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Smoking is a poor prognostic factor for male nasopharyngeal carcinoma treated with radiotherapy
Radiotherapy and Oncology 110 (2014) 409–415
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Radiotherapy of NPC
Smoking is a poor prognostic factor for male nasopharyngeal carcinoma treated with radiotherapy Chen Chen a,c,1, Lu-Jun Shen a,c,1, Bo-Fei Li a,c, Jin Gao a,b, Yun-Fei Xia a,b,⇑ a Department of Radiation Oncology; b State Key Laboratory of Oncology in Southern China, Cancer Center, ; and c Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 14 October 2012 Received in revised form 14 May 2013 Accepted 7 August 2013 Available online 7 September 2013 Keywords: Matched-pair analysis Nasopharyngeal carcinoma Prognostic factor Radiotherapy Smoking Smoking index
a b s t r a c t Background and Purpose: To evaluate the effect of smoking on prognosis of male nasopharyngeal carcinoma by comparing the treatment outcomes between smokers and non-smokers. Materials and Methods: A total of 2450 nasopharyngeal carcinoma patients were enrolled, including 1865 male patients. Matching was performed between smokers and non-smokers in male patients according to age, UICC clinical stage, T stage, N stage and treatment. Survival outcomes were compared using Kaplan– Meier analysis and Cox regression. Smoking index was calculated by multiplying cigarette packs per day and smoked time (year). Results: In male patients, smokers had significantly lower 5-year overall survival (70.1% vs. 77.5%, P < 0.001) and locoregional recurrent free survival (76.8% vs.82.4%, P = 0.002) compared with non-smokers. Matched-pair analysis showed that smokers kept a high risk of death compared with non-smokers (HR = 2.316, P < 0.001). High degree of smoking index (>15 pack-years) had a poor effect on overall survival (HR = 1.225, P = 0.016). When smoking index was more than 45 and 60 pack-years, the risk for death increased to 1.498 and 1.899 fold compared with non-smokers (P = 0.040, 0.001), respectively. Conclusions: Smoking was a poor prognostic factor for male nasopharyngeal carcinoma. The heavier the patients smoked, the poorer prognosis they suffered. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 110 (2014) 409–415
Nasopharyngeal carcinoma (NPC) presents a high incidence in Southern China and Southeast Asia [1–4]. Smoking, as a non-viral personal factor, was significantly associated with a 2 to 3 fold higher incidence of NPC than non-smoking in a dose-dependent manner [5–9]. In the past decade, great effort had been made in exploring the relationship between tobacco and prognosis of head and neck cancer (HNC) [10–12]. A prospective study, involving 115 advanced HNC patients receiving radiotherapy, reported that smoking during radiation would lead to a lower complete response and overall survival rate [13]. Matched-pair studies concerning head and neck cancer also found that smoking, both before diagnosis and during the treatment could lead to a poor outcome [14,15]. However, rare study specifically focused on the impact of smoking on prognosis in NPC patients. Therefore, in this study, a large database of NPC patients in our center was involved to investigate whether smoking had any effect on prognosis. Moreover, matchedpair analysis between non-smokers and smokers was used to assess the real impact and quantity analysis of ascending smoking in-
⇑ Corresponding author. Address: 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China. E-mail address: [email protected] (Y.-F. Xia). 1 These authors contributed equally to this work. 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.08.003
dex (SI) was performed to dig out the trend and threshold between smoking and prognosis of NPC. Materials and methods Patient populations This work had been approved by the ethics committees of Sun Yat-Sen University Cancer Center (SYSUCC). The medical records of 2820 patients newly diagnosed with NPC without distant metastasis in SYSUCC from November of 2000 to December of 2004 were reviewed. All patients received radical radiotherapy and completed the prescribed course of treatment. The exclusion criteria included: (1) lost follow-up within 5 years from diagnosis, (2) lack of the record of smoking habits. A total of 2450 patients were enrolled. The information on smoking habits of patients, containing smoking status, packs of cigarettes/day, years that the patient had smoked and years since smoking cessation, was collected by physicians at entry and by nurses during hospitalization at SYSUCC. Only the records from physicians and nurses were consistent, they were considered credible. Smokers were identified as those who said ‘‘yes’’ when asked ‘‘smoking/smoked or not’’. Patients who said ‘‘no’’ were considered as non-smokers. Patient information on smoking cessation defined the smoker as either [14,16,17]: (1) Current smokers, who did not quit before
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presentation, (2) Long-term quitters, who quit longer than 1 year, (3) Recent quitters, who quit no longer than 1 year. Karnofsky Performance Status Scale (KPS) was used to evaluate general performance of patients [18].
