatin 60 mg/m2 on day 1 and capecitabine 625 mg/m2 twice daily on days 1 through 21 for 4 cycles with radiation therapy (RT) delivered to 50 Gy at 2 Gy per fraction given during cycles 3 and 4. RT was given with 3-dimensional conformal technique to the primary tumor plus a 2-cm mucosal margin and a 1-cm radial margin
Cisplatin 60 mg/m2 on day 1 and capecitabine 625 mg/m2 twice daily on days 1 through 21 for 4 cycles with radiation therapy (RT) delivered to 50 Gy at 2 Gy per fraction given during cycles 3 and 4. RT was given with 3-dimensional conformal technique to the primary tumor plus a 2-cm mucosal margin and a 1-cm radial margin. Cetuximab 400 mg/m2 on day 1 followed by 250 mg/m2 weekly for 12 weeks Cetuximab: Initial doses 400 mg/m2 (day 1), followed by weekly doses of 250 mg/m2 for 14 weeks in total, IV 5-FU: 1000 mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750 mg/m2/day as continuous infusion on day 71-74 and 99-102; Cisplatin 20 mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102); Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.57 weeks (5 9 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery Cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions plus weekly cetuximab (400 mg/m2 day 1 then weekly 250 mg/m2).
Survival rate, Objective response rate, Disease control rate, Progressionfree survival, Grade 3/4/5 toxicities, Quality of life Objective response rate, Disease control rate, Progression-free survival, Overall survival, Survival rate, Grade 3/4 toxicities Progression-free survival, Overall survival, Survival rate, Grade 3/4 toxicities
Survival rate, Objective response rate
Reported outcomes
5-FU: 1000 mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750 mg/ m2/day as continuous infusion on day 64-67 and 92-95; Cisplatin 20 mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95); Radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 9 1.8 Gy per week) on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery
Cisplatin 100 mg/m2, day 1, plus 5-FU 1000 mg/m2, days 1-5
Standard concurrent chemoradiotherapy which based on cisplatin and 5-fluorouracil (5-FU) and radiotherapy with intensity-modulated radiotherapy (IMRT) Standard radiotherapy-alone
Interventions in Control group
Cisplatin 100 mg/m2, day 1, plus 5-FU 1000 mg/m2, days 1-5, plus cetuximab (400 mg/m2 initial dose followed by 250 mg/m2 weekly thereafter)
Cetuximab plus concurrent chemoradiotherapy which based on cisplatin and 5-fluorouracil (5-FU) and radiotherapy with intensitymodulated radiotherapy (IMRT) Radiotherapy plus Erbitux
Interventions in Treatment group
Table 1 | Basic characteristics of 6 studies included in this systematic review and meta-analysis
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Fig. 2 Risk of bias graph (a), Risk of bias summary (b)
Quality of life was analyzed as a primary outcome in two included studies; however, data cannot be derived from one trial, and thus, descriptive analysis was performed. One [24] at the combination therapy can effectively improve dysphagia, feed and eating restriction conditions in patients with esophageal cancer (P \ 0.05). In contrast, remaining one trial revealed that the change in the physical function, role function, fatigue, dysphagia and eating restriction scores from baseline to week 13 did not differ significantly between groups (P [ 0.05).
