DOI: https://doi.org/10.21203/rs.3.rs-1819591/v1
There are conflicting results regarding the role of IC in T3-4N0-1 NPC patients from endemic area of China. Therefore, it is worth verifying the consistency of study between endemic area and non-endemic area for NPC and providing treatment guidance for non-endemic NPCs. We conducted a multicenter real-world study to investigate the value of adding IC to CCRT for T3-4N0-1 NPC in Northwest of China.
Data was extracted in three hospitals from Northwest China between May 1, 2010 and August 30, 2018. The Kaplan-Meier method was used to estimate the endpoints, survival curves were compared using the log-rank test. Initial propensity matching was conducted with a 1:1 match of IC + CCRT to CCRT. The primary endpoint of this study was overall survival (OS).
A total of 108 patients with staging T3-4N0-1 were included in this study. The median follow-up time was 50 months (range: 6-118 months). IC followed by CCRT had trend to improve OS compared with CCRT (89.5% vs.77.6%, HR:0.41, 95%CI:0.16–1.04, P = 0.100). After analysis of well-balanced propensity score-matched cohort, IC followed by CCRT provided superior OS than CCRT alone. Adjusted 4-year OS was 89.5% for IC followed by CCRT vs. 71.1% for CCRT (HR:0.30, 95%CI:0.11–0.80, P = 0.027). No significant differences were detected in side effects between two groups.
This study implied IC followed by CCRT improved OS in patients with T3-4N0-1M0 NPC from Northwest China compared with CCRT. However, prospective studies with large sample are warranted to confirm the result.
Most newly diagnosed nasopharyngeal carcinoma (NPC) present with locoregionally advanced disease at initial diagnosis [1]. According to the recent phase 3 randomized controlled studies, induction chemotherapy (IC) followed by chemoradiotherapy (CCRT) achieved better survival outcome than CCRT alone in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) [2, 3]. IC followed by CCRT has therefore been recommended as preferable treatment regimen by both national comprehensive cancer network (NCCN) guideline and Chinese society of clinical oncology (CSCO) guideline.
Distant metastasis is the predominant failure pattern in LA-NPC patients [4]. Consistent with data from endemic data, our studies, which are from Northwest China where is considered as non-endemic area for this disease, also found that more than 75% distant failure occurred in advanced N stage (N2 or N3) rather than late T stage [5, 6]. Patients of non-endemic area made it reasonable to consider IC followed by CCRT in these late N stage patients. Until now, IC followed by CCRT and CCRT alone were recommended to all LA-NPC patients, including T3-4 patients with lymph nodes staged as N0-1. However, it is worth noting that LA-NPC with N0-1 stage is routinely excluded by clinical trials due to the relatively low risk of distant metastasis [2, 3, 7, 8]. Therefore, whether adding IC to CCRT could further improve survival in T3-4N0-1 patients need further investigation.
There are conflicting results regarding the role of IC in T3-4N0-1 NPC patients. One retrospective study indicated that addition of IC to CCRT failed to improve survival in T3-4N0-1M0 NPC [9]. Another retrospective study including 362 T3N0M0 NPC patients showed that IC + CCRT lead to worse prognosis in comparison to CCRT [10]. However, these results were from single institution of endemic regions and the data from non-endemic regions are still lacking. Our previous studies showed NPC patient from non-endemic region of Northwest China had relatively higher rate of nonkeratinizing differentiated subtype (approximate 30%) and low level of EBV DNA copies than endemic NPC [6, 11, 12]. And different ethnic groups between Southern China and Northwest China may lead to varied gene characteristic of NPC according to genetic and anthropological investigation [13]. Therefore, it is worth verifying the consistency of study between endemic area and non-endemic area for NPC and providing treatment guidance for non-endemic NPCs.
Here, we conducted a multicenter retrospective study to investigate the value of adding IC to CCRT for T3-4N0-1 NPC in Northwest of China. This study may help to provide a risk stratification for LA-NPC patients, especially those with T3-4N0-1 stage.
