Skip to main content
Erschienen in: BMC Cancer 1/2020

Open Access 01.12.2020 | Research article

Comparing three induction chemotherapy regimens for patients with locoregionally advanced nasopharyngeal carcinoma based on TNM stage and plasma Epstein–Barr virus DNA level

verfasst von: Sai-Lan Liu, Xue-Song Sun, Hao-Jun Xie, Qiu-Yan Chen, Huan-Xin Lin, Hu Liang, Yu-Jing Liang, Xiao-Yun Li, Jin-Jie Yan, Chao Lin, Zhen-Chong Yang, Shan-Shan Guo, Li-Ting Liu, Qing-Nan Tang, Yu-Yun Du, Lin-Quan Tang, Ling Guo, Hai-Qiang Mai

Erschienen in: BMC Cancer | Ausgabe 1/2020

Abstract

Background

We compared the efficacy and toxicity of three IC regimens (TPF: taxanes, cisplatin, and 5-fluorouracil; TP: taxanes and cisplatin; and PF: cisplatin and 5-fluorouracil) followed by CCRT in locoregionally advanced NPC.

Methods

The retrospective study involved 1354 patients with newly diagnosed stage III-IVA NPC treated with IC and CCRT. The median follow-up time in our cohort was 50 months. Based on EBV DNA level, all the patients with stage IV were divided into low- (pre-EBV DNA < 1500 copies) and high-risk group (pre-EBV DNA ≥ 1500 copies). Progression free survival (PFS), overall survival (OS), locoregional relapse free survival (LRFS), distant metastasis free survival (DMFS) and grade 3–4 toxicities were compared among different IC regimens. The survival rates were compared using log-rank test and a Cox proportional hazards model was used to perform multivariate analyses.

Results

A multivariate analysis revealed TPF to be more effective than TP. Among stage III patients, no significant difference in clinical outcome between the different IC regimens was showed, while TPF was associated with significantly better survival conditions in the stage IV patients. A further subgroup analysis revealed that only patients with pre-EBV DNA ≥ 1500 copies could benefit from the application of TPF among stage IV NPC. In terms of acute toxicities, PF was associated with fewer grade 3/4 acute toxicities.

Conclusions

In low-risk NPC patients, PF-based IC showed similar efficacy as TPF and TP but was associated with fewer grade 3/4 acute toxicities. In high-risk patients, however, the TPF regimen was superior to PF and TP, although grade 3/4 toxicities were more common with the TPF regimen.
Hinweise
Sai-Lan Liu, Xue-Song Sun and Hao-Jun Xie are contributed equally
Lin-Quan Tang, Ling Guo and Hai-Qiang Mai the senior authors contributed equally to this work.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abkürzungen
2D-CRT
Two-dimensional radiotherapy
CCD
Cumulative cisplatin dose
CCRT
Concurrent chemoradiotherapy
CIs
Confidence intervals
DMFS
Distant metastasis-free survival
EBV
Epstein–Barr Virus
HRs
Hazard ratios
IC
Induction chemotherapy
IMRT
Intensity-modulated radiotherapy
KPS
Karnofsky performance score
LRFS
Locoregional relapse-free survival
MRI
Magnetic resonance imaging
NPC
Nasopharyngeal carcinoma
OS
Overall survival
PET/CT
Positron emission tomography/computed tomography
PF
Cisplatin and 5-fuorouracil)
PFS
Progression-free survival
RT
Radiotherapy
TP
Taxanes and cisplatin
TPF
Taxanes, cisplatin and 5-fuorouracil
WHO
World Health Organization

Background

Nasopharyngeal carcinoma (NPC) is a malignant disease arising from the nasopharyngeal epithelium. It is most endemic to Southern China, where 50–80 cases per 100,000 persons are reported each year [1]. Because of the radiosensitive nature of NPC and the typically deep-seated location of the lesions, radiation therapy (RT) is the primary treatment for NPC [2]. The development of modern RT has resulted in improved local control rates for NPC [35]. However, the prevention of distant metastasis in advanced NPC remains unsatisfactory and is the main cause of treatment failure [6]. Therefore, an effective treatment protocol is necessary to achieve better outcomes in these cases.
For non-metastatic locoregionally advanced NPC, concurrent chemoradiation therapy (CCRT) has been shown to be more effective than RT alone and has been accepted as the standard treatment for advanced NPC [7, 8]. Nevertheless, induction chemotherapy (IC) combined with the established CCRT regimen has recently attracted attention for the management of advanced NPC. The use of IC followed by definitive CCRT is associated with decreased distant metastases, which could improve clinical outcomes [915].
IC has been widely used in clinical practice; however, thus far, there is no consensus on the most suitable IC regimen. Therefore, it is important to evaluate the different IC regimens according to their efficacy and toxicity. Unfortunately, there was no large-scale clinical trial with convincing results to compare the efficacy of different IC regimen up to now [16]. To address this problem, in this study, we retrospectively analyzed 1354 NPC patients who received IC before concurrent chemotherapy. Taxanes, cisplatin, and 5-fluorouracil (TPF); cisplatin and 5-fluorouracil (PF); and taxanes and cisplatin (TP) were the most frequently used IC regimens in our center and were evaluated in this cohort. We especially analyzed the differences in patients’ survival outcomes in the three IC groups as well as the acute toxicity of the regimens. Besides, the plasma EBV DNA level has been proved to be useful in the prognostic prediction for NPC [17]. Accordingly, we divided patients in different risk level based on their pre-treatment EBV DNA and compared the curative effect of these three IC regimens in different subgroups, which was not reported in previous studies.

Methods

Patients

From 2008 to 2017, 1354 previously untreated NPC patients were enrolled in the study. The eligibility criteria for inclusion were newly diagnosed biopsy-proven NPC; receipt of first-line IC for at least 2 cycles followed by CCRT; Karnofsky performance score (KPS) > 70; adequate organ functions and with available hematological sample and EBV serology results. Key exclusion criteria were as the following: received palliative treatment; a history of malignancy; received previous anti-tumor treatment (radiotherapy, chemotherapy, or surgery [except diagnostic procedures]); the presence of lactation, pregnancy or severe coexisting illness.
The following examinations were performed for all patients: a complete physical examination, head and neck magnetic resonance imaging (MRI), chest radiography, abdominal sonography, electrocardiography, bone scan, nasopharyngoscopy, and complete blood count including differential cell counts, biochemical profile, and EBV serology. For partial patients, positron emission tomography/computed tomography (PET-CT) was also optionally performed to evaluate distant lesions. The study was approved by the Sun Yat-sen University Cancer Center Research Ethics Committee.

Chemotherapy and RT

All patients received one of the following IC regimens: PF (comprising cisplatin [80–100 mg/m2, day 1] and 5-fluorouracil [800–1000 mg/m2, day 1–5, 120 h of continuous intravenous infusion]); TP (comprising docetaxel [75 mg/m2, day 1], paclitaxel [150–180 mg/m2, day 1] or paclitaxel liposome [150–180 mg/m2, day 1], and cisplatin [20–25 mg/m2/day, day 1–3]); and TPF (comprising docetaxel [60 mg/m2, day 1], paclitaxel [135 mg/m2, day 1] or paclitaxel liposome [135 mg/m2, day 1], cisplatin [20–25 mg/m2/day, days 1–3], and 5-fluorouracil [500–800 mg/m2, 120 h of continuous intravenous infusion]). All regimens were administered every 3 weeks over 2–4 cycles. RT was administered to the nasopharynx and neck by using intensity-modulated RT (IMRT) or two-dimensional RT (2D-CRT). IC was followed by concurrent cisplatin-based chemotherapy (80–100 mg/m2 every 3 weeks or 30–40 mg/m2 weekly) [7, 18]. Five daily fractions of a total dose of 68~70 Gy at about 2 Gy per fraction were prescribed per week. Other details of the IMRT plan were in line with the principles described in previous studies [1921].

