Literature DB >> 34706159

Definitive concurrent chemoradiotherapy with paclitaxel plus carboplatin is superior to cisplatin plus 5-fluorouracil in patients with inoperable esophageal squamous cell carcinoma using retrospective, real-world evidence.

Jason Chia-Hsun Hsieh1,2,3, Pin-Chun Chiang1,3, Tsung-Min Hung3,4, Yin-Kai Chao3,5, Yung-Chia Kuo1,2,3, Chih-Tsung Wen3,5,6, Po-Jung Su2,3, Meng-Ting Peng2,3, Huan-Wu Chen3,7,8, Hui-Ling Liu9, Hsien-Kun Chang1,2,3, Min-Hsien Wu1,2,3, Hung-Ming Wang1,2,3.   

Abstract

BACKGROUND: The optimal definitive chemotherapy regimen during concurrent chemoradiotherapy (CRT) for patients with advanced esophageal squamous cell carcinoma (ESCC) remains unclear because of conflicting evidence. This study aimed to compare the effectiveness of taxane-based chemotherapy with that of conventional cisplatin plus 5-fluorouracil (PF) as the chemotherapy regimen in definitive CRT for ESCC. PATIENTS AND METHODS: This retrospective study included patients with ESCC who received paclitaxel plus carboplatin (PC) or PF during definitive CRT between May 2012 and February 2015 in a medical center in Taiwan. Survival outcomes were compared after adjustment for risk factors.
RESULTS: Overall, 229 patients were evaluated. Patients in the PC group had an objective response rate of 71.1% compared with the 51.4% of the PF group (p = 0.016). The PC group showed a significantly longer progression-free survival (PFS, p = 0.002) and overall survival (OS, p = 0.019) than the PF group. Salvage surgery also helped prolong both the PFS and OS (p < 0001). Sex (male vs. female, HR, 1.831; 95% CI, 1.016-3.303), clinical stage (HR, 1.282; 95% CI, 1.069-1.537), accumulative radiation dose (≥41.4 Gy vs. <41.4 Gy; HR, 0.640; 95% CI, 0.413-0.993), salvage surgery (yes vs. no, HR: 0.412, 95% CI: 0.298-0.570), and regimen (PF vs. PC; HR, 1.514; 95% CI, 1.109-2.067) were independent prognostic factors for cancer mortality.
CONCLUSION: Compared with the PF regimen, the PC regimen for definitive CRT yielded significantly increased response rates and longer survival times; therefore, the PC regimen may be preferable for chemotherapy for definitive CRT in patients with advanced ESCC.
© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Entities:  

Keywords:  5-fluorouracil; carboplatin; cisplatin; definitive chemoradiotherapy; esophageal squamous cell carcinoma; paclitaxel

Mesh:

Substances:

Year:  2021        PMID: 34706159      PMCID: PMC8633257          DOI: 10.1002/cam4.4025

Source DB:  PubMed          Journal:  Cancer Med        ISSN: 2045-7634            Impact factor:   4.452


INTRODUCTION

Esophageal cancer (EC) is one of the 10 most common cancers in men worldwide. , It is highly common in Taiwan, with a crude incidence of 21.87 male cases per million and 1.73 female cases per million. Histologically, EC can be classified into esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). EAC is more prevalent in North America and Europe with gastroesophageal reflux disease and obesity being the main risk factors. Meanwhile, ESCC is the more predominant EC in Asia, Africa, and South America. It is also predominant in African Americans in North America. Tobacco use and alcohol consumption are the main risk factors and esophageal squamous dysplasia is the precursor lesion. Surgery is the primary curative modality for EC, but inoperable patients are treated primarily with definitive concurrent CRT (dCRT). Chemotherapy and CRT are used as neoadjuvant therapies to improve long‐term survival. , , , , Among the chemotherapy regimens in CRT, cisplatin plus 5‐fluorouracil (PF regimen) remains the most common choice (Category 1) [9]. However, long PF infusions are associated with toxicity and intolerance, prompting the development of other regimens, in recent years. The National Comprehensive Cancer Network guideline also recommends paclitaxel and carboplatin (PC) for dCRT based on the findings of the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) in 2012 that demonstrated not only a better 5‐year overall survival (OS) but also lower toxicity of PC as the chemotherapy regimen in CRT. , , , Local recurrence and distant metastasis are common after primary treatment. However, prospective trials evaluating the efficacy of different CRT regimens are lacking, and thus, the optimal regimen for dCRT or nCRT is yet to be established. Therefore, this study aimed to evaluate and compare the efficacies of PC and PF as chemotherapy regimens in CRT for EC.

