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- Hindawi Publishing Corporation
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- Copyright © 2019 Fengxia Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 1687-8450
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- 1687-8469
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- 10.1155/2019/6340567
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Abstract
Hindawi Journal of Oncology Volume 2019, Article ID 6340567, 8 pages https://doi.org/10.1155/2019/6340567 Review Article Esophageal Cancer: Should Gender Be Considered as an Influential Factor for Patient Safety in Drug Treatment? 1,2 1,2 2,3 4 1 5 Fengxia Liu, Helin Feng, Sumin Guo, Yuhan Chen, Qingyi Liu, Feng Wu, 2,6 1 Weikuan Gu , and Baoen Shan eTh Fourth Hospital, Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei Province 050011, China Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Center, Memphis, TN 38163, USA Department of Oncology, Chest Hospital of Hebei Province, Shijiazhuang, Hebei 050041, China Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China The 2nd Affiliated Hospital of Harbin Medical University, No. 7 building, Baojian Road, Harbin, Heilongjiang 161005, China Research Service, Veterans Aaff irs Medical Center, 1030 Jeeff rson Avenue, Memphis, TN 38104, USA Correspondence should be addressed to Weikuan Gu; wgu@uthsc.edu and Baoen Shan; baoenshan@hbydsy.com Received 6 May 2018; Revised 15 February 2019; Accepted 3 March 2019; Published 23 May 2019 Academic Editor: om Th as R. Chauncey Copyright © 2019 Fengxia Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. Analyze the gender difference of esophageal cancer patients in response to drug treatment. Methods. All publications on clinical trials were collected from PubMed, Scopus, and PMC. Each publication was examined to determine whether the publication is a clinical trial and whether data on gender difference were reported. Results.Selectedfromatotalof191 publications,datafrom7 trials with a total of 2041 patients were evaluated for gender differences. es Th e clinical trials involve different drugs and disease phenotype. A significant difference was obtained between male and female groups from Student’s t-test. er Th e is no conclusive result on age, ethnicity, tumor size, and drug influence. Conclusions. Gender difference in response to treatment potentially most likely exists in esophageal cancer patients, regardless of age, race, and drugs. 1. Introduction at the US National Institutes of Health [1]. Potential sex differences in genes in the epidermal growth factor receptor The National Institutes of Health (NIH) recognized in 2014 (EGFR) axis have been reported in humans and in rat models that sex and gender play a role in how health and disease [16–20]. processes differ across individuals and requested that sex In this review, safety data on patients in phase III trials be factored into research designs, analyses, and reporting in over the past ten years were examined. The data on hazard vertebrate animal and human studies as a biological variable ratio (HR) were analyzed for the gender, age, and gender [1]. Esophageal cancers, including cancer arising from the and drug interactions. The emphasis is on whether there are gastroesophageal junction, are challenging diseases world- differences between and among gender, age, and drugs in wide. Surgery has been the only option for treatment for the these clinical trials. past few decades. Recently, positive results from several new drugs, including ramucirumab, everolimus, capecitabine, and 2. Methods oxaliplatin, raise the hope for chemotherapy [2–10]. The gender difference in esophageal cancer incidence has All of the possible publications on clinical trials were col- been well known [8, 9]. Particularly, the male to female ratio lected from PubMed, Scopus, and PMC. Each publication of esophageal cancer incidence is 3:1. Gender differences in was examined to determine whether the