Outcome and follow-up

The primary endpoint of our study was PFS, defined as the period from the first day of treatment to the date of disease progression or death from any cause. The other clinical endpoints were OS (defined as the period from the date of treatment to the date of death from any cause), LRFS (defined as the period from date of treatment to the date of local/regional relapse), and distant metastasis-free survival (DMFS), (defined as the time from date of treatment to the date of distant metastasis). Hematological reactions were evaluated for acute IC-associated toxicity, classified based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, and compared between the groups. Physical examination, nasopharyngoscopy, and MRI of the head and neck were performed 3–6 months after RT completion. We evaluated tumor responses according to the Response Evaluation Criteria in Solid Tumors [22]. After treatment completion, the patients were evaluated every 3 months during the first 3 years and every 6 months thereafter until death. Nasopharyngoscopy, head and neck MRI, chest radiography, abdominal sonography, and plasma EBV DNA measurement were routinely performed.

Statistical analysis

Statistical analyses were performed using SPSS package for Windows version 22.0 (Chicago, IL). Correlations between the different IC regimens and clinical characteristics of NPC were evaluated using the χ2 or Fisher’s exact test as appropriate. Kaplan–Meier survival curves were used to evaluate long-term survival; the survival rates were compared using log-rank test. A Cox proportional hazards model was used to perform multivariate analyses involving the following variables: age, sex, T stage, N stage, clinical stage, EBV DNA, and IC regimen. All analyses were two-sided. The level of significance was set at P < 0.05.

Results

Patient characteristics

New, consecutive patients (1354 patients including 335 [24.7%] females and 1019 [75.3%] males) diagnosed with non-metastatic NPC between June 2008 and November 2017 were included in this study. In the cohort, 1341 (99.0%) patients had WHO type III disease. The median patient age was 44 (8–74) years, and 772 (57.0%), 340 (25.1%), and 242 (17.9%) patients received TPF, PF, and TP chemotherapy, respectively. The median follow-up time was 27.3 months (range: 0.5–113.2 months) in the whole cohort, and 25.1 months (range: 3.1–90.8 months), 42.6 months (range: 3.2–113.2 months) and 25.7 months (range: 0.5–87.8 months) in TPF, PF and TP groups respectively. The cumulative cisplatin dose (CCD) was less than 200 mg/m2 in most patients (1059/1354, 78.2%). The patients’ other baseline characteristics are shown in Table 1.
Table 1
Patient demographics and clinical characteristics
 
TPF(n = 772)
PF(n = 340)
TP(n = 242)
 
Characteristics
No. (%)
No. (%)
No. (%)
No. (%)
P value
Age, years
    
0.307a
 Median (range)
44(8–74)
43(8–74)
44(15–71)
46(18–71)
 
 <  45
698(51.6)
411(53.2)
171(50.3)
116(47.9)
 
 ≥ 45
656(48.4)
361(46.8)
169(49.7)
126(52.1)
 
Sex
    
0.580a
 Female
335(24.7)
184(23.8)
91(26.8)
60(24.8)
 
 Male
1019(75.3)
588(76.2)
249(73.2)
182(75.2)
 
Pathological type
    
0.217b
 WHO type I
4(0.3)
3(0.4)
1(0.3)
0(0.0)
 
 WHO type II
9(0.7)
4(0.5)
5(1.5)
0(0.0)
 
 WHO type III
1341(99.0)
765(99.1)
334(98.2)
242(100)
 
T stagec
    
0.199a
 T1
18(1.3)
11(1.4)
5(1.5)
2(0.8)
 
 T2
149(11.0)
71(9.2)
49(14.4)
29(12.0)
 
 T3
665(49.1)
379(49.1)
168(49.4)
118(48.8)
 
 T4
522(38.6)
311(40.3)
118(34.7)
93(38.4)
 
N stagec
    
< 0.001a
 N0
35(2.6)
15(1.9)
11(3.2)
9(3.7)
 
 N1
315(23.3)
193(25.0)
57(16.8)
65(26.9)
 
 N2
695(51.3)
367(47.5)
197(57.9)
131(54.1)
 
 N3
309(22.8)
197(25.5)
75(22.1)
37(15.3)
 
Clinical stagec
    
0.005a
 III
612(45.2)
320(41.5)
167(49.1)
125(51.7)
 
 IVa-b
742(54.8)
452(58.5)
173(50.9)
117(48.3)
 
EBV DNA
    
< 0.001a
 ≥ 1500
875(64.6)
514 (66.6)
231(67.9)
130(53.7)
 
 < 1500
479(35.4)
258 (33.4)
109(32.1)
112(46.3)
 
RT technique
    
< 0.001a
 2D RT
119(8.8)
7(0.9)
101(29.7)
11(4.5)
 
 IMRT
1235(91.2)
765(99.1)
239(70.3)
231(95.5)
 
CCD (mg/m2)
    
0.127a
 Median (range)
160(20–300)
160(25–300)
160(40–250)
160(20–300)
 
 ≥ 200
295(21.8)
183(23.7)
63(18.5)
49(20.2)
 
 < 200
1059(78.2)
589(76.3)
277(81.5)
193(79.8)
 
Abbreviations: TPF Taxanes plus cisplatin with fluorouracil, PF Cisplatin with fluorouracil, TP Taxanes with cisplatin, EBV Epstein–Barr virus, CCD Cumulative cisplatin dose during radiotherapy
aP values were calculated by the Chi-square test. bP value calculated with Fisher’s exact test
cAccording to the 7th edition of UICC/AJCC staging system

Survival analysis of patients treated with different IC regimens

The 3-year PFS, OS, LRFS, and DMFS rates for the entire patient cohort were 79.4, 95.9, 88.0, and 85.6%, respectively. Regarding short-term tumor response, the complete response (CR)/partial response (PR) ratio was higher (79.7%) in TPF-receiving patients than in PF- and TP-receiving patients (67.2 and 71.4%, respectively; P < 0.001, Table 2). However, differences in long-term survival were only observed between TPF- and TP-treated patients and not between TPF- and PF-treated patients. Furthermore, the corresponding 3-year PFS, OS, LRFS and DMFS rates for TPF vs. PF vs. TP were 82.4% vs. 77.4% vs. 73.8% (PTPF vs. PF = 0.335, PTPF vs. TP = 0.049, PPF vs. TP = 0.345; Fig. 1a), 97.2% vs. 92.1% vs. 97.0% (PTPF vs. PF = 0.064, PTPF vs. TP = 0.741, PPF vs. TP = 0.339; Fig. 1b), 92.5% vs. 91.5% vs. 91.7% (PTPF vs. PF = 0.707, PTPF vs. TP = 0.614, PPF vs. TP = 0.984; Fig. 1c), and 88.4% vs. 83.3% vs. 80.7% (PTPF vs. PF = 0.118, PTPF vs. TP = 0.054, PPF vs. TP = 0.565; Fig. 1d) (Table 6 in Appendix 1). In the multivariate analysis, the following prognostic factors were evaluated: age, gender, pathological type, T stage, N stage, EBV DNA, and IC regimen. As shown in Table 3, TPF was associated with significantly better OS and DMFS than TP (OS: HR, 1.630; 95% CI, 0.151–2.308; P = 0.006; DMFS: HR, 1. 692; 95% CI, 1.115–2.569; P = 0.013), whereas not an independent prognostic factor compared with PF in all clinical outcome. As there was higher proportion of 2D-RT in PF group, we performed multivariate analysis involving RT method in PF group. As shown in the supplementary table, RT method was not an independent prognostic factor for all endpoints, indicating that its impact on survival conditions was relatively small (Table 7 in Appendix 2).
Table 2
Overall response rates at central review after the induction phase
 