MATERIALS AND METHODS

Study design and patients

This retrospective study was approved by the institutional review board of Chang Gung Memorial Hospital (Approval number 201701030B0). We evaluated the patients with ESCC who were administered PC or PF during CRT between May 2012 and February 2015 at Chang Gung Memorial Hospital, Linkou, Taiwan. The inclusion criteria were: (i) age ≥20 years; (ii) Eastern Cooperative Oncology Group (ECOG) performance status 0–2; (iii) histologically confirmed ESCC; (iv) locally advanced, inoperable, newly diagnosed disease; (v) adequate liver and renal functions for dCRT; and (iv) had received chemotherapy or radiotherapy for at least 4 weeks. All patients received standard examinations for staging at diagnosis and were restaged according to the 8th edition of the American Joint Cancer Committee (AJCC) guidelines. The patients were divided into two groups, the PF and PC groups, according to their chemotherapy regimen.

Chemoradiotherapy protocol

After the medical oncologists discussed the differences between the regimens with the patients and their families, a clinical shared decision‐making model was used to select the regimen to be followed. For chemotherapy, the PF regimen involved cisplatin at a dose of 60–75 mg/m2 on day 1 and 5‐fluorouracil (5‐FU) at a dose of 800–1000 mg/m2 on days 1 to 4 every 4 weeks and the PC regimen involved paclitaxel at a dose of 50 mg/m2 every week for six weeks. Carboplatin was delivered simultaneously at a dose calculated from an area under the curve of 2 mg/ml/min every week for 6 weeks. All the patients were premedicated intravenously with dexamethasone, cimetidine, diphenhydramine, and granisetron according to the standard protocol of the institution. All adverse effects were documented according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3.0.10. Radiotherapy was performed with a total external‐beam radiation dose of 50.4–59.4 Gy in 28–30 fractions at 1.8 Gy per fraction. Radiotherapy commenced on the first day of the first chemotherapy cycle and was performed in five fractions per week. In this study, we defined the cumulative RT dose of more than 4.14 Gy as the completion threshold of CCRT. The radiotherapy technique was based on the institution's guidelines.

Surgery after definitive chemoradiation

All the patients received dCRT. Surgery was performed for those who had cancer down‐staging. In these patients, surgery was performed within 4 to 6 weeks after completion of the CRT. All the pathological characteristics were documented.

Follow‐up

Patients who underwent surgery were followed up every 3 months in the first year, every 6 months in the second year, and then annually thereafter until 5 years. Late toxic effects, disease recurrence, and death were reviewed using data from the medical charts. Recurrence was evaluated at the time of the first recurrence. Follow‐up diagnostic investigations were performed only when recurrence was suspected. Among patients who underwent dCRT alone, those with good responses were commonly followed up with only close surveillance.

Statistical analysis

All the data, including the staging according to the AJCC guidelines, were revised and updated until February 2020, which guaranteed a follow‐up duration of at least 2 years. All the patients intended for dCCRT were enrolled for analysis. Age, sex, histology, clinical stage, locations of the primary tumor, radiation dose, and the number of salvage surgeries were analyzed using a simple descriptive method, while the Chi‐square or Fisher exact tests were used to compare the PF and PC groups. All the significant factors from the univariate analysis were analyzed in the multivariate Cox regression model. A forward LR model was used to evaluate statistical significance. Progression‐free survival (PFS) and overall survival (OS) were calculated from the date of diagnosis (with tissue evidence) to the date of disease progression/relapse and death, respectively. Survival curves were generated using the Kaplan–Meier method and compared using the log‐rank test. All the statistical analyses were performed using SPSS software, version 17.0 (SPSS Inc.). A p‐value of less than 0.05 was considered to be statistically significant.