publication is a medicine have commanded attention in recent years [11–15]. clinical trial and whether data on gender, age, and drugs were Health disparity research is one recently emphasized program reported in the clinical trials. A minimum of 100 patients 2 Journal of Oncology Records identified Records identified through Records identified through through PubMed Scopus searching PMC searching (n=2) searching (n=191) (n=126) Records aer duplicates removed (n=237) Records excluded: Records irrelevant to esophageal cancer 125 Clinical trials about esophageal Records review and Meta analysis 36 cancer Records phase I/II esophageal cancer 19 (n=57) (n=180) Records excluded: Full-text articles assessed for Records no full-text 8 eligibility (n=7) Records less than 100 cases 16 Records no data of gender HR 26 (n=50) Studies included in qualitative synthesis (n= 7) Figure 1: Flow diagram of selecting studies. intheclinicaltrial wasalsousedasselectioncriteria.This 3. Results selection criterion is designed to avoid potential bias because 3.1. Sex Balance in the Study of Clinical Trials of Esophageal of the small number of female patients in sparsely populated Cancer Has Not Been Adequately Addressed. Our literature trials. eTh female patients in the reported clinical trials are review indicated that the majority of the studies did not usually within the range between 10% and 25% of total analyze female and male patients separately. For example, participants [2, 4, 5, 7–10]. eTh number of female patients from PubMed, among 30 clinical trials that had more than in a clinical trial with less than 100 patients would be too 100 participants in the trials, 23 of them did not analyze smalltobeusedintheanalysis ofsexdieff rences. Forallthree gender influence on effectiveness of the drugs. Only in databases, searches were limited to the title of the article in seven trials was the gender difference analyzed. The ratio of English and those articles published between 2005 and 2016, gender-analyzed and nonanalyzed trials is 1:4. All of these 23 inclusive. nonanalyzed trials were reported aeft r 2010, when the public For searching PubMed, key words “esophageal cancer had begun to demand attention to sex differences [13, 14]. trial phase-III” were used to retrieve the publications. In In particular, 13 were published on or after 2014, when the total, 237 articles were identified from the three databases NIH imposed the policy on gender analysis for its supported after duplicates were removed (Figure 1). Aeft r the titles and studies [1]. Accordingly, the countries of origin for these 13 abstracts of these studies were examined, 180 papers were publications were examined. Based on the institute addresses excluded either because they were not trials, not associated of the rst fi authors, only one of these 13 rst fi authors was from with esophageal cancer, or because they were phase I/II trials. the US, but possibly reporting an international collaborative Another 50 trials were excluded due to the following reasons: clinical trial because coauthors were from large number of full-text was not available for 7 studies; 14 studies had fewer countries such as China, Korea, Poland, Ukraine, Brazil, Italy, than 100 cases; and 29 studies did not present gender HR data. Chile, Russia,Belgium,andFrance [20].Therestofthe trials Ultimately, seven trials were included for systematic review were conducted from countries in Europe and Asia. eTh se [2,4,5,7–10],all foundinPubMed. 