Study design The flowchart of our study design is shown in Fig. 1. We first analyzed the impact of smoking on outcome in the all 2450 patients. Given female smokers were few (5 females), we took only male patients (1865) into analysis to eliminate the confounding of gender. In order to balance other prognostic factors and validate the real association between smoking and outcomes in male NPC, we performed 1 to 1 match between smokers and non-smokers based on randomization pairing principle for matched-pair analysis. Matching was preformed according to age (±5 years), UICC clinical stage, T stage, N stage and treatment (radiotherapy or chemoradiotherapy). Finally, we got 363 pair matched patients. Smoking quantity was evaluated by smoking index (SI), which was calculated by multiplying cigarette packs/day and years that the patient had smoked. A pack contained 20 cigarettes, and 1 pack-year was defined as the equivalent of smoking one pack of cigarettes per day for 1 year [16,19].The receiver operating characteristic (ROC) curve based on data of male patients indicated a best cut-off value of 15.5 pack-year (the sensitivity was 46.8% and the specificity was 65.4%) to divide NPC patients into low degree of SI (615 pack-years) and high degree of SI (>15 pack-years) groups, with an area of 0.577 (95% CI 0.549–0.605; P < 0.001). Furthermore, an interval of 15 pack-years divided the patients as a series of ascending SI groups: (1) SI = 0 pack-year; n = 697; (2) 0 < SI 6 15 pack-years; n = 447; (3) 15 < SI 6 30 pack-years; n = 464; (4) 30 < SI 6 45 pack-years; n = 144; (5) 45 < SI 6 60 pack-years; n = 61; (6) SI > 60 pack-years; n = 52. The ROC curve was also used to determine the best threshold difference value of age, with a
cut-off value of 49.5 year-old (the sensitivity was 54.5% and the specificity was 65.6%). Treatment Radiotherapy alone was given for the early stage cases, and radiotherapy combined with chemotherapy was given for the advanced stage cases. All patients were treated with radiotherapy with high energy 6-8 MV X-ray by linear accelerator. Isocenter radiation by face-neck joint field with low melting point lead block was used, and the radiation field included the skull base, nasopharynx and neck. Face-neck joint field and lower cervical anterior tangent field were irradiated, firstly, with anterior nasal field added when the nasal cavity had been invaded, to a dose of 36 Gy, and then followed by bilateral preauricular fields plus anterior tangent field to a total dose of 60 to 78 Gy. Chemotherapy included induction chemotherapy, concomitant chemotherapy, and adjuvant chemotherapy. Chemotherapy regimen was mainly cisplatin (DDP) plus 5-fluorourac(5-FU) for 1 to 3 cycles. Follow-up Patients were evaluated by phone and out-patient clinic followup. The follow-up mainly included recurrence, distant metastasis and survival status. All recurrence and distant metastasis were confirmed by pathological examination and/or imaging. The last date of follow-up was February 2011. The follow-up time was at least 5 years. Endpoints and statistical analysis The primary endpoint was death and the secondary endpoints were recurrence and metastasis. Overall survival (OS) time was defined as time from diagnosis to death from any cause. Locoregional recurrent free survival (LRFS) time was defined as time to the first
Fig. 1. Flowchart of study design. NPC = nasopharyngeal carcinoma, pts = patients, UICC = International Union Against Cancer, SI = smoking index.