TPF(n = 707)
PF(n = 137)
TP(n = 147)
P value
Complete response
14(2.0%)
3(2.2%)
3(2.0%)
0.013
Partial response
548(77.5%)
89(65.0%)
102(69.4%)
 
Stable disease
142(20.1%)
45(32.8%)
40(27.2%)
 
Progressive disease
3(0.4%)
0 (0.0%)
2(1.4%)
 
P value calculated with Fisher’s exact test
Abbreviations: TPF Taxanes plus cisplatin with fluorouracil, PF Cisplatin with fluorouracil, TP Taxanes with cisplatin
Table 3
Multivariable analysis of prognostic factors for III-IVb NPC patients
 
Hazard ratio* (95% CI)
P value
Progression-free survival
 Age (y) (≥ 45 vs. <  45)
1.543(1.100–2.164)
0.012
 Gender(F vs. M)
1.055(0.814–1.366)
0.686
 T category (3–4 vs. 1–2)
1.280(0.846–1.937)
0. 242
 N category (2–3 vs. 0–1)
1.357(0.977–1.886)
0.069
 Overall stage (IVa-b vs. III)
1.487(1.133–1.951)
0.004
 EBV DNA
1.579(1.151–2.164)
0.005
 IC regimen; PF vs. TPF
1.189(0.880–1.605)
0.260
 IC regimen; TP vs. TPF
1.630(1.151–2.308)
0.006
Overall survival
 Age (y) (≥ 45 vs. <  45)
0.892(0.510–1.560)
0.688
 Gender(F vs. M)
1.846(1.115–3.055)
0.017
 T category (3–4 vs. 1–2)
0.967(0.475–2.177)
0.927
 N category (2–3 vs. 0–1)
1.161(0.620–2.177)
0.641
 Overall stage (IVa-b vs. III)
1.606(0.950–2.715)
0.077
 EBV DNA
3.881(1.657–9.090)
0.002
 IC regimen; PF vs. TPF
1.604(0.917–2.804)
0.098
 IC regimen; TP vs. TPF
1.571(0.719–3.436)
0.258
Locoregional relapse-free survival
 Age (y) (≥ 45 vs. <  45)
1.525(0.872–2.668)
0.139
 Gender(F vs. M)
0.970(0.631–1.492)
0.891
 T category (3–4 vs. 1–2)
1.189(0.598–2.364)
0.622
 N category (2–3 vs. 0–1)
0.890(0.542–1.462)
0.645
 Overall stage (IVa-b vs. III)
1.240(0.798–1.928)
0.339
 EBV DNA
1.672(0.983–2.843)
0.058
 IC regimen; PF vs. TPF
1.157(0.709–1.887)
0.559
 IC regimen; TP vs. TPF
1.298(0.711–2.369)
0.395
Distant metastasis-free survival
 Age (y) (≥ 45 vs. <  45)
1.592(1.051–2.411)
0.028
 Gender(F vs. M)
0.951(0.694–1.303)
0.756
 T category (3–4 vs. 1–2)
1.428(0.852–2.393)
0.177
 N category (2–3 vs. 0–1)
1.706(1.118–2.606)
0.013
 Overall stage (IVa-b vs. III)
1.488(1.071–2.068)
0.018
 EBV DNA
1.424(0.980–2.069)
0.063
 IC regimen; PF vs. TPF
1.349(0.940–1.936)
0.104
 IC regimen; TP vs. TPF
1.692(1.115–2.569)
0.013
A Cox proportional hazards regression model was used to detect variables individually without adjustment. All variables were transformed into categorical variables. HRs were calculated for age (years) (≥45 vs. < 45), sex (female vs. male), T stage (T3–4 vs. T1–2), N stage (N2–3 vs. N0–1), plasma EBV DNA before the first treatment (≥1500 copies/ml vs. < 1500 copies/ml), overall stage (IVa-b vs. III), and IC regimen (PF vs. TPF, TP vs. TPF)
Abbreviations: CI Confidence interval, EBV Epstein–Barr virus, IC Induction chemotherapy, TPF Taxanes plus cisplatin with fluorouracil, PF Cisplatin with fluorouracil, TP Taxanes with cisplatin

Subgroup analysis according to the TNM stage and EBV level

Patients at different TNM stages exhibited different tumor burdens and treatment failure rates. Thus, we divided the patients according to the TNM stage into stage III and IV disease groups (Table 8 in Appendix 3) and compared the prognostic impact of the IC regimens in the two groups. Among the three IC regimens, patients in TPF groups showed the highest complete response/ partial response rate after the induction phase (TPF vs. PF vs. TP: 79.5% vs. 67.2% vs. 71.4%, P = 0.013). Stage III patients showed no significant difference in clinical outcome between the different IC regimens (Fig. 2). However, in the IVA-IVB stage subgroup, TPF was associated with significantly better OS and DMFS than was PF and better PFS and DMFS than was TP (Fig. 3). EBV DNA is a prognostic factor for NPC patients. Therefore, we divided stage IV patients into low-risk and high-risk subgroups according to the EBV DNA level. Interestingly, prognostic factors differed between these two subgroups. Among low-risk patients (pre-EBV DNA < 1500 copies), the 3-year PFS, OS, LRFS, and DMFS rates in the different IC groups were similar and the survival curves were superimposable (data not shown). However, in the high-risk group (pre-EBV DNA ≥ 1500 copies), TPF was associated with significantly better PFS, OS, LRFS, and DMFS than were PF and TP. The 3-year PFS, OS, LRFS, and DMFS rates for TPF vs. PF vs. TP were 81.5% vs. 67.6% vs. 57.3% (PTPF vs. PF = 0.019, PTPF vs. TP < 0.001, PPF vs. TP = 0.048 Fig. 4a), 97.3% vs. 86.6% vs. 85.8% (PTPF vs. PF = 0.012, PTPF vs. TP = 0.031, PPF vs. TP = 0.954 Fig. 4b), 93.7% vs. 85.7% vs. 78.8% (PTPF vs. PF = 0.040, PTPF vs. TP = 0.021, PPF vs. TP = 0.722 Fig. 4c), and 86.8% vs. 78.0% vs. 67.1% (PTPF vs. PF = 0.025, PTPF vs. TP = 0.002, PPF vs. TP = 0.221 Fig. 4d) (Table 9 in Appendix 4).
As shown in Table 4, after adjusting for various factors, the IC regimen was established as an independent prognostic factor for PFS (PF vs. TPF: HR, 1.657; 95% CI, 1.079–2.544; P = 0.021; TP vs. TPF: HR, 3.222; 95% CI, 1.917–5.416: P < 0.001), OS (PF vs. TPF: HR, 2.608; 95% CI, 1.180–5.762; P = 0.018; TP vs. TPF: HR, 3.117; 95% CI, 1.051–9.244; P = 0.040), and DMFS (PF vs. TPF: HR, 2.978; 95% CI, 1.566–5.663; P = 0.001; TP vs. TPF: HR, 1.724; 95% CI, 1.076–2.763; P = 0.024). Clinical stage was also considered as a prognostic factor for DMFS.
Table 4
Multivariable analysis of prognostic factors for IVa-b patients with EBV DNA level ≥ 1500 copies/ml
 