RESULTS

Patient characteristics

Of the 293 patients (including 22 patients with cervical EC) who received dCRT, 44 (15.0%) patients who had initial metastasis at diagnosis and 20 (6.8%) patients who had concurrent synchronous double cancer, were excluded. Some patients with relatively early‐stage disease (Stages IIa–IIb) also refused surgery and received dCRT mainly because of (i) their medically inoperable status or (ii) the primary location being at the cervical esophagus. Consequently, 229 patients were included in the analyses. Among them, 146 patients received the PF regimen and 83 patients received the PC regimen (Figure 1). The patients’ characteristics are shown in Table 1. The median age was 60 (range, 39–92) years. All the patients were followed until March 2020, with a median follow‐up time of 12.0 (range, 0.8–85.7) months. There were no significant differences in the clinicopathological features, including age, sex, histology, clinical stages, primary tumor locations, tumor grade, baseline ECOG performance status, cumulative radiation doses, and surgery rates, after concurrent CRT, between the PF and PC groups. In total, 78 of the 83 patients (94%) in the PC group and 133 of the 146 patients (91.1%) in the PF group were female. The majority of patients in both groups had ESCC (224 of 229, 97%). Most of the patients in both groups had stage IIIB (50.6% and 42.5% in the PC and PF groups, respectively) and stage IVA (40.9% and 49.3% in PC and PF groups, respectively) disease. The reasons for the enrolled patients being categorized as inoperable or unresectable are based primarily, on their initial stages (at least stage III, 91.5% and 91.8% in PC and PF, respectively, Table 1) and age/performance/willing to undergo surgery (8.5% and 8.2% in PC and PF, respectively, Table 1). Most tumors were located in the middle and lower part of the esophagus (PC group: 60/83 patients [72.2%]; PF group, 99/146 patients [67.8%]). Most patients had a performance status of −0–1(96.4%, 91.8%, for PC and PF groups, respectively).
FIGURE 1

CONSORT flow diagram of patient enrollment

TABLE 1

Clinicopathological patient characteristics by the group

Parameters

PC group (n = 83),

n (%)

PF group (n = 146)

n (%)

p value
Age (years), median (range)62(42–92)59 (39–89)0.065
Sex0.436
Male/female5 (6.0%)/78 (94.0%)13 (8.9%)/133 (91.1%)
Histology
SqCC80 (96.4%)144 (98.6%)
Adenocarcinoma2 (2.4%)1 (0.7%)
Others a 1 (1.2%)1 (0.7%)0.314
Stage (AJCC 8th edition)
IIA‐IIB b 2 (2.4%)8 (5.5%)
IIIA5 (6.0%)4 (2.7%)
IIIB42 (50.6%)62 (42.5%)
IVA34 (40.9%)72 (49.3%)0.467
Tumor location
Cervical7 (8.4%)15 (10.3%)
Upper third15 (18.1%)31 (21.2%)
Middle third31 (37.3%)51 (34.9%)
Lower third29 (34.9%)48 (32.9%)0.896
Performance status (ECOG)
0–180 (96.4%)134 (91.8%)
≥23 (3.6%)12 (8.2%)0.185
Cumulative radiation dose
<41.4 Gy8 (9.6%)20 (13.7%)
≥41.4 Gy75 (90.4%)126 (86.3%)0.367
Surgery after CCRT
No53 (63.9%)92 (63.0%)
Yes30 (36.1%)54 (37.0%)0.899
Grading
GX4 (4.8%)21 (14.4%)
G10 (0.0%)1 (0.7%)
G259 (71.1%)101 (69.2%)
G320 (24.1%)23 (15.8%)0.072
Response to CCRT
CR13 (15.7%)9 (6.2%)
PR46 (55.4%)66 (45.2%)
SD11 (13.3%)24 (16.4%)
PD10 (12.0%)39 (26.7%)
Not assessed3 (3.6%)8 (5.5%)0.016
Pathologic CR (n/total)3/30 (10%)6/54 (11.1%)0.875

Abbreviations: 5‐FU, 5‐fluorouracil; CCRT, concurrent chemoradiotherapy; CR, complete remission; ECOG, Eastern Cooperative Oncology Group; G1, grade 1 well‐differentiated; G2, moderately differentiated; G3, poorly differentiated; PC, paclitaxel plus carboplatin; PD, progressive disease; PF, cisplatin+5‐fluorouracil; PR, partial response; SD, stable disease; SqCC, squamous cell carcinoma.

Other pathology includes one sarcomatoid carcinoma and one basaloid carcinoma.

Early stage (stage IIa–IIb) patients did not receive conventional surgery because of a medically inoperable status or primary location at the cervical esophagus.