Patients
Data was extracted in three hospitals from Northwest China between May 1,2010 and August 30, 2018. Patients were reviewed according to the following eligibility criteria: age 18-70 years; histologically confirmed newly diagnostic nasopharyngeal squamous cell carcinoma; stages T3-4N0-1M0 disease according to the 8th edition of AJCC staging system for NPC; receiving CCRT with or without IC as initial treatment modalities; treated with intensity-modulated radiotherapy (IMRT); patients’ primary residences limited to the Northwest China. The exclusion criteria included: non-squamous cell carcinoma; long-term resident history in endemic area; receiving molecular targeted drug and immunotherapy at initial treatment. Ultimately, a total of 108 patients were included according to the inclusion and exclusion criteria. The protocol was approved by by the medical enthics committee, and the study was conducted in accordance with the principles of the Declaration of Helsinki.
Diagnosis and restaging
Except for complete history, physical examination, blood work of patients must be collected, and imageological examinations of whole body were indispensable for stage, including Chest computed tomography, abdominal sonography, and whole-body bone scan. Real-time quantitative polymerase chain reaction was used to measure plasma EBV DNA concentrations. The precise staging of NPC depended on the magnetic resonance imaging (MRI) of head and neck. 18F-fluorodeoxyglucose positron emission tomography (PET) and CT (PET/CT) was not routinely conducted unless patient was unfit for MRI. Restaging was conducted by two radiation oncologist specializing head and neck cancer according to 8th edition AJCC staging system through reviewing imaging.
Treatment
The delineating targets were defined as follow: gross tumor volume (GTV) from nasopharynx and regional lymph nodes were defined as GTVnx and GTVnd; clinical target volume (CTV)1 included 5mm margin of GTVnx which was the area of high-risk tumor invasion; CTV2 encompassed CTV1, area of moderate-risk tumor invasion and lymphatic levels of high-risk metastasis in neck; CTV3 covered the low risk of lymphatic levels of neck. GTV and CTV were contoured on the fusion image of CT and MRI by a radiation oncologist, and then verified by another radiation oncologist. Planning target volume (PTV) was created on the basis of CTVs with 3mm margin. The prescribed radiation doses were defined as follows: a total of 68-74Gy in 30-33 fractions to the PTV of GTVnx, 66 to 72.6Gy to metastatic lymph nodes, 60-64Gy to PTV of CTV1, 55-60Gy to PTV of CTV2, and 50Gy to PTV of CTV3. All patients were treated with 1 fraction daily for 5 days per week. Received doses of organ at risk (OAR) should be accordance with 2012 criteria of Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC).
The induction chemotherapy (IC) included TP regimen (docetaxel 75 mg/m2, cisplatin 75 mg/m2), PF regimen (cisplatin 80 mg/m2, 5-FU 800–1000 mg/m2 days 1 to 5), GP regimen (gemcitabine 1000 mg/m2, cisplatin 75 mg/m2), and TPF regimen (docetaxel 75 mg/m2, cisplatin 75 mg/m2, 5-FU 750 mg/m2 days1 to 5) given every 3 weeks for 2–3 cycles. Concurrent chemotherapy consisted of cisplatin (100 mg/m2 every 3 weeks or 40 mg/m2 weekly). IC was administrated to patients with adverse prognostic status of lymph nodes, such as extracapsular nodal spread, central nodal necrosis, > 3 cm in greatest dimension, and nodal grouping metastasis.
Endpoints evaluation
The follow-up time was calculated from the end of treatment to the last follow-up or death. Treatment response and side effects were evaluated at the first month after treatment, then patients were regularly evaluated every 3 months during the first three years. Treatment-related toxicities were classified according to the National Cancer Institute Common Toxicity Criteria version (CTCAE) 3.0.
The primary endpoint of this study was OS. The secondary endpoints included disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregionally recurrence-free survival (LRFS) and treatment-related toxicities. OS was defined as the time from end of treatment to death; DFS was calculated from the end of treatment to the date of disease progression or death from any causes; DMFS was defined as the time from end of treatment to the date of first detection of distant metastasis; LRFS was defined as the time from end of treatment to the date of first finding local and/or lymph node regional relapse.
Statistical analysis
The endpoints were estimated by the Kaplan-Meier method, the differences of survival curves were compared using the log-rank test. X2 test was used to evaluate the group differences in proportions. If numerical variable was not accordance with Gaussian distribution, it would be transformed to categorical variable for comparison. Prognostic factors were screened out by cox proportional hazard model, and the proportional-hazards assumption was tested with Schoenfeld residuals. The hazard ratio (HR) and its 95% confidence interval (95% CI) were used to indicate the prognostic value of risk factors. Propensity scores with a 1:1 match of IC + CCRT to CCRT were conducted to balance group bias by logistic regression for each patient using the following covariates: age, gender, T category, N category, histological WHO type, tumor volume. Subgroup analysis was used to explore the variation of treatment effect. A 2-sided p value of less than 0.05 was considered significant.