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occurrence of tumor growth at the primary site or regional lymph nodes and death from the primary cancer without a documented site of recurrence or metastasis. Distant metastasis free survival (DMFS) time was defined as time to the first occurrence of distant failure during follow-up. Outcomes analyses were compared by the Kaplan–Meier method. Pair-wise comparisons were performed with two-sided log-rank test. Factors associated with outcomes or matched factors were evaluated by the Pearson v2 test and Fisher’s exact test to detect significant differences between smokers and nonsmokers in the whole population and male patient population. Multivariable analysis and matched-pair analysis were performed by Cox regression in backward conditioned method with corresponding hazard ratio (HR), 95% confidence interval (95% CI) and P value estimated. The covariates entering into the multivariable analysis included gender, age, UICC T stage, N stage, and treatment. All tests were two tailed, with a probability (P) value of less than 0.05 considered statistically significant. Statistical analyses were performed by Statistical Product and Service Solutions (SPSS) software, version 17.0.
Results Demographics The baseline characteristics of the whole patients, male patients and matched-pair male patients are listed in Table 1. Gender and age proportion were significantly different in total patients and male patients with P < 0.001. No statistically different distribution existed in matched-pair patients. Due to most pathological types of the whole patients were undifferentiated non-keratinizing carcinoma (86.7%), we did not list pathological types in the baseline table. The KPS was mostly 90 scores (90.4%), and others were 80 (9.2%) or 100 (0.4%). The distribution of KPS was balanced between smokers and non-smokers. Details of smoking status in male patients are shown in Table 2. Survival analysis of smoking or not In the whole patients In 2450 patients, 421 smokers and 339 non-smokers died. OS rates of 1, 3, and 5 years for smokers and non-smokers were
Table 1 Characteristics of patients. Characteristics
Total patients (N = 2450)
Male patients (N = 1865)
Matched-pair male patients (N = 726)
Non-smokers n (%)
Smokers n (%)
P
Non-smokers n (%)
Smokers n (%)
Gender Male Female
697 (54.6) 580 (45.4)
1168 (99.6) 5 (0.4)
<0.001
697 (100) 0 (0)
1168 (100) 0 (0)
Age (year) <50 P50
891 (69.8) 386 (30.2)
611 (52.1) 562 (47.9)
<0.001
490 (70.3) 207 (29.7)
609 (52.1) 559 (47.9)
UICC clinical stage I 68 (5.3) IIa 17 (1.3) IIb 459 (35.9) III 515 (40.3) IVa 176 (13.8) IVb 42 (3.3)
59 (5.0) 8 (0.7) 380 (32.4) 471 (40.2) 207 (17.6) 48 (4.1)
0.038
37 (5.3) 7 (1.0) 249 (35.7) 277 (39.7) 100 (14.3) 27 (3.9)
UICC T stage T1 T2a T2b T3 T4
216 (16.9) 48 (3.8) 488 (38.2) 342 (26.8) 183 (14.3)
180 (15.3) 29 (2.5) 467 (39.8) 284 (24.2) 213 (18.2)
0.020
UICC N stage N0 N1 N2 N3a N3b
357 (28.0) 513 (40.2) 365 (28.6) 4 (0.3) 38 (3.0)
284 (24.2) 468 (39.9) 373 (31.8) 4 (0.3) 44 (3.8)
Treatment RT CRT
594 (46.5) 683 (53.5)
501 (42.7) 672 (57.3)
P
Non-smokers n (%)
Smokers n (%)
P
363 (100.0) 0 (0.0)
363 (100.0) 0 (0.0)
—
<0.001
253 (69.7) 110 (30.3)
250 (68.9) 113 (31.1)
—
59 (5.1) 8 (0.7) 379 (32.4) 468 (40.1) 206 (17.6) 48 (4.1)
0.422
24 (6.6) 0 (0.0) 144 (39.7) 159 (43.8) 31 (8.5) 5 (1.4)
24 (6.6) 0 (0.0) 144 (39.7) 159 (43.8) 31 (8.5) 5 (1.4)
—
132 (18.9) 26 (3.7) 259 (37.2) 175 (25.1) 105 (15.1)
180 (15.4) 29 (2.5) 466 (39.9) 281 (24.1) 212 (18.2)
0.060
75 (20.7) 3 (0.8) 157 (43.3) 97 (26.7) 31 (8.5)
75 (20.7) 3 (0.8) 157 (43.3) 97 (26.7) 31 (8.5)
—
0.165
204 (29.3) 271 (38.9) 195 (28.0) 3 (0.4) 24 (3.4)
282 (24.1) 466 (39.9) 372 (31.8) 4 (0.3) 44 (3.8)
0.142
97 (26.7) 157 (43.3) 104 (28.7) 0 (0.0) 5 (1.4)
97 (26.7) 157 (43.3) 104 (28.7) 0 (0.0) 5 (1.4)
—
0.058
329 (47.2) 368 (52.8)
498 (42.6) 670 (57.4)
0.055
179 (49.3) 184 (50.7)
179 (49.3) 184 (50.7)
—
—
UICC = International Union Against Cancer; RT = radiotherapy; CRT = chemo radiotherapy. The cut-off value of age was 49.5 year-old (11–78 year-old, mean 46.3 year-old, median 46 year-old, standard deviation 11.7 year-old). P < 0.05 was considered statistically significant.