13 clinical trials included 3014 patients, which would be a For Scopus, a total of 126 publications were identified. tremendous resource for the analysis of gender differences if They were all excluded for the following reasons: 79 were such analysis was conducted as part of the trials’ reporting. duplicated with PubMed, 10 were reviews, 4 were phase I/II trials, 3 cases had fewer than 100 patients, and 2 cases had 3.2. Gender Eec ff t on the Efficacy of Drugs. We are able more than 100 patients, but without gender HR information. For PMC, 2 cases were identified but were duplicated in to obtain separated hazard ratio data of female and male subjects from 7 studies. es Th e 7 trials have a total of 2041 PubMed. patients (Table 1), including 326 female patients. Among the Altogether, data from seven publications reporting results 7 publications, one reported by Crehange and colleagues [10] of clinical trials on the treatment of esophageal cancer were used for our analysis. analyzed both progression-free survival (PFS) and overall Journal of Oncology 3 Table 1: Summary of hazard ratio of men and women with esophageal cancer in clinical trials. PFS OS Cox Authors/reference N N N Death ratio HR (95% CI) HR (95% CI) regression #/year (%Men) (%women) (Women/Men)% HR (95% CI) analysis metastatic locoregional recurrence recurrence F/M Robb W.B. et al. 146/170 24/170 24/146 Univariable Univariable - - /[4]/2015 =85.9 =14.1 =16.4 F/M 0.26(0.06-1.09) 0⋅68 (0⋅24, Multivariable 1⋅90) 0⋅35 (0⋅08, 1⋅47) Death M: 0.89(0.75- Zhao Y, et al. 297/346 49/346 49/297 -- 1.07) /[5]/2015 =85.8 =14.2 =16.5 F:0.83(0.57- 1.21) Dutton S.J. et al. 372/449 77/449 77/372 M 0.82 (0.67–1.01) -- /[2]/2014 =82.9 =17.1 =20.7 F 0.70 (0.44–1.12) Oppedijk V. et al. 298/374 76/374 76/298 M/F 1.12(0.67-1.87) - - /[7]/2014 =80 =20 =25.5 Swisher S.G. et al. 141/157 16/157 16/141 M:1.0(0.5-1.7) - - [8]/2010 =90 =10 =11.3 F: 1.0 Crehange G. et 412/446 34/446 34/412 M/F1.4(0.8-2.45) - - al./[9]/2007 =92.4 =7.6 =8.3 PFS M 0.93(0.67-1.29) 50/206 F 0.42(0.19-0.91) Burmeister B.H. et 206/256 50/256 24.3 M/F:1.28(0.86- al./[10]/2005 =80.5 =19.5 1.90) OS M/F 1.36(0.93-1.99) survival (OS) ratio (Table 1). In both cases, female patients 3.3. Age Eeff ct on the Efficacy of Drugs. Five of these clinical showed a better response to chemoradiotherapy followed by trials provided data on the HR values of age dieff rences surgery [10]. Two studies provided PFS [2, 7] only, while one (Table 2) [4, 5, 8–10]. However, there was no evidence provided OS only [8]. One compared the death rate between showing age differences in the drug treatment of esophageal sexes [5]. One study calculated the PFS for both metastatic cancer. From the two studies that compared age difference, recurrence and locoregional recurrence [4]. Within these 7 the ratio is 1.0 and 1.01 (Table 1) [8, 9]. The other three studies, the hazard ratios of men were all higher than that of studies made comparisons between age 60 and above. In women except for one trial, which studied the comparison the comparison of chemoradiotherapy and surgery versus of preoperative chemotherapy or preoperative C/RT groups surgery alone, authors obtained a ratio of 1⋅49 and 0.88 in [8]; this study had the smallest patient population among the comparing patients of age>60 versus.<=60 for locoregional 7 studies. We first conducted a blunted Student’s t-test. For recurrence and univariable HR, respectively [4]. In the other this test, we listed every hazard ratio of men and women, study [10], the PFS and the OS patients of age>60 versus<=60 without separating the nature of the ratio. eTh average HRs were 1.43 and 1.53, respectively. In another study, patients in female and male patients were 0.811 and 1.07, respectively. were divided into three age groups,<60, 60-69, and>=70 [5]. In thet-test, thedataweretreated aspaired andanalysis The death risks were 0.85, 0.92, and 0.93, respectively. was conducted as a two-tailed test. A P value of 0.030 was u Th s, a definitive conclusion cannot be drawn from the obtained from our t-test. Because one study provided data inconsistencies of age effects from these studies. In order of both PFS and OS, we analyzed the data from this trial to better understand the age eeff ct, a consensus on the age separately with either PFS or OS from this study [10]. eTh P grouping among researchers may be necessary. At present, we do not see any age effect on the HR values of gender values for inclusion of only PFS or only OS from this