Clinical features
The median follow-up time was 50 months (range:6-118 months). Of all patients included in this study, 43 (39.8%) received IC followed by CCRT, 65 (60.2%) received CCRT;83 (76.9%) were male and 25 (23.1%) were female. Nonkeratinizing undifferentiation was the most common histological type (73.1%), the proportion of nonkeratinizing differentiation was 26.9%. More patients with stage N1 were administrated with IC followed by CCRT (67.4%) and patients with N0 were more like to be received CCRT (52.3%), but the distribution biases was eliminated after propensity score-matching (PSM). Only 9 patients (8.3%) had more than 1000 copies of EBV DNA in this study. The median of primary tumor and lymph node were 52.60cc (range: 11.70–232.00 cc) and 2.13cc (range: 0-66.68cc), respectively. TP was the most common IC regimen (74.4%), the second was GP (16.2%).
treatment outcomes
At the last follow-up time, there were total of 19 deaths, including 5 of 43(11.6%) patients in IC followed by CCRT group and 14 of 65 (21.5%) patients in CCRT group. Treatment failure patterns included only locoregional recurrence (4 patients), only distant metastasis (13 patients) and locoregional recurrence combined with distant metastasis (2 patients). Four-year OS, DFS, LRFS and DMFS were 82.2%, 72.8%, 94.4% and 86.0%, fore entire cohort. IC followed by CCRT failed to improve OS and DFS compared with CCRT in the initial analysis. Unadjusted 4-year OS and DFS were 89.5% and 75.7% for IC followed by CCRT compared with for 77.6% and 70.3% CCRT alone (OS, HR:0.41, 95%CI:0.16–1.04, P = 0.100; DFS, HR:0.62, 95%CI:0.30–1.30, P = 0.231) (Fig. 1). 4-year LRFS and DMFS were 93.9% and 84.5% for IC followed by CCRT compared with for 94.8% and 87.0% CCRT alone (LRFS, HR:0.97, 95%CI:0.16–5.77, P = 0.973; DMFS, HR:0.93,95%CI:0.33–2.58, P = 0.884) (Fig. S1).
After analysis of well-balanced propensity score-matched cohort, IC followed by CCRT provided superior OS than CCRT alone. Adjusted 4-year OS was 89.5% for IC followed by CCRT vs. 71.1% for CCRT (HR:0.30, 95%CI:0.11–0.80, P = 0.027) (Fig. 1). However, adjusted 4-year DFS, LRFS and DMFS were not significant differences between IC followed by CCRT (75.7%, 93.9% and 84.5%) and CCRT (64.3%, 94.9% and 85.0%) (Fig. 1 and Fig. S1). Subgroup analysis adjusted by propensity score-match showed IC followed by CCRT could provide better OS than CCRT for patients with>45 year (88.9% vs. 63.0%, P = 0.017) and primary tumor volume ≦ 52.60cc (90.9% vs. 65.0%, P = 0.024) (Fig. 2). For nonkeratinizing differentiation subgroup, IC followed by CCRT significantly improved DFS (P = 0.031) and DMFS (P = 0.015) (Fig. S2-3). Patients with N1 stage were more likely to have the death when they accepted CCRT alone (31%) instead of IC followed by CCRT (13.87%), but statistically significant difference was not achieved (Fig. 2).
Multivariate analysis
Multivariate analysis was conducted to identify the independent prognostic factors using the following covariates: sex, age, histological type, T stage, N stage, treatment, EBV DNA copies, primary tumor volume, lymph nodes volume. In multivariate analysis, EBV DNA copies was an independently prognostic factor for DMFS (HR: 0.18, 95%CI: 0.04–0.85, P = 0.03). For OS and DFS, there were not independently prognostic factor with significant differences detected by multivariate analysis (Table 2).