Hazard ratio* (95% CI)
P value
Progression-free survival
 Age (y) (≥ 45 vs. <  45)
1.171(0.802–1.710)
0.414
 Gender(F vs. M)
1.421(0.857–2.357)
0.173
 Clinical stage (IVb vs. IVa)
1.275(0.870–1.870)
0.213
 IC regimen; PF vs. TPF
1.657(1.079–2.544)
0.021
 IC regimen; TP vs. TPF
3.222(1.917–5.416)
< 0.001
Overall survival
 Age (y) (≥ 45 vs. <  45)
1.895(0.941–3.817)
0.074
 Gender(F vs. M)
0.689(0.320–1.485)
0.342
 Clinical stage (IVb vs. IVa)
0.814(0.401–1.651)
0.568
 IC regimen; PF vs. TPF
2.608(1.180–5.762)
0.018
 IC regimen; TP vs. TPF
3.117(1.051–9.244)
0.040
Locoregional relapse-free survival
 Age (y) (≥ 45 vs. <  45)
0.868(0.466–1.617)
0.594
 Gender(F vs. M)
1.513(0.635–3.603)
0.350
 Clinical stage (IVb vs. IVa)
0.919(0.490–1.724)
0.792
 IC regimen; PF vs. TPF
2.091(1.043–4.191)
0.038
 IC regimen; TP vs. TPF
2.626(0.490–1.724)
0.037
Distant metastasis-free survival
 Age (y) (≥ 45 vs. <  45)
1.103(0.692–1.756)
0.680
 Gender(F vs. M)
1.210(0.675–2.171)
0.522
 Clinical stage (IVb vs. IVa)
1.762(1.046–2.967)
0.033
 IC regimen; PF vs. TPF
2.978(1.566–5.663)
0.001
 IC regimen; TP vs. TPF
1.724(1.076–2.763)
0.024
Abbreviations: CI Confidence interval, IC Induction chemotherapy, TPF Taxanes plus cisplatin with fluorouracil, PF Cisplatin with fluorouracil, TP = Taxanes with cisplatin
A Cox proportional hazards regression model was used to detect variables individually without adjustment. All variables were transformed into categorical variables. HRs were calculated for age (years) (≥45 vs. < 45 years), sex (female vs. male), clinical stage (IVb vs. IVa), and IC regimen (PF vs. TPF, TP vs. TPF)

Acute toxicity profile

In terms of acute toxicity during the IC period, patients in the TPF group experienced significantly more toxic effects than patients in the PF group, but similar toxic effects as patients in the TP group: leukocytopenia (grade 0–2: 75% vs. 95.3% vs. 82.2%; grade 3–4: 25.0% vs. 4.7% vs. 17.1%; P < 0.001) and neutropenia (grade 0–2: 57.4% vs. 87.1% vs. 64.5%; grade 3–4: 42.6% vs. 12.9% vs. 35.5%; P < 0.001). Intergroup differences in other acute toxicities such as anemia, ALT level increase, AST level increase, and BUN increase were not significant (Table 5).
Table 5
Grade 3–4 acute toxicities due to IC between the three arms
Adverse event (toxicity grade)
TPF(n = 772)
PF(n = 340)
TP(n = 242)
P
0–2(%)
3–4(%)
0–2(%)
3–4(%)
0–2(%)
3–4(%)
Leukocytopenia
579(75.0)
193(25.0)
324(95.3)
16(4.7)
199(82.2)
43(17.1)
< 0.001a
Neutropenia
443(57.4)
329(42.6)
296(87.1)
44(12.9)
156(64.5)
86(35.5)
< 0.001a
Anemia
763(98.8)
9(1.2)
339(99.7)
1(0.3)
240(99.2)
2(0.8)
0.441 b
Thrombocytopenia
765(99.1)
7(0.9)
338(99.4)
2(0.6)
239(98.8)
3(1.2)
0.672b
ALT increase
763(99.0)
8(1.0)
337(99.1)
3(0.9)
239(98.8)
3(1.2)
0.871 b
AST increase
771(99.9)
1(0.1)
339(99.7)
1(0.3)
241(99.6)
1(0.4)
0.395b
Creatinine increase
771(99.9)
1(0.1)
339(99.7)
1(0.3)
242(100)
0(0.0)
0.675b
BUN increase
771(99.9)
1(0.1)
340(100)
0(0.0)
240(99.2)
2(0.8)
0.134b
Abbreviations: IC Induction chemotherapy, TPF Taxanes plus cisplatin with fluorouracil, PF Cisplatin with fluorouracil, TP Taxanes with cisplatin, ALT Alanine aminotransferase, AST Aspartate aminotransferase, BUN blood urea nitrogen
aP values were calculated by Chi-square test. bP value calculated with Fisher’s exact test

Discussion

Distant metastasis remains a critical issue in cases of advanced NPC [23, 24], and IC could facilitate the eradication of micro-metastatic lesions and reduce locoregional failure. With the increasing evidence for the effectiveness of IC followed by CCRT for advanced NPC [10, 2528], IC is being widely used in clinical settings. TPF, PF, and TP are the three induction regimens most frequently used for advanced NPC worldwide, and all of them can improve survival in patients with locoregionally advanced NPC [10, 25, 26]. Our study indicates that TPF is the best choice among these three induction regimens for lowering the distant metastasis rate and improving the overall survival (OS) rate in high-risk NPC patients (IVa-b NPC patients with EBV DNA ≥ 1500 copies/ml).
Our data showed that most patients in the PF and TP groups were treated in the early years while the recent ones were distributed to the TPF group. The TPF IC regimen is commonly used in advanced head and neck cancer [29, 30]. In comparison with the standard PF regimen, regimens including taxanes, which are microtubule-stabilizing drugs that have been extensively used as effective chemotherapeutic agents for solid tumor treatment [31], showed significantly better PFS and OS and higher CR rates in head and neck cancers [29, 30, 32]. In another study, TPF demonstrated long-term survival benefits over PF in locally advanced head and neck cancer [33]. Long-term follow-up data confirm that TPF could increase larynx preservation and larynx dysfunction-free survival [34]. Undoubtedly, these benefits may also apply to NPC. Compared with the TP regimen, regimens including fluorouracil may also provide therapeutic gains. Lee et al. [35] found that the fluorouracil dose during the adjuvant phase was associated with significantly improved distant failure-free survival in a combined analysis of NPC-9901 and NPC-9902. This effect may also be present in the induction phase. Therefore, a combination of these three active agents seems to be the most effective regimen to provide optimal therapeutic benefit. Based on the above reasons, more clinicians preferred to select the TPF regimen recently.
Previous studies have suggested that TPF is superior to TP and PF for NPC patients. One report [16] demonstrated that the TP regimen may be sufficient for patients receiving a CCD ≥ 200 mg/m2, while TPF may be superior to TP and PF for patients receiving a CCD < 200 mg/m2. In Liu’s study [36], the TPF regimen yielded better long-term survival for patients with locoregionally advanced NPC in comparison with the PF regimen. In another study [37], TPF showed an improved early response of lymph node size reduction in comparison with the PF and TP regimens. These findings support the results of the present study, in which IC with TPF showed the best short-term tumor response and provided survival benefits compared with those of TP in all cases of locally advanced nasopharyngeal carcinoma.
However, one of the major limitations of previous studies was that they did not present data for plasma EBV DNA levels, which is an important prognostic factor for NPC patients and, in combination with the TNM stage, could identify patients with locoregionally advanced NPC who are at a high risk of locoregional recurrence and distant metastasis [17]. In a subgroup analysis stratified by clinical stage and EBV DNA levels, we observed an interesting scenario. Among patients with stage III NPC, survival outcomes were comparable between the three groups. However, among patients with stage IVa-b NPC, TPF could not only reduce distant metastasis but also prolong PFS and OS in comparison with TP and PF. Thus, TPF could reduce distant metastasis and improve the local control rate for patients (IVa-b) with a high tumor burden in comparison with TP and PF. A subgroup analysis of stage IVa-b NPC patients stratified by EBV DNA levels showed no survival benefit of TPF over PF and TP among low-risk patients (IVa-b with EBV DNA < 1500 copies/ml). However, in high-risk patients (IVa-b with EBV DNA ≥ 1500 copies/ml), TPF achieved the best outcomes among the three induction regimens for improving the survival rate and lowering the distant metastasis rate. Hence, the more effective regimen, TPF, is particularly important for high-risk (IVa-b with EBV DNA ≥ 1500 copies/ml) patients.
Obviously, a combination of three agents produced more grade 3–4 toxicities. Notably, leukocytopenia and neutropenia were significantly higher in the TPF arm (25.0 and 42.6%, respectively) and TP arm (17.1 and 35.5%, respectively) than in the PF arm (4.7 and 12.9%, respectively), whereas other toxicities were common in the three arms. This difference should be attributable to taxanes since the most common adverse event after taxane therapy is myelosuppression. Finally, the results showed that survival outcomes were comparable between the three groups in low-risk NPC patients (stage III and IVa-b with EBV DNA < 1500 copies/ml), and the incidences of leukocytopenia and neutropenia were lower in the PF arm than in the TPF and TP arms. These findings indicate that PF-based IC has similar efficacy to TPF and TP in low-risk NPC patients (stage III and IVa-b with EBV DNA < 1500 copies/ml) but is associated with fewer grade 3/4 acute toxicities.
The data reported in this article also have several limitations. First, there was an inevitable bias caused by the retrospective nature of this study. Because of the selective bias, there were certain clinicopathologic differences among the patients receiving different IC regimens. Besides, the follow-up periods were also various in different IC groups. Although all potential prognostic factors were included in the multivariate analyses to avoid confounding effects, the credibility of our conclusions was still affected to some extent. Second, although our cohort is likely to be representative of the majority of patients diagnosed with NPC in South China, this was a single-center study. A multi-center study is needed to fully compare different IC regimens for locoregionally advanced nasopharyngeal carcinoma.