Table 2 Detailed information of smoking status in male patients. Smoking status
N
SI/pack-year Range (median)
High degree/n
Quit time/year Range (median)
Non-smokers Smokers Current smokers Recent quitters Long-term quitters
697 1168 876 124 168
0 0.08–125 (20) 0.08–125 (20) 0.25–100 (20) 0.5–120 (10)
0 721 582 71 70
0 0 0 0.01–1 (0.42) 1.1–30 (6)
SI = Smoking Index; High degree: smoking index > 15.5 pack-years.
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96.1% and 97.3% (P = 0.080); 80.5% and 86.8% (P < 0.001); 70.2% and 79.0% (P < 0.001) respectively. LRFS rates of 1, 3, and 5 years for smokers and non-smokers were 96.8% and 97.4% (P = 0.333); 84.7% and 89.7% (P < 0.001); 76.8% and 83.9% (P < 0.001) respectively. No statistical difference existed in 5-year DMFS (93.4% vs. 94.7%, P = 0.161). Univariable analyses showed that male, age P 50 years, UICC T3/T4, N2/N3, and chemoradiotherapy were associated with a lower OS rate (all, P < 0.001). In a multivariate analysis involving smoking and above factors, smoking was unexpectedly excluded
from the Cox model (HR 1.152, P = 0.104), partly due to the imbalance of sex proportion between two groups (seen in Table 1). In male patients In 1865 male patients, 420 smokers and 198 non-smokers died. OS rates of 1, 3, and 5 year for smokers and non-smokers were 96.1% and 97.3% (P = 0.167); 80.5% and 85.9% (P = 0.002); 70.1% and 77.5% (P < 0.001), respectively. 5-year OS rate and LRFS rate of smokers were significantly lower than those of non-smokers (Fig. 2a and b), while no statistical difference existed in 5-year
Fig. 2. Survival analyses of smoking or not: overall survival (OS) curve and locoregional free survival (LRFS) curve of male patients and matched-pair male patient populations are shown respectively. Corresponding rates, P values and the number of patients at risk at time points have been presented. N = non-smokers, S = smokers. P < 0.05 was considered statistically significant.
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Table 3 Univariable and multivariable analyses of overall survival in man patients. Characteristics
Multivariable⁄
Univariable
Smoking Quantity
Smoking Rate (%)
P
Age (year) <50 P50
74.4 56.0
<0.001
UICC T stage T1–T2 T3–T4
71.3 60.5
UICC N stage N0–N1 N2–N3 Treatment RT CRT
95% CI
P
1 2.028
Reference 1.729–2.378
<0.001
<0.001
1 1.366
Reference 1.160–1.610
70.2 60.4
<0.001
1 1.430
72.2 62.6
<0.001
Smoking/smoking quantity Noa/low degreeb 71.6a/71.2b Yesa/high degreeb 64.0a/59.9b
<0.001/<0.001b
HR
HR
95% CI
P
1 1.913
Reference 1.619–2.259
<0.001
<0.001
1 1.357
Reference 1.152–1.600
<0.001
Reference 1.208–1.694
<0.001
1 1.425
Reference 1.203–1.688
<0.001
1 1.287
Reference 1.077–1.538
0.006
1 1.286
Reference 1.076–1.537
0.006
1a 1.146a
Referencea 0.964–1.362a
0.121a
1b 1.225b
Referenceb 1.038–1.445b
0.016b
RT = radiotherapy; CRT = chemoradiotherapy; HR = hazard ratio; 95% CI = 95% confidence interval; NS = not significant. ⁄Multivariate analysis alternatively involved smoking or smoking quantity as candidate factors. Smoking quantity was assessed by smoking index with a cut-off value of 15.5 pack-years. P < 0.05 was considered statistically significant. Upper label ‘‘a’’ represents smoking, and upper label ‘‘b’’ represents smoking quantity.