|
Characteristic |
Primary cohort |
PSM cohort |
||||
|---|---|---|---|---|---|---|
|
IC+CCRT |
CCRT |
P Value |
IC+CCRT |
CCRT |
P Value | |
|
Total |
43 |
65 |
43 |
43 |
||
|
Sex |
0.626 |
0.802 |
||||
|
Male |
32(74.4%) |
51(78.5%) |
32(74.4%) |
33(76.7%) |
||
|
Female |
11(25.6%) |
14(21.5%) |
11(25.6%) |
10(23.3%) |
||
|
Age(years) |
||||||
|
Median age(range) |
48(23–65) |
51(18–83) |
0.495 |
48(23–65) |
49(18–83) |
0.867 |
|
≤ 45 |
16(37.2%) |
20(30.8%) |
0.487 |
16(37.2%) |
16(37.2%) |
0.488 |
|
> 45 |
27(62.8%) |
45(69.2%) |
27(62.8%) |
27(62.8%) |
||
|
Histological types |
0.809 |
0.802 |
||||
|
nonkeratinizing undifferentiation |
32(74.4%) |
47(72.3%) |
32(74.4%) |
33(76.7%) |
||
|
nonkeratinizing differentiation |
11(25.6%) |
18(27.7%) |
11(25.6%) |
10(23.3%) |
||
|
T stage |
0.930 |
0.776 |
||||
|
T3 |
7(16.3%) |
11(16.9%) |
7(16.3%) |
8(18.6%) |
||
|
T4 |
36(83.7%) |
54(83.1%) |
36(83.7%) |
35(81.4%) |
||
|
N stage |
0.043 |
1.000 |
||||
|
N0 |
14(32.6%) |
34(52.3%) |
14(32.6%) |
14(32.6%) |
||
|
N1 |
29(67.4%) |
31(47.7%) |
29(67.4%) |
29(67.4%) |
||
|
EBV DNA copies |
||||||
|
≤ 1000 |
41(95.3%) |
58(89.2%) |
0.312 |
41(95.3%) |
36(83.7%) |
0.156 |
|
> 1000 |
2(4.7%) |
7(10.8%) |
2(4.7%) |
7(16.3%) |
||
|
Primary tumor volume(cc) |
||||||
|
Median(range) |
52.6(12.3-200.7) |
52.6(11.7–232.0) |
0.559 |
52.6(12.3-200.7) |
57.2(23.2–232.0) |
0.355 |
|
≤ 52.60 |
22(51.2%) |
33(50.8%) |
0.968 |
22(51.2%) |
20(46.5) |
0.666 |
|
> 52.60 |
21(48.8%) |
32(49.2%) |
21(48.8%) |
23(53.5%) |
||
|
Lymph nodes volume(cc) |
||||||
|
Median(range) |
2.32(0.0-66.7) |
0.66(0.0-17.4) |
0.100 |
2.32(0.0-66.7) |
3.8(0.0-17.4) |
0.765 |
|
≤ 2.13 |
19(44.2%) |
35(53.8%) |
0.326 |
19(44.2%) |
17(39.5) |
0.662 |
|
> 2.13 |
24(55.8%) |
30(46.2%) |
24(55.8%) |
26(60.5) |
||
|
IC regimen |
||||||
|
TP |
32(74.4%) |
32(74.4%) |
||||
|
GP |
7(16.3%) |
7(16.3%) |
||||
|
TPF |
3(7.0%) |
3(7.0%) |
||||
|
PF |
1(2.3%) |
1(2.3%) |
||||
| IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy. | ||||||
|
Endpoints |
Univariate analysis HR (95% CI) P value |
Multivariate analysis HR (95% CI) P value |
||
|---|---|---|---|---|
|
Overall survival |
||||
|
Sex* |
0.74(0.26–2.10) |
0.571 |
0.74(0.22–2.53) |
0.635 |
|
Age† |
0.47(0.15–1.45) |
0.189 |
0.36(0.11–1.20) |
0.097 |
|
Histology type‡ |
1.33(0.71–2.49) |
0.369 |
1.15(0.28–4.67) |
0.848 |
|
T stage†† |
0.53(0.12–2.33) |
0.403 |
0.48(0.10–2.23) |
0.348 |
|
N stage§ |
0.58(0.19–1.78) |
0.342 |
0.72(0.15–3.44) |
0.680 |
|
Treatment¶ |
0.36(0.13–1.04) |
0.058 |
0.34(0.11–1.02) |
0.055 |
|