CONSORT flow diagram of patient enrollment Clinicopathological patient characteristics by the group PC group (n = 83), n (%) PF group (n = 146) n (%) Abbreviations: 5‐FU, 5‐fluorouracil; CCRT, concurrent chemoradiotherapy; CR, complete remission; ECOG, Eastern Cooperative Oncology Group; G1, grade 1 well‐differentiated; G2, moderately differentiated; G3, poorly differentiated; PC, paclitaxel plus carboplatin; PD, progressive disease; PF, cisplatin+5‐fluorouracil; PR, partial response; SD, stable disease; SqCC, squamous cell carcinoma. Other pathology includes one sarcomatoid carcinoma and one basaloid carcinoma. Early stage (stage IIa–IIb) patients did not receive conventional surgery because of a medically inoperable status or primary location at the cervical esophagus. With respect to treatment characteristics, there was no significant difference in the radiation dose between the two groups (accumulative doses: ≥41.4 Gy vs. <41.4 Gy, p = 0.367). There was also no significant difference in the proportion of patients who underwent salvage surgery between the PC and PF groups (30 (36.1%) vs. 54 (37.0%), p = 0.899). The reasons for the 28 dropouts in this study were (i) intolerance to CCRT (toxicity) (n = 18), (ii) economic issues (n = 3), and (iii) malnutrition or sepsis (n = 7).

Survival outcomes

The PC group had a significantly longer PFS (p = 0.002; Figure 2A, median PFS: 16.5 vs. 8.4 months) and OS (p = 0.019; Figure 2B, median OS: 18.6 vs. 10.9 months) than the PF group. Surgery after concurrent CRT also prolonged both the PFS (Figure 2C p < 0.001, median PFS: 20.0 vs. 7.5 months) and OS (Figure 2D, p < 0.001, median OS: 24.5 vs. 9.4 months). In addition, patients who received a higher cumulative radiation dose of ≥41.4 Gy during CRT had a longer OS (Figure 2F, p = 0.018, median OS: 12.8 vs. 8.7 months) than those who received less than 41.4 Gy. However, these findings were not observed with PFS (Figure 2E, p = 0.349, median PFS: 10.8 vs. 7.8 months).
FIGURE 2

Kaplan–Meier survival curves of the two groups. The patients who received chemoradiotherapy using paclitaxel plus carboplatin (PC group) achieved significantly longer progression‐free survival (PFS, p = 0.002) (A) and overall survival (OS, p = 0.019) (B) than those who received cisplatin plus 5‐fluorouracil (PF group). Surgery after concurrent chemoradiotherapy was associated with a significantly better PFS (p < 0.001) (C) and OS (p < 0.001) (D). A cumulative radiation dose of 41.4 Gy was not related to PFS (p = 0.349) (E), but associated with significantly better OS (p = 0.018) (F)

Kaplan–Meier survival curves of the two groups. The patients who received chemoradiotherapy using paclitaxel plus carboplatin (PC group) achieved significantly longer progression‐free survival (PFS, p = 0.002) (A) and overall survival (OS, p = 0.019) (B) than those who received cisplatin plus 5‐fluorouracil (PF group). Surgery after concurrent chemoradiotherapy was associated with a significantly better PFS (p < 0.001) (C) and OS (p < 0.001) (D). A cumulative radiation dose of 41.4 Gy was not related to PFS (p = 0.349) (E), but associated with significantly better OS (p = 0.018) (F)

Univariate and multivariate analyses of the prognostic factors

To confirm the independent prognostic factors in this cohort, we used a Cox regression model for the univariate and multivariate analyses after adjustments for all the basic factors. As shown in Table 2, the chemotherapy regimen (PF vs. PC, hazard ratio [HR], 1.840; 95% confidence interval [CI]: 1.275–2.656), AJCC stage (HR, 1.347; 95% CI, –1.096–1.657), and salvage surgery (HR, 0.417; 95% CI, 0.289–0.600) were independent prognostic factors for disease progression after concurrent dCRT. Meanwhile, sex (male vs. female; HR, 1.831; 95% CI, 1.016–3.303), AJCC stage (HR, 1.282; 95% CI, 1.069–1.537), cumulative radiation dose (≥41.4 Gy vs. <41.4 Gy; HR, 0.640; 95% CI, 0.413–0.993), salvage surgery (HR, 0.412; 95% CI: 0.298–0.570), and chemotherapy regimen (PF vs. PC; HR, 1.514; 95% CI, 1.109–2.067) were independent prognostic factors of cancer‐related mortality. Low AJCC stage at baseline, salvage surgery after definitive CRT, and chemotherapy regimen (preferably PC) can predict better survival outcomes than PF regimen in patients with locally advanced, inoperable ESCC who received dCRT.
TABLE 2