DMFS (93.3% vs. 94.5%, P = 0.280). Univariable and multivariable analyses of OS are listed in Table 3. In a multivariable analysis, smoking did not show a significant difference, which may be caused by the imbalance of covariates between the two groups with more strength than smoking in predicting prognosis (such as age). In matched-pair male patients In 726 paired patients, 155 smokers and 84 non-smokers died. OS rates of 1, 3, and 5 year for smokers and non-smokers were 94.8% vs. 97.8% (P = 0.032); 77.7% vs. 89.5% (P < 0.001); 64.7% vs. 81.5% (P < 0.001), respectively. Smokers have significantly lower 5-year OS (Fig. 2c), LRFS (Fig. 2d), and DMFS (93.9% vs. 97.5%, P = 0.017) rates than non-smokers. We defined pairs in which each patient experienced the same event as concordant, and pairs in which one patient experienced an event and the other did not as discordant. For the endpoint of OS, there were 50 concordant pairs in which both smokers and non-smokers died, 105 discordant pairs in which smoker died and non-smoker did not, and 34 discordant pairs in which nonsmoker died and smokers did not. Stratified Cox regression showed smoking had a significant risk of OS (HR = 2.316; 95% CI, 1.697 to 3.159; P < 0.001). In male patients regarding quitters Survival rates and comparisons of 5-year OS, LRFS, and DMFS for non-smokers, current smokers, recent quitters and long-term quitters are presented in Supplementary material, Table 1. Quitters (long/recent) and current smokers had unfavorable 5-year OS and LRFS compared with non-smokers, while no differences existed among long-term quitters, recent quitters and current smokers. Survival analysis of smoking quantity in male NPC patients Low degree of SI group vs. high degree of SI group There were 1144 patients in low degree of SI group and 721 patients in high degree of SI group among male patients. In a univariate analysis, low degree of SI group presented to have higher 5-year OS (Fig. 3a) and LRFS (75.3% vs. 81.1%, P = 0.002) rates compared with high degree of SI group, while no
statistical difference in 5-year DMFS was observed (92.6% vs. 94.5%, P = 0.107). In a multivariable analysis, smoking quantity remained in the Cox regression model as an independent risk factor (HR = 1.225, P = 0.016) together with age, UICC T, N stage and treatment (Table 3). Ascending SI groups OS data of six SI groups are labeled in Fig. 3b. In a univariate analysis, a significantly lower OS rate and LRFS rate were observed from the third group (64.4%, P = 0.007; 72.8%, P = 0.024) to the sixth group (40.4%, P < 0.001; 59.6%, P < 0.001) compared with the first group (71.6%; 78.6%), while no significant difference was found for DMFS (P = 0.333, data not shown). In a multivariate OS analysis adjusted for age, UICC T and N stage, and treatment, no statistically significant difference appeared except in the fifth group (HR = 1.498, P = 0.040) and the sixth group (HR = 1.899, P = 0.001) compared with the first group (Fig. 3b). An increasing trend of death risk was observed along with the ascending smoking index. Accumulated smokers vs. recent smokers Survival analyses of 5-year OS, LRFS and DMFS were carried out in patients who smoked 10 (n = 159), 20 (n = 217), 30 (n = 182), and 40 (n = 99) pack-years, respectively (Supplementary material, Fig. 1). No significant differences were obtained between accumulated smokers and recent smokers with the same amount of packyears. Discussion Our study showed that smoking poorly impacts the prognosis of male NPC patients treated by radiotherapy (HR = 2.316, P < 0.001; matched-pair analysis). Quitting could not change the survival outcomes if the patient had smoked ever. Quantity analysis showed that, for male patients, high degree of SI group had a 1.225 fold hazard ratio of death risk compared with low degree of SI group (P = 0.016). Further analysis indicated that the impact of smoking quantity on prognosis was mainly caused by heavy smoking (SI > 45 pack-years). And with the ascending of the smoking index, the risk of death increased in male NPC. There was no advantage