Conclusions

In summary, our study concluded that an induction TPF regimen was superior to TP and PF regimens for high-risk (IVa-b with EBV DNA ≥ 1500 copies/ml) NPC, although grade 3–4 toxic events were more common but tolerable in the TPF arm. However, PF-based IC has similar efficacy to TPF and TP in low-risk NPC patients (stage III and IVa-b with EBV DNA < 1500 copies/ml) but is associated with fewer grade 3/4 acute toxicities. Further studies are needed to validate our findings.

Acknowledgments

We thank all the patients who participated in this study.
This retrospective study was approved by the Clinical Research Committee of Sun Yat-Sen University Cancer Center, China. All of the participants provided written informed consent before treatment.
Not applicable.

Competing interests

The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Anhänge

Appendix 1

Table 6
Three-year PFS, OS, LRFS, DMFS based on different IC regimens in III-IVb patients
 
TPF (%) n = 772
PF (%) n = 340
TP (%) n = 242
P value
Progression-free survival
 Failures
108(14.0%)
42(22.6%)
47 (19.4%)
0.127
 Rate at 3 years
82.4% (78.9–85.9)
77.4% (72.3–82.5)
73.8% (66.7–80.9)
 
Overall survival
 Deaths
23(3.0%)
32 (9.4%)
9(3.7%)
0.029
 Rate at 3 years
97.2% (95.6–98.8)
92.1% (88.8–95.4)
97.0% (93.9–100)
 
Locoregional relapse-free survival
 Locoregional failure
40(5.2%)
30 (8.8%)
15 (6.2%)
0.835
 Rate at 3 years
92.5% (90.0–95.0)
91.5% (88.0–95.0)
91.7% (87.2–96.2)
 
Distant metastasis-free survival
 Distant failures
72(9.3%)
53 (15.6%)
33 (13.6%)
0.103
 Rate at 3 years
88.4% (85.7–91.1)
83.3% (78.8–87.8)
80.7% (74.0–87.4)
 
Data are n (%) or rate (95% CI). P values were calculated with the unadjusted log-rank test

Appendix 2

Table 7
Multivariable analysis of prognostic factors for III-IVb NPC patients treated with PF regimen
 
HR (95%CI)
P-value value
Progression-free survival
 Age (y) (≥ 45 vs. <  45)
1.319(0.839–2.074)
0.231
 Gender (F vs. M)
1.496(0.844–2.651)
0.168
 T category (3–4 vs. 1–2)
1.556(0.755–3.208)
0.231
 N category (2–3 vs. 0–1)
1.736(0.897–3.361)
0.101
 Overall stage (IVa-b vs. III)
1.711(1.047–2.796)
0.032
 EBV DNA (< 1500 vs. ≥1500)
2.327(1.223–4.427)
0.010
 RT method (IMRT vs. 2D-RT)
1.159(0.910–1.477)
0.232
Overall survival
 Age (y) (≥ 45 vs. <  45)
2.067(0.986–4.33)
0.054
 Gender (F vs. M)
0.710(0.329–1.535)
0.384
 T category (3–4 vs. 1–2)
0.921(0.335–2.533)
0.874
 N category (2–3 vs. 0–1)
1.150(0.446–2.966)
0.772
 Overall stage (IVa-b vs. III)
1.998(0.911–4.384)
0.084
 EBV DNA (< 1500 vs. ≥1500)
5.091(1.209–21.430)
0.027
 RT method (IMRT vs. 2D-RT)
0.875(0.660–1.290)
0.244
Locoregional relapse-free survival
 Age (y) (≥ 45 vs. <  45)
1.035(0.500–2.140)
0.927
 Gender (F vs. M)
0.866(0.378–1.986)
0.734
 T category (3–4 vs. 1–2)
1.136(0.371–3.479)
0.823
 N category (2–3 vs. 0–1)
0.812(0.334–1.975)
0.646
 Overall stage (IVa-b vs. III)
2.002(0.890–4.502)
0.093
 EBV DNA (< 1500 vs. ≥1500)
3.431(1.032–11.400)
0.044
 RT method (IMRT vs. 2D-RT)
1.213(0.818–1.801)
0.337
Distant metastasis-free survival
 Age (y) (≥ 45 vs. <  45)
0.913(0.531–1.571)
0.742
 Gender (F vs. M)
2.125(0.993–4.548)
0.052
 T category (3–4 vs. 1–2)
2.041(0.791–5.265)
0.140
 N category (2–3 vs. 0–1)
2.353(0.984–5.626)
0.054
 Overall stage (IVa-b vs. III)
1.619(0.902–2.905)
0.107
 EBV DNA (< 1500 vs. ≥1500)
1.912(0.927–3.946)
0.079
 RT method (IMRT vs. 2D-RT)
1.242(0.919–1.679)
0.158
A Cox proportional hazards regression model was used to detect variables individually without adjustment. All variables were transformed into categorical variables. HRs were calculated for age (years) (≥45 vs. < 45), sex (female vs. male), T stage (T3–4 vs. T1–2), N stage (N2–3 vs. N0–1), plasma EBV DNA before the first treatment (≥1500 copies/ml vs. < 1500 copies/ml), overall stage (IVa-b vs. III), and RT method (IMRT vs. 2D-RT)
Abbreviations: CI Confidence interval, EBV Epstein–Barr virus, PF Cisplatin with fluorouracil

Appendix 3

Table 8
Patient demographics and clinical characteristics
 
III
IVA-IVB
Characteristic
TPF(n = 320) No. (%)
PF(n = 167) No. (%)
TP(n = 125) No. (%)
P
TPF(n = 452) No. (%)
PF(n = 173) No. (%)
TP(n = 117) No. (%)
P
Age, y
   
0.106a
   
0.865a
 Median (range)
42(13–70)
44(18–68)
46 (19–64)
 
45(8–74)
45(15–71)
46 (18–71)
 
 < 45
186(58.1)
89(53.3)
59(47.2)
 
225(49.8)
82(47.4)
57(48.7)
 
 ≥ 45
134(41.9)
78(46.7)
66(52.8)
 
227(50.2)
91(52.6)
60(51.3)
 