Univariate and multivariate analyses

FactorsProgression‐free survivalOverall survival
UnivariateMultivariate* UnivariateMultivariate*
p valueHR (95% CI) p valueHR (95% CI) p valueHR (95% CI) p valueHR (95% CI)
Age0.4330.993 (0.977–1.010)0.7710.998 (0.984–1.012)
Sex (Male vs. female)0.1481.694 (0.829–3.463)0.0781.695 (0.943–3.049)0.0441.831 (1.016–3.303)
ECOG PS0.5551.099 (0.803–1.503)0.1171.246 (0.946–1.641)
AJCC stage<0.0011.466 (1.187–1.810)0.0051.347 (1.096–1.657)0.0011.368 (1.139–1.642)0.0071.282 (1.069–1.537)
Tumor location0.1590.888 (0.752–1.048)0.3490.933 (0.806–1.079)
Histology (SqCC vs. non‐SqCC)0.6290.84 5 (0.427–1.673)0.7801.080 (0.629–1.854)
RT dose (≥41.4 Gy vs. <41.4 Gy)0.3520.781 (0.464–1.314)0.0200.600 (0.390–0.922)0.0470.640 (0.413–0.993)
Surgery (yes vs. no)<0.0010.397 (0.278–0.567)<0.0010.417 (0.289–0.600)<0.0010.384 (0.281–0.525)<0.0010.412 (0.298–0.570)
Treatment regimen (PF vs. PC)0.0031.749 (1.217–2.514)0.0011.840 (1.275–2.656)0.0201.436 (1.058–1.949)0.0091.514 (1.109–2.067)

All the factors in the univariate analysis were examined in the multivariate model. Only factors shown to be significant in the multivariate analysis are listed in the table.

Univariate and multivariate analyses All the factors in the univariate analysis were examined in the multivariate model. Only factors shown to be significant in the multivariate analysis are listed in the table.

DISCUSSION

Novelty of the present study with comparisons

The current study reported real‐world evidence of the effectiveness of the PC regimen during dCRT in Asian patients with inoperable ESCC. We found that patients who received the PC regimen had significantly longer PFS and OS than those who received the PF regimen. In addition, the baseline AJCC stage, surgery after the CRT, and chemotherapy regimens were independent prognostic factors after adjusting for related risk factors. To the best of our knowledge, this is the largest retrospective study to report that PC had superior effectiveness to PF as the chemotherapy regimen in concurrent CRT for EC. Table 3 summarizes the previous studies on the chemotherapy regimens for concurrent CRT, using a two‐arm comparative design. There were two main types of chemotherapy regimens in the literature, namely, the taxane‐based regimens , , , , , , , , , (e.g., paclitaxel or docetaxel) and the platinum plus 5‐fluorouracil regimen. , , , , , Our findings were in line with those of previous studies from Japan and China demonstrating that patients who received concurrent CRT with a taxane–platinum regimen have more prolonged survival than those who received the PF regimen. However, it should be noted these studies used docetaxel–cisplatin, whereas we used paclitaxel–carboplatin. In contrast to our findings, Qu et al. (2017) reported that PF (n = 34) was superior to PC (n = 26) in inoperable EC. Moreover, some studies found similar outcomes between PF and PC in concurrent CRT. , , , , Fang et al. (2017) compared paclitaxel plus cisplatin with TS‐1 plus cisplatin and found that TS‐1 plus cisplatin could yield statistically better compliance in inoperable patients with EC. In their study, more than 30% (vs. the 95.6% in our cohort) of patients were inoperable. The population differences may be the reason for a non‐significant difference in the OS and PFS. Münch et al. (2017 and 2018) also reported no significant difference in the OS and relapse‐free survival between PF and PC. , However, these two studies only enrolled 25 and 31 patients who received PC, which may have been the cause of the nonsignificant impact on the OS and DFS. Horning et al. (2014) and Blom et al. (2014) both concluded that although there were no differences in the OS and DFS, PC had a comparable efficacy but lesser toxicity than PF. ,
TABLE 3

Literature review of two‐arm primary/definitive concurrent chemoradiotherapy studies in esophageal cancer