EBV DNA copies†† |
0.49(0.14–1.74) |
0.273 |
0.87(0.18–4.11) |
0.857 |
|
Primary tumor volume|| |
1.03(0.40–2.66) |
0.956 |
1.07(0.39–2.99) |
0.891 |
|
Lymph nodes volume** |
0.52(0.18–1.48) |
0.223 |
0.50(0.12–2.05) |
0.335 |
|
Disease-free survival |
||||
|
Sex* |
1.15(0.46–2.85) |
0.763 |
1.13(0.42–3.05) |
0.809 |
|
Age† |
0.79(0.36–1.77) |
0.572 |
0.65(0.27–1.55) |
0.334 |
|
Histology type‡ |
1.15(0.73–1.81) |
0.549 |
0.97(0.34–2.74) |
0.951 |
|
Tstage†† |
0.76(0.26–2.20) |
0.613 |
0.67(0.22–2.04) |
0.477 |
|
N stage§ |
0.65(0.28–1.55) |
0.336 |
0.87(0.26–2.95) |
0.824 |
|
Treatment¶ |
0.58(0.27–1.26) |
0.170 |
0.61(0.27–1.37) |
0.229 |
|
EBV DNA copies†† |
0.53(0.18–1.56) |
0.251 |
0.60(0.18–2.02) |
0.405 |
|
Primary tumor volume|| |
0.83(0.39–1.76) |
0.622 |
0.87(0.40–1.90) |
0.726 |
|
Lymph nodes volume** |
0.61(0.27–1.35) |
0.221 |
0.64(0.21–1.93) |
0.424 |
|
Distant metastasis-free survival |
||||
|
Sex* |
1.32 (0.62–2.80) |
0.472 |
2.15(0.42–10.86) |
0.356 |
|
Age† |
1.37(0.46–4.09) |
0.570 |
1.13(0.32-4.00) |
0.852 |
|
Histology type‡ |
0.80(0.24–2.61) |
0.711 |
0.48(0.12–2.03) |
0.321 |
|
T stage†† |
0.78(0.17–3.52) |
0.746 |
0.68(0.13–3.55) |
0.645 |
|
N stage§ |
1.21(0.40–3.71) |
0.734 |
3.31(0.53–20.84) |
0.202 |
|
Treatment¶ |
0.74 (0.25–2.22) |
0.597 |
0.89(0.28–2.83) |
0.837 |
|
EBV DNA copies†† |
0.32(0.09–0.93) |
0.044 |
0.18(0.04–0.85) |
0.030 |
|
Primary tumor volume|| |
0.80(0.27–2.37) |
0.681 |
0.80(0.25–2.58) |
0.710 |
|
Lymph nodes volume** |
0.80 (0.26–2.45) |
0.698 |
0.41(0.07–2.39) |
0.319 |
| HR, hazard ratio; CI, confidence interval; *Male vs. female; †≤45 vs.>45; ‡ nonkeratinizing undifferentiation vs. nonkeratinizing differentiation; ††T3 vs. T4; §N0 vs. N1; ¶Induction chemotherapy followed by concurrent chemoradiotherapy vs. concurrent chemoradiotherapy;††≤ 1000 vs. > 1000;||≤ 52.60cc vs. > 52.60cc; **≤2.13cc vs. >2.13cc. | ||||
Adverse events of treatment
After complete the whole treatment course, 24 of 108 (22.2%) patients had grade 3 or grade 4 adverse effect. The most common hematological toxicities included leukopenia (56.5%) and anemia (70.4%). Grade 4 neutropenia was more likely to occur in patients receiving IC followed by CCRT (4.7%) than CCRT (0%). The incidence of nausea and vomiting were not different between two groups. Most patients experienced mucositis (79.6%) and dry mouth (79.6%) during radiotherapy course, but the incidences were not differences between two groups. Overall, only a few patients presented hepatotoxic events (10.2%) and nephrotoxic events (6.5%) (Table 3).