Gender
   
0.151a
   
0.668a
 Female
78(24.4)
53(31.7)
29(26.1)
 
106 (23.5)
38(22.0)
31(26.5)
 
 Male
242(75.6)
114(68.3)
96(76.8)
 
346(76.5)
135(78.0)
86(73.5)
 
Pathological type
  
0.660b
   
0.370b
 WHO type I
0(0)
0(0)
0(0)
 
3(0.7)
1(0.6)
0(0)
 
 WHO type II
2(0.6)
2(1.2)
0(0)
 
2(0.4)
3(1.7)
0(0)
 
 WHO type III
318(99.4)
165(98.8)
125(100)
 
447(98.9)
169(97.7)
117(100)
 
T stagec
   
0.049b
   
0.426a
 T1
4(1.3)
3(1.8)
1(0.8)
 
7(1.5)
2(1.2)
1(0.9)
 
 T2
41(12.8)
38(22.8)
23(18.4)
 
30(6.6)
11(6.4)
6(5.1)
 
 T3
275(85.9)
126(75.4)
101(80.8)
 
104(48.1)
168(48.4)
118(47.6)
 
 T4
0 (0)
0 (0)
0 (0)
 
311(39.5)
118(34.0)
93(37.5)
 
N stagec
   
< 0.001a
   
0.047 a
 N0
6(1.9)
1(0.6)
5(4.0)
 
9(2.0)
10(5.8)
4(3.4)
 
 N1
95(29.7)
17(10.2)
32(25.6)
 
98(21.7)
40(23.1)
33(28.2)
 
 N2
219(68.4)
149(89.2)
88(70.4)
 
148(432.7)
48(27.7)
43(36.8)
 
 N3
0 (0)
0 (0)
0 (0)
 
197(43.6)
75(43.4)
37(31.6)
 
EBV DNA
   
0.085a
   
0.007 a
 ≥ 1500
188(58.8)
104(62.3)
62(49.6)
 
326(72.1)
127(73.4)
68(58.1)
 
 < 1500
132 (41.3)
63(37.7)
63(50.4)
 
126(27.9)
46(26.6)
49(41.9)
 
RT technique
  
< 0.001a
  
< 0.001 b
 2D RT
5(1.6)
52(31.1)
9(7.2)
 
2(0.4)
49(28.3)
2(1.7)
 
 IMRT
315(98.4)
115(68.9)
116(92.8)
 
450(99.6)
124(71.7)
115(98.3)
 
CCD (mg/m2)
   
0.032 a
   
0.791 a
 Median (range)
160(68–300)
160(40–250)
160(60–300)
 
160(25–300)
160(50–240)
160(20–300)
 
 ≥ 200
85(26.6)
27(16.3)
27(21.6)
 
98(21.7)
36(20.8)
22(18.8)
 
 < 200
235(73.4)
140(83.8)
98(78.4)
 
354(78.3)
137(79.2)
95(81.2)
 
Abbreviations: TPF Taxanes plus cisplatin with fluorouracil, PF Cisplatin with fluorouracil, TP Taxanes with cisplatin, EBV Epstein–Barr virus, CCD Cumulative cisplatin dose during radiotherapy
aP values were calculated by the Chi-square test. bP value calculated with Fisher’s exact test
cAccording to the 7th edition of the UICC/AJCC staging system

Appendix 4

Table 9
Three-year PFS, OS, DMFS, LRFS based on different IC regimens in IVa-b patients of EBV ≥ 1500 copies/ml
 
TPF (%) n = 326
PF (%) n = 127
TP (%) n = 68
P value
Progression-free survival
 Failures
46(14.1%)
42(33.0%)
22 (32.4%)
< 0.001
 Rate at 3 years
81.5% (75.6–87.4)
67.6% (58.2–77.0)
57.3%(41.0–73.6)
 
Overall survival
 Deaths
10(3.1%)
19 (15.0%)
5(7.3%)
0.029
 Rate at 3 years
97.3% (94.8–99.8)
86.6%(79.7–93.5)
85.8%(69.7–102)
 
Locoregional relapse-free survival
 Locoregional failure
15(4.6%)
19 (15.0%)
7 (10.3%)
0.032
 Rate at 3 years
93.7% (90.0–97.4)
85.7%(78.6–92.8)
78.8%(59.0–98.6)
 
Distant metastasis-free survival
 Distant failures
31(9.5%)
28 (22.0%)
14 (20.6%)
0.003
 Rate at 3 years
86.8% (81.9–91.7)
78.0%(69.8–86.2)
67.1%(49.9–84.3)
 