AuthorYearCountryDesignPhaseResectabilityNumber of patientsArmsRegimens and resultsRT dose (Gy)Ref.
Taxane‐platinum regimens
Definitive chemoradiotherapy
Tamaki et al.2018JapanRSNAU38+832DCF>PF60[20]
Fang et al.2017ChinaRSNAU124+792P‐S1=PC60[15]
Münch et al.2018GermanyRSNAU25+202PF=PC54[16]
Qu et al.2017CanadaRSNAU34+13+263PF=CF>PC50[17]
Honing et al.2014NetherlandsRSNAU47+552PF=PC50.4[14]
Current study2020TaiwanRSNAInoperable83+1462PC>PF41.4–50.4
Neoadjuvant chemoradiotherapy
van Hagen et al.2012Netherlands PS IIIR178+1882

PC +surgery >

surgery alone

41.4[12]
Xi et al.2017ChinaRSNAR32+982DP>PF40[18]
Münch et al.2017GermanyRSNAR31+202PC=PF41.4[19]
Haisley et al.2017GermanyRSNAR87+552PF>PC50.4[11]
Blom et al.2014NetherlandsRSNAR73+922PF=PC41.4–50.4[21]
Non‐taxane‐containing regimens in the neoadjuvant setting or in chemoradiotherapy
Conroy et al.2014FrancePSIIIU134+1332FOLFOX=PF50[28]
Alderson et al.2017UKPSIIIR451+4462ECX=PFno RT[29]
Yoon et al.2015KoreaPSIIR47+502ICT>no ICT46[22]
von Döbeln GA et al.2019Sweden, NorwayPSIIR90+912nCRT=no nCRT40[23]
Xing et al.2014ChinaRSN/AU40+352CCRT=SCRT54–60[24]
Suh et al.2014KoreaRSN/AU77+492CCRT RT dose high>low54[25]
Chen et al.2018ChinaRSN/AU49+412CCRT=RT56[26]
Li et al.2017ChinaRSN/AU29+312CCRT (AP=PC)59.6[27]

Abbreviations: AP, pemetrexed plus cisplatin; CCRT, concurrent chemoradiotherapy; CF, carboplatin plus 5‐fluorouracil; DCF, docetaxel, cisplatin, 5‐fluorouracil; dCRT, definitive chemoradiotherapy; DP, docetaxel plus cisplatin; ECX, epirubicin plus cisplatin plus capecitabine; ICT, induction chemotherapy; nCRT, neoadjuvant chemoradiotherapy; PC, paclitaxel plus carboplatin; PF, cisplatin plus 5‐fluorouracil; PS, prospective; P‐S1, cisplatin plus TS‐1; R, resectable; RS, retrospective; RT, radiotherapy; SCRT, sequential chemoradiotherapy; U, unresectable.

Literature review of two‐arm primary/definitive concurrent chemoradiotherapy studies in esophageal cancer PC +surgery > surgery alone Abbreviations: AP, pemetrexed plus cisplatin; CCRT, concurrent chemoradiotherapy; CF, carboplatin plus 5‐fluorouracil; DCF, docetaxel, cisplatin, 5‐fluorouracil; dCRT, definitive chemoradiotherapy; DP, docetaxel plus cisplatin; ECX, epirubicin plus cisplatin plus capecitabine; ICT, induction chemotherapy; nCRT, neoadjuvant chemoradiotherapy; PC, paclitaxel plus carboplatin; PF, cisplatin plus 5‐fluorouracil; PS, prospective; P‐S1, cisplatin plus TS‐1; R, resectable; RS, retrospective; RT, radiotherapy; SCRT, sequential chemoradiotherapy; U, unresectable. In our study, PC showed a high survival benefit, consistent with the findings of the CROSS study and other Asian studies. , Other regimens using non‐taxane agents, different schedules, or different intensities of radiotherapy have also been explored. , , , , , These reported regimens included the SOX (oxaliplatin‐TS‐1) regimen, FOLFOX regimen, ECX (epirubicin, cisplatin, and capecitabine), pemetrexed plus cisplatin, neoadjuvant CRT versus chemotherapy with PF regimen before surgery, concurrent CRT and sequential CRT with capecitabine and cisplatin in elderly patients, , a higher dose or RT (>60 Gy) with the PF regimen, and RT alone in the elderly. However, there is still no evidence to support changing the current practice guidelines to concurrent CRT. The success of immunotherapy as the second‐line therapy , in patients with recurrent or metastatic EC might someday contribute to the development of new, more combination regimens with radiotherapy.