|
Events |
IC + CCRT |
CCRT |
P Value |
|---|---|---|---|
|
Leukopenia |
0.544 |
||
|
0 |
15(34.9%) |
10(23.3%) |
|
|
1 |
8(18.6%) |
10(23.3%) |
|
|
2 |
12(27.9%) |
17(39.5%) |
|
|
3 |
8(18.6%) |
6(14.0%) |
|
|
Neutropenia |
0.755 |
||
|
0 |
25(58.1) |
26(60.5%) |
|
|
1 |
5(11.6%) |
5(11.6%) |
|
|
2 |
8(18.6%) |
8(18.6%) |
|
|
3 |
3(7.0%) |
4(9.3%) |
|
|
4 |
2(4.7%) |
0(0) |
|
|
Anemia |
0.533 |
||
|
0 |
5(11.6%) |
5(11.6%) |
|
|
1 |
26(60.5%) |
29(67.4%) |
|
|
2 |
11(25.6%) |
9(20.9%) |
|
|
3 |
1(2.3%) |
0(0) |
|
|
Thrombocytopenia |
0.317 |
||
|
0 |
19(44.2%) |
24(55.8%) |
|
|
1 |
19(44.2%) |
15(34.9%) |
|
|
2 |
5(11.6%) |
3(7.0%) |
|
|
3 |
0(0) |
1(2.3%) |
|
|
Nausea |
0.686 |
||
|
0 |
7(16.3%) |
6(14.0%) |
|
|
1 |
15(34.9%) |
19(44.2%) |
|
|
2 |
21(48.8%) |
18(41.9%) |
|
|
Vomiting |
0.644 |
||
|
0 |
13(30.2%) |
14(32.6%) |
|
|
1 |
23(53.5%) |
24(55.8%) |
|
|
2 |
7(16.3%) |
5(11.6%) |
|
|
Radiation dermatitis |
0.831 |
||
|
1 |
27(62.8%) |
26(60.5%) |
|
|
2 |
15(34.9%) |
16(37.2%) |
|
|
3 |
1(2.3%) |
2(2.3%) |
|
|
Mucositis |
0.732 |
||
|
1 |
3(7.0%) |
7(16.3%) |
|
|
2 |
33(76.7%) |
27(62.8%)) |
|
|
3 |
7(16.3%) |
9(20.9%) |
|
|
Dry mouth |
0.812 |
||
|
1 |
12(27.9%) |
13(30.2%) |
|
|
2 |
31(72.1%) |
30(69.8%) |
|
|
Hepatotoxic event |
0.754 |
|
Events |
IC + CCRT |
CCRT |
P Value |
|---|---|---|---|
|
0 |
37(86.0%) |
38(88.4%) |
|
|
1 |
5(11.6%) |
4(9.3%) |
|
|
2 |
1(2.3%) |
1(2.3%) |
|
|
Nephrotoxic event |
0.722 |
||
|
0 |
39(90.7%) |
40(93.0%) |
|
|
1 |
4(9.3%) |
2(4.7%) |
|
|
2 |
0(0) |
1(2.3%) |
|
| IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy. | |||
The distribution of NPC has obvious regional differences in China. Our previous studies found NPC from Northwest China had much higher proportion of nonkeratinizing differentiation subtype and lower EBV DNA copies than NPC from endemic area [6, 11, 12]. And ethnic origin was different between endemic area and Northwest China [13]. Given the potential differences in histological type, expression of EBV DNA copies and ethnic origin, patients from Northwest China might have different treatment outcomes in spite of they received similar treatment regimen with endemic patients [14, 15]. Therefore, it is necessary to evaluate the consistency of study between endemic area and non-endemic area for NPC.
Until now, the treatment option is still unclear for T3-4N0-1M0 patients whose mostly were exclueded by randomised control studies. Several studies from endemic area reported adding induction chemotherapy to CCRT failed to further improve OS insteading of bringing more adverse effects in T3-4N0-1 patients [9, 10, 16]. To verify the necessity of adding IC to CCRT in T3-4N0-1 NPC from Northwest China, we first designed the multicenter study to evaluate the treatment effect of IC followed by CCRT compared with CCRT. In this study, IC followed by CCRT provided much better 4-year OS than CCRT (89.5% vs.71.1%, P = 0.027) after analysis of propensity score-matched cohort. Not only that, there was no significantly increase adverse effects after adding IC to CCRT. Further analysis found IC followed by CCRT had trend to improve OS in all subgroups when compared with CCRT, despite no statistical differences in most cases. Therefore, this study indicated adding IC to CCRT might be beneficial to improve OS for T3-4N0-1 NPC from Northwest China. However, this need to be confirmed by large sample prospective study.