study differences among these patients. [10] were 0.037 and 0.072, respectively. u Th s, it is most likely that there are gender disparities existing for patients as to the HR in drug treatments for 3.4. Gender and Age Interaction. At present, there is no patients with esophageal cancer. separate statistical data on the age of women and men. 4 Journal of Oncology Table 2: Summary of hazard ratio of <65 versus>=65 with esophageal cancer in clinical trials. Univariable HR Age Difference PFS (> 60 Authors/reference N<65 N>=65 Age mean Age (> 60 HR (95% CI): versus≤ #/year (range) versus≤ 60 years) 60 years) locoregional metastatic Robb W.B. et al. 57⋅8 -- recurrence recurrence 0⋅88 /[4]/2015 (36⋅9–76⋅4) 1⋅49 (0⋅81, 2⋅76) (0⋅49, 1⋅60) (<65 vs>=65) HR (95% CI):<60: Zhao Y, et al. 0.85(0.69-1.05) 174 172 59 (23-90) -- /[5]/2015 60-69: 0.92(0.67-1.25) >70:0.93(0.62- 1.39) Dutton S.J. et al. 64.8(58.0- -- --- /[2]/2014 70.7) Oppedijk V. et al. -- 60(36-79) - - - /[7]/2014 Swisher S.G. et al. - - 58(23-77) 1.0 (0.9–1.1) - - [8]/2010 1.01 (0.99 to 1.03) Local Crehange G. et -- 59 Relapse-Free -- al./[9]/2007 Survival 1.01 (1.00 to 1.02) Overall Survival PFS Burmeister B.H. et HR:1.43(1.06- Overall survival -- 62(28-83) - al./[10]/2005 1.99) 1⋅53 (1⋅14–2⋅06) P:0.02 Although itis knownthatesophagealcanceris4timesmore ratios. In one of our tests, OS data from this study were common among men than among women, there is no report deleted. A P value of 0.0416 was obtained, and the average on the age difference between women and men. Since in HR value of women was 0.5475 while that of men was 0.7878. our selected trials there is no difference between age groups, We next eliminated PFS data from this study. A P value of ageisruledoutasapotentialfactorthatinufl ences gender 0.0852 wasobtained,andthe averageHRvalueswere0.655 differences. and 0.8375 for women and men, respectively. Overall, gender differences exist in North American and European populations. Moreover, considering the fact 3.5. Ethnic Groups and Gender Dier ff ence. Among these that most European or North American and Australian seven studies, one was from an Asian group [5]. Although the populations are mixtures of ethnically diverse groups, gender risk ofdeathrateinfemalepatientsislessthanthatinmale differences may potentially exist in all ethnic groups. patients, statistically there is no significant difference between these two groups. Among the rest of the six trials, four are from European 3.6. Eec ff t of Pathological Characteristics. The effect on treat- countries, one from North America 8 and one from Australia ment of pathological characteristics were examined (Table 3) [10]. Within these studies, no ethnic groups were revealed for any significant influence. es Th e seven studies used a vari- or analyzed from the patients. We assume that the results in ety of methodologies in characterization of patients. es Th e these trials were mainly from North American and European methods included WHO performance status, differentiation populations. Based on these studies, the average HR values status, length of tumor, histology/squamous cell carcinoma, are 0.7075 and 0.9538 for women and men, respectively. and location of tumor. Because of the different methodologies Student’s t-test for the HR between sex groups is 0.0345. These in different studies, a comprehensive statistical comparison can only be interpreted as evidence that these two groups is difficult. Nevertheless, a tentative conclusion was obtained are likely significantly different, because one of these trials through examination of these data. In WHO performance provided both progression-free survival (PFS) and overall status,≥1 versus 0 seemingly shows some difference, with a survival (OS) ratios while others provided only one of these P value of 0.0513. While the average HR values of 0 grade Journal of Oncology 5 Table 3: Summary of hazard ratio of pathological characteristics with esophageal cancer in clinical trials. Drug vs