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Fig. 3. Survival analyses of smoking quantity in male patients: (a) was overall survival (OS) curve of male patients. Corresponding rates, P value and the number of patients at risk at time points have been presented. The male patients were divided into two groups by smoking index cut-off value 15.5 pack-year obtained from ROC curve: low degree of SI group (615 pack-years) and high degree of SI group (>15 pack-years). L = low degree of smoking index group, H = high degree of smoking index group; (b) was a boxplot figure about hazard ratio (HR) of six ascending SI groups. The HR values and 95% confident interval were labeled on the right side of boxplot. The sample size (n), the number of patients dead (D) in six SI groups and the P values of the last five groups compared with the first groups are displayed below the X-axis (smoking index). P < 0.05 was considered statistically significant.
for patients who had accumulated several pack-years compared to recent smokers with the same amount of pack-years. Previous reports had indicated smoking was a poor prognostic factor for head and neck cancer [11,12]. K. Kian Ang et al. [17,19] had reported that tobacco smoking was a risk factor for prognosis of oropharyngeal cancer and the risk of death increased by 1% per pack-year, then further established risk-of-death categories model based on HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. However, such systematic study of NPC was rare. Only two studies specifically focused on the impact of smoking on NPC. Fu Min et al., in his study of 347 NPC patients receiving conformal radiotherapy, found that a smoking habit was associated with a higher locoregional failure [20]. A large-sample prospective study conducted by Weihua Jia further showed that current
smokers had significantly 1.88-fold mortality risk in comparison with never smokers, and the patients smoked more than 25 pack-years had nearly two fold risk of death compared with who did not. Nevertheless, gender was excluded in multivariate analysis due to its colinearity with smoking in their study, which might confound the real impact of smoking [21]. In our study, we specifically analyze prognostic impact of smoking in male NPC patients and found that high degree of SI group, rather than smoking status, was an independent prognostic risk factor for male NPC (HR = 1.225, P = 0.016). Moreover, the heavier the patients smoked, the poorer the prognosis they suffered. However, whether smoking cessation had a favor for survival was far from conclusive. Kristen B. Pytynia et al. [14] showed 2year OS rates were similar between former and current smokers. But, Allen M. Chen et al. [10] showed that active smokers who continued to smoke during radiotherapy had significantly lower 5-year OS and LRFS compared with former smokers. In addition, Sonia A. Duffy et al. [12] showed current and former smokers both had significant associations with poor survival compared with never smokers. While, an analysis by K. Kian Ang et al. [17] presented that former smokers had no significant difference with never smokers for OS. In our study, the results presented that both current smokers and quitters had poorer survival than never smokers, and no significant differences existed between quitters and current smokers. Although matched-pair analysis had been commonly applied in investigating the effect of smoking in HNC before due to its advantages in minimizing the confounding effect of covariates [10,14,15], no previous matched-pair analyses in NPC were reported. After matching for age, gender, treatment modality, T stage, and N stage, our result revealed that smoking poorly impacts the prognosis of male NPC patients treated by radiotherapy (HR = 2.316), which was consistent with the study involving 50 matched-pair HNC patients, in which Ptynia et al. showed that smoking was significantly associated with three fold risk of cancer-specific mortality and tumor recurrence. Several hypotheses have been proposed attempting to explain why smokers have unfavorable prognosis. One of the possible mechanisms involves hypoxia [13,22–24]. Cigarette smoking is associated with increased blood carboxyhemoglobin concentrations, which will cause a leftward shift of the hemoglobin-oxygen dissociation curve [25]. A study in 2008 by Fortin A et al. [24] reported that combined exposure of