Data are n (%) or rate (95% CI). P values were calculated with the unadjusted log-rank test
Literatur
1.
Zurück zum Zitat Wee JT, Ha TC, Loong SL, Qian CN. Is nasopharyngeal cancer really a "Cantonese cancer"? Chin J Cancer. 2010;29(5):517–26.CrossRef Wee JT, Ha TC, Loong SL, Qian CN. Is nasopharyngeal cancer really a "Cantonese cancer"? Chin J Cancer. 2010;29(5):517–26.CrossRef
2.
Zurück zum Zitat Choa G. Nasopharyngeal carcinoma. Some observations on the clinical features and technique of examination. Pac Med Surg. 1967;75(3):172–4.PubMed Choa G. Nasopharyngeal carcinoma. Some observations on the clinical features and technique of examination. Pac Med Surg. 1967;75(3):172–4.PubMed
3.
Zurück zum Zitat Peng G, Wang T, Yang K, Zhang S, Zhang T, Li Q, Han J, Wu G. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol. 2012;104(3):286–93.CrossRef Peng G, Wang T, Yang K, Zhang S, Zhang T, Li Q, Han J, Wu G. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol. 2012;104(3):286–93.CrossRef
4.
Zurück zum Zitat Zhang M, Li J, Shen G, Zou X, Xu J, Jiang R, You R, Hua Y, Sun Y, Ma J, et al. Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: a 10-year experience with a large cohort and long follow-up. Eur J Cancer. 2015;51(17):2587–95.CrossRef Zhang M, Li J, Shen G, Zou X, Xu J, Jiang R, You R, Hua Y, Sun Y, Ma J, et al. Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: a 10-year experience with a large cohort and long follow-up. Eur J Cancer. 2015;51(17):2587–95.CrossRef
5.
Zurück zum Zitat Yi J, Huang X, Gao L, Luo J, Zhang S, Wang K, Qu Y, Xiao J, Xu G. Intensity-modulated radiotherapy with simultaneous integrated boost for locoregionally advanced nasopharyngeal carcinoma. Radiat Oncol. 2014;9:56.CrossRef Yi J, Huang X, Gao L, Luo J, Zhang S, Wang K, Qu Y, Xiao J, Xu G. Intensity-modulated radiotherapy with simultaneous integrated boost for locoregionally advanced nasopharyngeal carcinoma. Radiat Oncol. 2014;9:56.CrossRef
7.
Zurück zum Zitat Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol. 1998;16(4):1310–7.CrossRef Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol. 1998;16(4):1310–7.CrossRef
8.
Zurück zum Zitat Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol. 2003;21(4):631–7.CrossRef Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol. 2003;21(4):631–7.CrossRef
9.
Zurück zum Zitat Hong R, Ting L, Ko J, Hsu M, Sheen T, Lou P, Wang C, Chung N, Lui L. Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol. 2001;19(23):4305–13.CrossRef Hong R, Ting L, Ko J, Hsu M, Sheen T, Lou P, Wang C, Chung N, Lui L. Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol. 2001;19(23):4305–13.CrossRef
10.
Zurück zum Zitat Hui E, Ma B, Leung S, King A, Mo F, Kam M, Yu B, Chiu S, Kwan W, Ho R, et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol. 2009;27(2):242–9.CrossRef Hui E, Ma B, Leung S, King A, Mo F, Kam M, Yu B, Chiu S, Kwan W, Ho R, et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol. 2009;27(2):242–9.CrossRef
11.
Zurück zum Zitat Airoldi M, Gabriele P, Gabriele A, Garzaro M, Raimondo L, Pedani F, Beatrice F, Pecorari G, Giordano C. Induction chemotherapy with carboplatin and taxol followed by radiotherapy and concurrent weekly carboplatin + taxol in locally advanced nasopharyngeal carcinoma. Cancer Chemother Pharmacol. 2011;67(5):1027–34.CrossRef Airoldi M, Gabriele P, Gabriele A, Garzaro M, Raimondo L, Pedani F, Beatrice F, Pecorari G, Giordano C. Induction chemotherapy with carboplatin and taxol followed by radiotherapy and concurrent weekly carboplatin + taxol in locally advanced nasopharyngeal carcinoma. Cancer Chemother Pharmacol. 2011;67(5):1027–34.CrossRef
12.
Zurück zum Zitat Bossi P, Orlandi E, Bergamini C, Locati L, Granata R, Mirabile A, Parolini D, Franceschini M, Fallai C, Olmi P, et al. Docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer. Ann Oncol. 2011;22(11):2495–500.CrossRef Bossi P, Orlandi E, Bergamini C, Locati L, Granata R, Mirabile A, Parolini D, Franceschini M, Fallai C, Olmi P, et al. Docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer. Ann Oncol. 2011;22(11):2495–500.CrossRef
13.
Zurück zum Zitat OuYang P, Xie C, Mao Y, Zhang Y, Liang X, Su Z, Liu Q, Xie F. Significant efficacies of neoadjuvant and adjuvant chemotherapy for nasopharyngeal carcinoma by meta-analysis of published literature-based randomized, controlled trials. Ann Oncol. 2013;24(8):2136–46.CrossRef OuYang P, Xie C, Mao Y, Zhang Y, Liang X, Su Z, Liu Q, Xie F. Significant efficacies of neoadjuvant and adjuvant chemotherapy for nasopharyngeal carcinoma by meta-analysis of published literature-based randomized, controlled trials. Ann Oncol. 2013;24(8):2136–46.CrossRef
14.
Zurück zum Zitat Boscolo-Rizzo P, Tirelli G, Mantovani M, Baggio V, Lupato V, Spinato G, Gava A, Da Mosto M. Non-endemic locoregionally advanced nasopharyngeal carcinoma: long-term outcome after induction plus concurrent chemoradiotherapy in everyday clinical practice. Eur Arch Otorhinolaryngol. 2015;272(11):3491–8.CrossRef Boscolo-Rizzo P, Tirelli G, Mantovani M, Baggio V, Lupato V, Spinato G, Gava A, Da Mosto M. Non-endemic locoregionally advanced nasopharyngeal carcinoma: long-term outcome after induction plus concurrent chemoradiotherapy in everyday clinical practice. Eur Arch Otorhinolaryngol. 2015;272(11):3491–8.CrossRef
15.
Zurück zum Zitat Sun X, Zeng L, Chen C, Huang Y, Han F, Xiao W, Liu S, Lu T. Comparing treatment outcomes of different chemotherapy sequences during intensity modulated radiotherapy for advanced N-stage nasopharyngeal carcinoma patients. Radiat Oncol. 2013;8:265.CrossRef Sun X, Zeng L, Chen C, Huang Y, Han F, Xiao W, Liu S, Lu T. Comparing treatment outcomes of different chemotherapy sequences during intensity modulated radiotherapy for advanced N-stage nasopharyngeal carcinoma patients. Radiat Oncol. 2013;8:265.CrossRef
16.
Zurück zum Zitat Peng H, Tang LL, Chen BB, Chen L, Li WF, Mao YP, Liu X, Zhang Y, Liu LZ, Tian L, et al. Optimizing the induction chemotherapy regimen for patients with locoregionally advanced nasopharyngeal carcinoma: a big-data intelligence platform-based analysis. Oral Oncol. 2018;79:40–6.CrossRef Peng H, Tang LL, Chen BB, Chen L, Li WF, Mao YP, Liu X, Zhang Y, Liu LZ, Tian L, et al. Optimizing the induction chemotherapy regimen for patients with locoregionally advanced nasopharyngeal carcinoma: a big-data intelligence platform-based analysis. Oral Oncol. 2018;79:40–6.CrossRef
17.
Zurück zum Zitat Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004;350(24):2461–70.CrossRef Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004;350(24):2461–70.CrossRef
18.
Zurück zum Zitat Lee AW, Ngan RK, Tung SY, Cheng A, Kwong DL, Lu TX, Chan AT, Chan LL, Yiu H, Ng WT, et al. Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma. Cancer. 2015;121(8):1328–38.CrossRef Lee AW, Ngan RK, Tung SY, Cheng A, Kwong DL, Lu TX, Chan AT, Chan LL, Yiu H, Ng WT, et al. Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma. Cancer. 2015;121(8):1328–38.CrossRef
19.
Zurück zum Zitat Lee A, Lau K, Hung W, Ng W, Lee M, Choi C, Chan C, Tung R, Cheng P, Yau T. Potential improvement of tumor control probability by induction chemotherapy for advanced nasopharyngeal carcinoma. Radiother Oncol. 2008;87(2):204–10.CrossRef Lee A, Lau K, Hung W, Ng W, Lee M, Choi C, Chan C, Tung R, Cheng P, Yau T. Potential improvement of tumor control probability by induction chemotherapy for advanced nasopharyngeal carcinoma. Radiother Oncol. 2008;87(2):204–10.CrossRef
20.
Zurück zum Zitat Lin S, Lu JJ, Han L, Chen Q, Pan J. Sequential chemotherapy and intensity-modulated radiation therapy in the management of locoregionally advanced nasopharyngeal carcinoma: experience of 370 consecutive cases. BMC Cancer. 2010;10:39.CrossRef Lin S, Lu JJ, Han L, Chen Q, Pan J. Sequential chemotherapy and intensity-modulated radiation therapy in the management of locoregionally advanced nasopharyngeal carcinoma: experience of 370 consecutive cases. BMC Cancer. 2010;10:39.CrossRef
21.
Zurück zum Zitat Yu Z, Luo W, Zhou QC, Zhang QH, Kang DH, Liu MZ. Impact of changing gross tumor volume delineation of intensity-modulated radiotherapy on the dose distribution and clinical treatment outcome after induction chemotherapy for the primary locoregionally advanced nasopharyngeal carcinoma. Ai Zheng. 2009;28(11):1132–7.PubMed Yu Z, Luo W, Zhou QC, Zhang QH, Kang DH, Liu MZ. Impact of changing gross tumor volume delineation of intensity-modulated radiotherapy on the dose distribution and clinical treatment outcome after induction chemotherapy for the primary locoregionally advanced nasopharyngeal carcinoma. Ai Zheng. 2009;28(11):1132–7.PubMed
22.
Zurück zum Zitat Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.CrossRef Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.CrossRef
23.
Zurück zum Zitat Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, Akazawa P, Weinberg V, Fu KK. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys. 2002;53(1):12–22.CrossRef Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, Akazawa P, Weinberg V, Fu KK. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys. 2002;53(1):12–22.CrossRef
24.
Zurück zum Zitat Sun X, Su S, Chen C, Han F, Zhao C, Xiao W, Deng X, Huang S, Lin C, Lu T. Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities. Radiother Oncol. 2014;110(3):398–403.CrossRef Sun X, Su S, Chen C, Han F, Zhao C, Xiao W, Deng X, Huang S, Lin C, Lu T. Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities. Radiother Oncol. 2014;110(3):398–403.CrossRef
25.
Zurück zum Zitat Cao SM, Yang Q, Guo L, Mai HQ, Mo HY, Cao KJ, Qian CN, Zhao C, Xiang YQ, Zhang XP, et al. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial. Eur J Cancer. 2017;75:14–23.CrossRef Cao SM, Yang Q, Guo L, Mai HQ, Mo HY, Cao KJ, Qian CN, Zhao C, Xiang YQ, Zhang XP, et al. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial. Eur J Cancer. 2017;75:14–23.CrossRef
26.
Zurück zum Zitat Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, Sun Y, Chen XZ, Li JG, Zhu XD, et al. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016;17(11):1509–20.CrossRef Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, Sun Y, Chen XZ, Li JG, Zhu XD, et al. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016;17(11):1509–20.CrossRef
27.
Zurück zum Zitat Chua DT, Ma J, Sham JS, Mai HQ, Choy DT, Hong MH, Lu TX, Min HQ. Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J Clin Oncol. 2005;23(6):1118–24.CrossRef Chua DT, Ma J, Sham JS, Mai HQ, Choy DT, Hong MH, Lu TX, Min HQ. Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J Clin Oncol. 2005;23(6):1118–24.CrossRef
28.
Zurück zum Zitat Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, Chan AT, Huang PY, Benhamou E, Zhu G, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol. 2015;16(6):645–55.CrossRef Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, Chan AT, Huang PY, Benhamou E, Zhu G, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol. 2015;16(6):645–55.CrossRef
29.
Zurück zum Zitat Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–15.CrossRef Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–15.CrossRef
30.
Zurück zum Zitat Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695–704.CrossRef Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695–704.CrossRef
31.
Zurück zum Zitat Colevas AD, Posner MR. Docetaxel in head and neck cancer: a review. Am J Clin Oncol. 1998;21(5):482–6.CrossRef Colevas AD, Posner MR. Docetaxel in head and neck cancer: a review. Am J Clin Oncol. 1998;21(5):482–6.CrossRef
32.
Zurück zum Zitat Hitt R, Lopez-Pousa A, Martinez-Trufero J, Escrig V, Carles J, Rizo A, Isla D, Vega ME, Marti JL, Lobo F, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005;23(34):8636–45.CrossRef Hitt R, Lopez-Pousa A, Martinez-Trufero J, Escrig V, Carles J, Rizo A, Isla D, Vega ME, Marti JL, Lobo F, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005;23(34):8636–45.CrossRef
33.
Zurück zum Zitat Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, Tan M, Fasciano J, Sammartino DE, Posner MR. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011;12(2):153–9.CrossRef Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, Tan M, Fasciano J, Sammartino DE, Posner MR. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011;12(2):153–9.CrossRef
34.
Zurück zum Zitat Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux J, Faivre S, Guerrif S, Alfonsi M, Calais G. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst. 2009;101(7):498–506.CrossRef Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux J, Faivre S, Guerrif S, Alfonsi M, Calais G. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst. 2009;101(7):498–506.CrossRef
35.
Zurück zum Zitat Lee AW, Tung SY, Ngan RK, Chappell R, Chua DT, Lu TX, Siu L, Tan T, Chan LK, Ng WT, et al. Factors contributing to the efficacy of concurrent-adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: combined analyses of NPC-9901 and NPC-9902 Trials. Eur J Cancer. 2011;47(5):656–66.CrossRef Lee AW, Tung SY, Ngan RK, Chappell R, Chua DT, Lu TX, Siu L, Tan T, Chan LK, Ng WT, et al. Factors contributing to the efficacy of concurrent-adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: combined analyses of NPC-9901 and NPC-9902 Trials. Eur J Cancer. 2011;47(5):656–66.CrossRef
36.
Zurück zum Zitat Liu GY, Lv X, Wu YS, Mao MJ, Ye YF, Yu YH, Liang H, Yang J, Ke LR, Qiu WZ, et al. Effect of induction chemotherapy with cisplatin, fluorouracil, with or without taxane on locoregionally advanced nasopharyngeal carcinoma: a retrospective, propensity score-matched analysis. Cancer commun (Lond). 2018;38(1):21.CrossRef Liu GY, Lv X, Wu YS, Mao MJ, Ye YF, Yu YH, Liang H, Yang J, Ke LR, Qiu WZ, et al. Effect of induction chemotherapy with cisplatin, fluorouracil, with or without taxane on locoregionally advanced nasopharyngeal carcinoma: a retrospective, propensity score-matched analysis. Cancer commun (Lond). 2018;38(1):21.CrossRef
37.
Zurück zum Zitat Chen J, Qi J, Yu B, Peng XH, Wang F, Tan JJ, Chen QQ, Peng XY, Zeng FF, Liu X. A retrospective study to compare five induction chemotherapy regimens prior to radiotherapy in the reduction of regional lymph node size in patients with nasopharyngeal carcinoma. Med Sci Monit. 2018;24:2562–8.CrossRef Chen J, Qi J, Yu B, Peng XH, Wang F, Tan JJ, Chen QQ, Peng XY, Zeng FF, Liu X. A retrospective study to compare five induction chemotherapy regimens prior to radiotherapy in the reduction of regional lymph node size in patients with nasopharyngeal carcinoma. Med Sci Monit. 2018;24:2562–8.CrossRef
Metadaten
Titel
Comparing three induction chemotherapy regimens for patients with locoregionally advanced nasopharyngeal carcinoma based on TNM stage and plasma Epstein–Barr virus DNA level
verfasst von
Sai-Lan Liu
Xue-Song Sun
Hao-Jun Xie
Qiu-Yan Chen
Huan-Xin Lin
Hu Liang
Yu-Jing Liang
Xiao-Yun Li
Jin-Jie Yan
Chao Lin
Zhen-Chong Yang
Shan-Shan Guo
Li-Ting Liu
Qing-Nan Tang
Yu-Yun Du
Lin-Quan Tang
Ling Guo
Hai-Qiang Mai
Publikationsdatum
01.12.2020
Verlag
BioMed Central
Erschienen in
BMC Cancer / Ausgabe 1/2020
Elektronische ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-020-6555-7