Impact of complete pathological remission

A study by Haisley et al. (2017) reported that the PF regimen is better than the PC regimen with respect to recurrence‐free survival and the OS benefit which could be due to a higher pathological complete remission rate (pCR) (33% vs. 22%). However, pCR was not analyzed in their multivariate regression model, which may have resulted in better survival outcomes in the PF group that had a higher pCR rate. In contrast, the pCR rates in the current study were 7.4% (n = 4/54) and 10% (3/30) in the PF and PC groups, respectively (p = 0.755), resulting in an overall pCR rate of 8.3% (7/84). The relatively low pCR rate in the present study was due mainly to (i) the population (neoadjuvant vs. definitive CCRT) and (ii) the post‐concurrent CRT surgical rate of 100.0% vs. 36.7% (84/229) in our study and Haisley et al.’s report, respectively. Collectively, these results support the line of thinking that PC may be better than PF during dCRT for patients with advanced EC.

Limitations of the study

There were some limitations in the current study. First, its retrospective nature limited the power of the scientific conclusion. However, except for the neoadjuvant PC regimen from the CROSS study in 2012, to the best of our knowledge, no prospective phase III study evaluating the regimens in concurrent CRT has been reported. Further, our study involved a relatively large population of inoperable patients with EC who received definitive CRT. Second, owing to the chart‐review design, the data on several toxicity profiles were incomplete, and thus, we could not evaluate the differences in toxicity between the PF and PC regimens. Third, we only compared the PC and PF regimens and did not enroll patients who received other regimens. Our findings need to be validated in prospective randomized phase III trials to establish the optimal chemotherapy regimen during dCRT for EC. Fourth, the patients did not choose their regimens randomly as is done in prospective trials. Thus, the final analysis may have been influenced by a selection bias. However, our comparison of the two groups in Table 1 indicated no apparent differences in the two groups’ essential characteristics. In conclusion, PC yielded superior OS and PFS benefits compared to PF as the chemotherapy regimen during dCRT for patients with advanced ESCC. On the basis of the findings from real‐world evidence, we propose that the PC regimen may be a preferable chemotherapy choice for dCRT in patients with advanced inoperable EC.

CONFLICT OF INTERESTS

The authors declare that they have no competing interests.
  30 in total

1.  High-dose versus standard-dose radiotherapy with concurrent chemotherapy in stages II-III esophageal cancer.

Authors:  Yang-Gun Suh; Ik Jae Lee; Wong Sub Koom; Jihye Cha; Jong Young Lee; Soo Kon Kim; Chang Geol Lee
Journal:  Jpn J Clin Oncol       Date:  2014-04-24       Impact factor: 3.019

2.  Randomized phase 2 trial of S1 and oxaliplatin-based chemoradiotherapy with or without induction chemotherapy for esophageal cancer.

Authors:  Dok Hyun Yoon; Geundoo Jang; Jong Hoon Kim; Yong-Hee Kim; Ji Youn Kim; Hyeong Ryul Kim; Hwoon-Yong Jung; Gin-Hyug Lee; Ho Young Song; Kyung-Ja Cho; Jin-Sook Ryu; Sung-Bae Kim
Journal:  Int J Radiat Oncol Biol Phys       Date:  2015-01-30       Impact factor: 7.038

3.  Recurrence Patterns and Long-term Results After Induction Chemotherapy, Chemoradiotherapy, and Curative Surgery in Patients With Locally Advanced Esophageal Cancer.

Authors:  Thomas Steffen; Daniel Dietrich; Annelies Schnider; Christoph Kettelhack; Olivier Huber; Walter R Marti; Markus Furrer; Beat Gloor; Marc Schiesser; Sandra Thierstein; Peter Brauchli; Thomas Ruhstaller
Journal:  Ann Surg       Date:  2019-01       Impact factor: 12.969

4.  Cisplatin-based chemoradiotherapy with 5-fluorouracil or pemetrexed in patients with locally advanced, unresectable esophageal squamous cell carcinoma: A retrospective analysis.

Authors:  Zengyun Li; Peiliang Zhang; Qingtong Ma; Dongqing Wang; Tao Zhou
Journal:  Mol Clin Oncol       Date:  2017-04-10

5.  Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.