Histology/ Preoperative Location of Authors/reference WHO squamous cell chemoradio- Differentiation status Length of tumor tumor #/year performance status carcinoma (SCC) therapy (CRT) nCRTs vs ≥1vs0 surgery only locoregional Univariable Below vs above recurrence HR:0.80(0.45- Adenocarcinoma Robb W.B. et al. carina HR:0.97(0.46,2.04) 1.43) -- vs SCC /[4]/2015 HR:1.09(0.34- metastatic Mulivariable HR:0.96(0.47-1.96) 3.52) recurrence HR:1.03(0.56- 0⋅67 (0⋅31, 1⋅43) 1.93) P:0.917 Perioperative vs preoperative Upper/middle 5-year relapse 0 HR:0.85(0.69 ≥8.0cm HR:0.86(0.66- free Zhao Y, et al. -1.04) HR:0.95(0.73-1.24) 1.13) HR:0.62(0.49- - - /[5]/2015 1 <8.0cm Lower 0.73) HR:0.97(0.76-1.23) HR; 0.86(0.71-1.04) HR:0.89(0.73- HR for 1.08) death:0.79(0.59- 0.95) 0 Oesophageal HR:0.67(0.46-0.98) Overall survival Adenocarcinoma HR:0.83(0.64- Dutton S.J. et al. 1 Getfi inib vs HR:0.81(0.65-1.01) 0.99) -- /[2]/2014 HR:0.83(0.64-1.08) placebo Squamous cell Junctional I/II 2 HR:0.90 HR:0.72(0.48-1.08) HR:0.73(0.48- HP:0.81(0.54-1.23) 1.09) Treatment arm(S vs S+CRT) SCC vs AC Univariable Univariable Oppedijk V. et al. HR:0.37(0.23- ≤5cm vs>5cm - HR:0.70(0.44-1.12) - /[7]/2014 0.59) HR:0.89(0.54-1.46) Mulivariable Multivariable HR:0.49(0.29-0.82) HR:0.50(0.29- 0.86) Preoperative C/RT vs preoperative C Well/moderate Overall survival HR:1.0 Upper/middle Swisher S.G. et al. 1vs0 HR:0.58(0.37- Poor/undifferentiated HR:1.0 -- [8]/2010 HR:1.24(0.91-1.70) 0.90) HR:1.3 P:0.2 Lower Disease free Unknown HR:0.8(0.5-1.4) survival HR:1.1 P:0.7 HR:0.55(0.35- 0.85) P-RT vs SC-RT Univariable HR:0.87(0.68- Dysphagia:grades 1-3 Crehange G. et HR:1.03(1.01-1.05) - 1.11) vs grades 4-5 -- al./[9]/2007 P:0.001 Multivariable HR:1.22(0.88-1.68) HR:0.83(0.63- 1.08) 6 Journal of Oncology Table 3: Continued. Drug vs Histology/ Preoperative Location of Authors/reference WHO squamous cell chemoradio- Differentiation status Length of tumor tumor #/year performance status carcinoma (SCC) therapy (CRT) CRT+S vs S Lower PFS Well/moderate >5cm Squamous HR:0.97(0.70- Burmeister B.H. et 1vs0 HR:0.82(0.61- HR:0.69(0.43-1.12) HR:0.72(0.44-1.17) HR:0.47(0.25-0.86) 1.33) al./[10]/2005 HR:1.24(0.91-1.70) 1.10) Poor ≤5cm Non-squamous Middle or upper Overall survival HR:0.92(0.59-1.45) HR:0.83(0.57-1.21) HR:1.02(0.72-1.44) HR:0.38(0.17- HR:0.89(0.67- 0.87) 1.19) are 0.873, the HR for 1 grade is 1.01. There were not enough to not be affected by other factors. Because no age effect data to analyze the influence of tumor differential and length was found on drug treatments, age may not be one of the of tumor on drug treatment. In the comparison between factors that influence gender difference. Also, data showed no squamous cell carcinoma (SCC) and other types, current data evidence on the gender effect from different drugs. Gender did not produce a significant P value, the P value beings differences were found from North American and European 0.179. Interestingly, there is no difference between the location populations with P value of 0.0345. The gender differences in of the cancer, comparing the upper and lower part of the the Asian population need to be confirmed with more studies. esophagus (P=0.398). Overall, it is not likely that pathological Therefore, gender differences in the response to treatment characteristics influence gender differences in treatment. of esophageal cancer should demand attention from basic researchers for understanding its molecular mechanism, as well as from clinicians for potential treatments based on 3.7. Drug and Gender Dier ff ence. We next examined whether gender such as dosage or frequency of drugs. particular drugs are linked to gender differences. Among all This review focuses on a very critical issue, the hazard these trials, only one did not show gender difference 8. aTh t ratio in clinical trials, and conducted a comprehensive anal- study is the comparison of preoperative chemoradiotherapy ysis on the available data. We included data from all the (C/RT) versus