Weitere Artikel der Ausgabe 1/2020

BMC Cancer 1/2020 Zur Ausgabe

„Überwältigende“ Evidenz für Tripeltherapie beim metastasierten Prostata-Ca.

22.05.2024 Prostatakarzinom Nachrichten

Patienten mit metastasiertem hormonsensitivem Prostatakarzinom sollten nicht mehr mit einer alleinigen Androgendeprivationstherapie (ADT) behandelt werden, mahnt ein US-Team nach Sichtung der aktuellen Datenlage. Mit einer Tripeltherapie haben die Betroffenen offenbar die besten Überlebenschancen.

So sicher sind Tattoos: Neue Daten zur Risikobewertung

22.05.2024 Melanom Nachrichten

Das größte medizinische Problem bei Tattoos bleiben allergische Reaktionen. Melanome werden dadurch offensichtlich nicht gefördert, die Farbpigmente könnten aber andere Tumoren begünstigen.

CAR-M-Zellen: Warten auf das große Fressen

22.05.2024 Onkologische Immuntherapie Nachrichten

Auch myeloide Immunzellen lassen sich mit chimären Antigenrezeptoren gegen Tumoren ausstatten. Solche CAR-Fresszell-Therapien werden jetzt für solide Tumoren entwickelt. Künftig soll dieser Prozess nicht mehr ex vivo, sondern per mRNA im Körper der Betroffenen erfolgen.

Blutdrucksenkung könnte Uterusmyome verhindern

Frauen mit unbehandelter oder neu auftretender Hypertonie haben ein deutlich erhöhtes Risiko für Uterusmyome. Eine Therapie mit Antihypertensiva geht hingegen mit einer verringerten Inzidenz der gutartigen Tumoren einher.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.