Authors:  Ken Kato; Byoung Chul Cho; Masanobu Takahashi; Morihito Okada; Chen-Yuan Lin; Keisho Chin; Shigenori Kadowaki; Myung-Ju Ahn; Yasuo Hamamoto; Yuichiro Doki; Chueh-Chuan Yen; Yutaro Kubota; Sung-Bae Kim; Chih-Hung Hsu; Eva Holtved; Ioannis Xynos; Mamoru Kodani; Yuko Kitagawa
Journal:  Lancet Oncol       Date:  2019-09-30       Impact factor: 41.316

6.  A phase II study of paclitaxel, carboplatin, and radiation with or without surgery for esophageal cancer.

Authors:  Henry Wang; Janice Ryu; David Gandara; Richard J Bold; Shiro Urayama; Michael Tanaka; Zelanna Goldberg; David Follette; Samir Narayan; Derick Lau
Journal:  J Thorac Oncol       Date:  2007-02       Impact factor: 15.609

7.  Comparing docetaxel plus cisplatin versus fluorouracil plus cisplatin in esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy.

Authors:  Mian Xi; Peng Zhang; Li Zhang; Ya-Di Yang; Shi-Liang Liu; Yong Li; Jian-Hua Fu; Meng-Zhong Liu
Journal:  Jpn J Clin Oncol       Date:  2017-08-01       Impact factor: 3.019

8.  Survival comparison between radical surgery and definitive chemoradiation in 267 esophageal squamous cell carcinomas in a single institution: A propensity-matched study.

Authors:  Hideomi Yamashita; Yasuyuki Seto; Ryousuke Takenaka; Kae Okuma; Tomoki Kiritooshi; Kazuhiko Mori; Kazuhiko Yamada; Takashi Fukuda; Michio Kaminishi; Osamu Abe; Keiichi Nakagawa
Journal:  PLoS One       Date:  2017-05-09       Impact factor: 3.240

9.  Concurrent Chemoradiotherapy with Docetaxel, Cisplatin, and 5-fluorouracil Improves Survival of Patients with Advanced Esophageal Cancer Compared with Conventional Concurrent Chemoradiotherapy with Cisplatin and 5-fluorouracil.

Authors:  Yukihisa Tamaki; Yoko Hieda; Masanobu Nakajima; Kazuhiro Kitajima; Rika Yoshida; Takeshi Yoshizako; Atsushi Ue; Mutsumi Tokudo; Noriyuki Hirahara; Ichiro Moriyama; Hiroyuki Kato; Taisuke Inomata
Journal:  J Cancer       Date:  2018-07-16       Impact factor: 4.207

10.  Comparison of definite chemoradiation therapy with carboplatin/paclitaxel or cisplatin/5-fluoruracil in patients with squamous cell carcinoma of the esophagus.

Authors:  Stefan Münch; Steffi U Pigorsch; Michal Devečka; Hendrik Dapper; Wilko Weichert; Helmut Friess; Rickmer Braren; Stephanie E Combs; Daniel Habermehl
Journal:  Radiat Oncol       Date:  2018-08-02       Impact factor: 3.481

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  2 in total

1.  Definitive concurrent chemoradiotherapy with paclitaxel plus carboplatin is superior to cisplatin plus 5-fluorouracil in patients with inoperable esophageal squamous cell carcinoma using retrospective, real-world evidence.

Authors:  Jason Chia-Hsun Hsieh; Pin-Chun Chiang; Tsung-Min Hung; Yin-Kai Chao; Yung-Chia Kuo; Chih-Tsung Wen; Po-Jung Su; Meng-Ting Peng; Huan-Wu Chen; Hui-Ling Liu; Hsien-Kun Chang; Min-Hsien Wu; Hung-Ming Wang
Journal:  Cancer Med       Date:  2021-10-27       Impact factor: 4.452

2.  Comparison of Efficacy and Safety of Taxanes Plus Platinum and Fluorouracil Plus Platinum in the First-Line Treatment of Esophageal Cancer: A Systematic Review and Meta-Analysis.

Authors:  Yue Zhao; Rui Song; Yuanyuan Jia; Xiaoyun Zhang; Shasha Zhang; Chensi Wu; Ruixing Zhang; Zhanjun Guo
Journal:  Curr Oncol       Date:  2022-09-16       Impact factor: 3.109

  2 in total

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