surgery alone. eTh two drugs used in this study, major clinical trials in the past ten years, which represent the cisplatinand paclitaxel,werethe same asintheother studies. general picture in drug development for gastric cancer. In our For example, a study by Oppedijk et al. [7] analyzed recur- initial literature searching, the excluded reports on clinical rence patterns in patients treated with either surgery alone or trials arethose thatareeitherdid notconduct thesubgroup surgery plus preoperative chemoradiotherapy (CRT), which analysis between female and male patients or were otherwise consisted of ve fi weekly courses of paclitaxel and carboplatin notaccessible forthisreview.In general,thesehaverelatively combined with concurrent radiation. In the study by Swisher small patient populations [3, 6]. etal.[8],treatmentconsistedofthreecyclesofcisplatinand5- To determine the causes for different responses to drugs, uo fl rouracil (5-FU) before surgery. Two courses of treatment such as whether the differential response is genetic, phys- with cisplatin and 5-FU were conducted in the study by iological, behavioral, or simply due to life habits, future Crehange et al. [9]. In the study by Burmeister et al. [10], studies and data collections are needed. Most likely, the randomly assigned treatments with cisplatin and 5-FU were interactions between genetic physiological complexes and also conducted. eTh refore, drugs were not the cause that led molecular mechanisms of drugs play an important role. to the different results from this study. The small number Subgroup analysis in future clinic trials, with either smaller of total patients, a total of 157, and the small number of or larger numbers of patients, is essential for clarifying these female patients, only 16 in total, were considered to be the critical issues in drug applications. reasons that this study did not show gender differences. us, Th drugs used in these clinical trials did not influence the gender difference. 4. Executive Summary 3.8. Conclusions and Prospective. The collective analysis of The male to female ratio of the esophageal cancer incidence previous studies suggests that gender differences in response is 3:1. An important question is whether there is a gender to drug treatment in esophageal cancer is potentially all dieff renceinresponsetodrugtreatmentsinpatientsof across the spectrum, regardless of age, race, and drugs. esophageal cancer. A P value from t-test with combined PFS and OS values Hazard ratio (HR) data were used to compare gender from seven qualified studies reached a significant level at differences. We have analyzed results using a total of 2198 0.030. Separated analysis of PFS and OS values produced patients from 7 selected clinical trials. Pvaluesof0.037 and0.072.Unlikepreviouslysuggested Student’s t-test indicated that there is a gender difference [21], our analysis indicated that gender difference seems in the HR during drug treatment. Journal of Oncology 7 Tests indicated that age and pathology status do not Acknowledgments influence the HR between male and female patients. This work was supported in part by the Department of Different drugs may influence the HR between male and Veterans Affairs (1IPIBX001607-01), the Veterans Adminis- female patients. tration Medical Center at Memphis TN, USA, and the Fourth Hospital, Hebei Medical University, China. The authors thank 4.1. er Th apeutic Implications. The gender difference in HR Dr. Richard Redfearn of the Office of Scientific Writing, suggests that physiological and biological differences in Ocffi e of Research at the University of Tennessee Health cancer development and response to drug treatments exist Science Center, for professional editing of this manuscript. between female and male patients. Such gender differences aeff ct the efficacy of drug treat- References ment. Age should not be considered as a factor that influences [1] J. A. Clayton and F. S. 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