Many studies identified age was a prognostic factor for poor OS of NPC [15, 17, 18]. In this study, IC followed by CCRT could significantly improve OS in patients with age > 45 year according to subgroup analysis. This result suggested that increasing treatment intensity might improve prognosis for elder patient with good status. Our previous study and published studies confirmed that primary tumor volume negatively affected prognosis of NPC [15, 19, 20]. In this study, IC followed by CCRT significantly decreased death risk for patient with primary tumor volume ≦ 52.6cc in subgroup analysis, indicating small primary tumor volume might be easier to achieve better survival benefit from IC followed by CCRT in T3-4 patient. Although there was potential benefit toward OS for patients receiving IC followed by CCRT when compared with CCRT, statistically significant difference was not achieved in patients with primary tumor volume > 52.60cc. This might be explained by treatment resistance of large tumor volume which always had anoxia and cellular atypia [18, 21].
Although there was no consensus on prognostic value of nonkeratinizing differention subtype, several studies still found the potentially negative impact of this histological type on NPC survival. Cheng et al. reported that locoregional control of nonkeratinizing differentiation subtype was lower than differentiation subtype [22]. Other studies also found this histological type contributed worse DMFS and OS for NPC patient [6, 23]. In this study, subgroup analysis found IC followed by CCRT significantly improved DMFS and DFS of NPC patient with nonkeratinizing differentiation subtype, and the improvement could also be observed for OS with critical point. These results implied it might be necessary to add induction chemotherapy for LA-NPC from Northwest China even in patient with low N stage risk.
Plasma EBV DNA copies has been extensively applied in disease detection, prognosis evaluation and stratifying patients for treatment selection for NPC from endemic area [24–26]. However, it was difficult to guide clinical practice for NPC from Northwest China due to low expression in most patients. In our institute, although plasma detection of EBV DNA is indispensable for each patient during the whole treatment process and follow-up time, only in a few patients had positive expression. There might be two reasons to explain this situation. The first was different segments of the same viral DNA or different viral genes might result in vary sensitivities in quantitative PCR assay [27]. The second reason was most NPC form Northwest China might belong to “EBV negative” type [28–30]. On multivariate analysis, high plasma EBV DNA copies (> 1000 copies/ml) was an independently prognostic factor for DMFS in this study, indicating prognostic value of EBV DNA copies still remained in NPC from Northwest China. In future, multicenter studies with large sample and same detection condition might be more helpful to explore the prognostic value in NPC from Northwest China.
This study implied IC followed by CCRT had potential benefit to improve OS in patients with T3-4N0-1M0 NPC from Northwest China when compared with CCRT. However, as this was a retrospective study, prospective studies with large sample are warranted to confirm the value of IC in these patients.
NPC: Nasopharyngeal carcinoma; IC: Induction chemotherapy; CCRT: Concomitant chemoradiotherapy; NCCN: National comprehensive cancer network; CSCO: Chinese society of clinical oncology; IMRT: Intensity-modulated radiotherapy; MRI: Magnetic resonance imaging; GTV: Gross tumor volume; PTV: Planning target volume; OAR: Organ at risk; QUANTEC: Normal Tissue Effects in the Clinic; CTCAE: Common Terminology Criteria for Adverse Events; OS: Overall survival; DFS: disease-free survival; DMFS: Distant metastasis-free survival; LRFS: locoregionally recurrence-free survival; HR: hazard ratio; PSM: propensity score-matching.
Acknowledgements
Not applicable.
Author Contributions
Conceptualization: JZ, LNZ and MS; Methodology: JZ, YL, QFL and YZ; Software: ZJ; Validation: YL, QFL and YZ; Formal analysis: JZ, YL, QFL and YZ; Investigation: ZJ, YL, SQL, XHL and JHW; Resources: MS; Data curation: YL, QFL, YZ., BXH and NS; Writing—original draft preparation: ZJ; Writing—review and editing: all authors; Visualization: JZ; Supervision: YL, QFL and YZ; Project administration: LNZ and MS. All authors have read and agreed to the published version of the manuscript.
Funding
No funding was received for this study.
Ethics approval and consent to participate
The trial was carried out in accordance with the principles of the Declaration of Helsinki.
Consent for publication
All authors have agreed to publish this manuscript.
Availability of data and materials
All original data will be made available upon request.
Competing interests
The authors declare that they have no competing interests.