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Discussion Esophageal cancer is a malignant disease characterized by poor prognosis. About 50 % of clients who suffered from esophageal cancer have been progressed into the terminal stage when diagnosis was identified, and most patients only survive the 8- to 10-month overall survival (OS) time, as well as 5–17 % patients can survive 5 years [29].The esophageal cancer recurrence rate and metastasis rate were noted in more than 65 % of patients after 5 years though
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Fig. 3 Meta-analyses result of survival rate (a), objective response rate (b), disease control rate (c), overall survival rate (d) and progression-free survival (e)
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Fig. 4 Meta-analyses result of most common CTCAE grade 3/4/5 toxicities
some curative surgical treatments were conducted [30]. Response rates in systemic chemotherapy based on cisplatin and 5-FU are low at 15–45 %, and median survival time is usually shorter than 8 months [31], as well as the published failure rate is 45–58 % of patients treated with radiotherapy [32]. In addition, the clinical effect can be enhanced by using the CRT; however, a majority of adverse events have occurred, which limited the use of the approach. A series of studies were expected to be
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completed to identify novel therapies, in which the esophageal cancer will be effectively treated. Results from a large number of trials suggested that EGFR is over-expressed in up to 50–70 % of gastroesophageal cancers [33– 35] and have been correlated with prognosis [34–36]. Cetuximab, a monoclonal EGFR antagonist that specifically targets the EGFR, has shown efficacy in the treatment of advanced colorectal adenocarcinomas [19], squamous cell head and neck cancer [20] and non-small cell lung cancer (NSCLC)
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[37]. In addition, preclinical studies revealed that cetuximab can overcome an important mechanism of radioresistance [32], and results of a phase 3 trial by Bonner and colleagues [38] in squamous cell carcinoma of the head and neck show that cetuximab plus standard radiotherapy can improve local control and overall survival versus radiotherapy only. To our knowledge, this is the first systematic review and meta-analysis to evaluate the effect and safety of cetuximab in combination with standard approaches for treating esophageal cancer. The findings of this meta-analysis suggest that cetuximab in combination with other standard approaches may be more effective than standard treatment interventions alone, increasing the survival rate for esophageal cancer; however, there was no evidence that the cetuximab addition into the standard interventions enhances the objective response rate, disease control rate, progression-free survival and overall survival compared with standard care only. More importantly, cetuximab plus other standard therapeutic methods can increase the incidence of acne-like rash. Moreover, the results on quality of life between the two included studies were inconsistent. There are a number of limitations in this systematic review and meta-analysis that need to be acknowledged. Firstly, and perhaps most notably, only a small number of studies met the inclusion criteria, thus reducing the power of the analyses. Only studies in English and Chinese language literature were eligible for the article, so it is possible that additional relevant studies may have been identified, if the search had been extended to literature in other languages. Seven databases and conference abstracts were electronically searched; however, Sciencedirect, SpringerLink, EBSCOhost and China Biomedical Literature Database (CBM) were included; therefore, the risk of incompletely retrieved information exists in the current study. In all of the trials included in the meta-analysis, methodological and clinical heterogeneity was not excluded. In addition, the test on publication bias for studies was not conducted due to the small number of eligible studies, and thus, it may have a negative effect on the pooled results of current meta-analysis. Finally, some unpublished and missing data might lead bias to the pooled effect. In two studies, treatment approach of cetuximab concurrent with chemotherapy [25] or radiotherapy [24] used was different from the remaining three studies in which cetuximab in combination with chemoradiotherapy was used [22, 26, 27], and the difference may induce heterogeneity to negatively affect the power of pooled results. The Feng study was a conference article, but detailed data were obtained via email to the authors. The small sample and the differences in intervention methods, classification of participants and study methods among the trials included may have hit the outcomes of the meta-analyses. For example, some of the studies involved esophageal
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adenocarcinomas [26, 27]. Differences in race and methodological heterogeneity could have resulted in some bias in the meta-analysis. There is insufficient high-quality evidence available in the current literature regarding the effectiveness and safety of cetuximab plus standard approaches for the treatment of patients with esophageal cancer. Hence, the findings from this systematic and meta-analysis are by no means definitive. Nevertheless, the findings suggest that the addition of cetuximab to standard approaches may be more effective in increasing the survival rate, improving the objective response rate and disease control rate, but other outcomes were not significantly different compared with control interventions. More importantly, cetuximab addition to the standard methods can cause serious grade 3 or 4 toxicities, particularly acne-like rash. Currently, there is no role for cetuximab combined with standard approaches for esophageal cancer. Acknowledgments We would like to appreciate the work of editors and anonymous reviewers. The authors have declared that no competing interests exist. The study was not supported by any sources. Conflict of interest
No conflict of interest to declare.
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