smoking during the radiation and antioxidant vitamin would increase the rate of long-term mortality and recurrence among HNC. A recent prospective study by Overgaard J et al. also supported the hypothesis of hypoxia [16]. Their study indicated that the negative impact of smoking in loco-regional control of radiotherapy could be explained by a rise of carboxyhemoglobin in smokers. A rise of carboxyhemoglobin reduced oxygen supply to tumor and influenced the efficacy of radiation therapy. They also confirmed a lower survival rate of patients with hypoxia tumor than that of patients with non-hypoxia tumor using hypoxia image in HNC [26] and pointed out the potential use of imaging to help improve clinical outcome to radiotherapy [27]. Another potential immunological mechanism may be associated with nature killer (NK) cell. Cigarette smoking suppresses NK cell activation and attenuate NK cytotoxic lymphocyte (CTL) activity, which can further influence tumor microenvironment, accelerate tumor progression and metastasis and increase tumor burden. Effects above were mainly based on the impairment of NK celldependent tumor immune surveillance, including the decreased release of anti-tumor factor and the weakened ability of binding and attacking pathogenic cells in mitosis [28–31]. Our study had several advantages. Firstly, we reviewed a large population of NPC patients (n = 2450), including 1865 male NPC patients, of a single center which can decrease the treatment skill
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bias from multicenter. Secondly, we performed a 1 to 1 match-pair analysis (n = 363 pairs) between non-smokers and smokers in male NPC to assess the real impact of smoking on survival. Lastly, we further carried out a quantity analysis of ascending smoking index (SI) to reveal the trend and threshold between smoking and prognosis of male NPC. Based on above reasons, our results were more powerful. The limitations of our study are related to its retrospective nature. We only chose six factors for matching. Factors such as alcohol consumption and weight were not matched and might influence treatment outcomes. Regardless, our study provide both clinicians and patients with tangible evidence supporting the role of smoking in poor prognosis, particularly with respect to heavy smoking (SI > 45 pack-years), and also provide guidance for individual treatment of nasopharyngeal carcinoma. Further studies are needed to clarify the molecular differences between smokers and non-smokers with NPC and the effect of smoking on metastasis site and competing mortality. Conflicts of interest and informed consent The authors have declared no conflicts of interest. Informed consent was obtained. Acknowledgement This work was supported by the Hi-Tech Research and Development Program of China (Grant number 2006AA02Z4B4). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2013. 08.003. References [1] Chan AT, Teo PM, Johnson PJ. Nasopharyngeal carcinoma. Ann Oncol 2002;13:1007–15. [2] Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 2002;12:421–9. [3] Brennan B. Nasopharyngeal carcinoma. Orphanet J Rare Dis 2006;1:23. [4] Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:1765–77. [5] Abdulamir AS, Hafidh RR, Abdulmuhaimen N, Abubakar F, Abbas KA. The distinctive profile of risk factors of nasopharyngeal carcinoma in comparison with other head and neck cancer types. BMC Public Health 2008;8:400. [6] Jia WH, Qin HD. Non-viral environmental risk factors for nasopharyngeal carcinoma: a systematic review. Semin Cancer Biol 2012;22:117–26. [7] Hsu WL, Chen JY, Chien YC, et al. Independent effect of EBV and cigarette smoking on nasopharyngeal carcinoma: a 20-year follow-up study on 9,622 males without family history in Taiwan. Cancer Epidemiol Biomarkers Prev 2009;18:1218–26. [8] Feng BJ, Khyatti M, Ben-Ayoub W, et al. Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa. Br J Cancer 2009;101:1207–12.
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Radiotherapy of NPC
Smoking is a poor prognostic factor for male nasopharyngeal carcinoma treated with radiotherapy Chen Chen a,c,1, Lu-Jun Shen a,c,1, Bo-Fei Li a,c, Jin Gao a,b, Yun-Fei Xia a,b,⇑ a Department of Radiation Oncology; b State Key Laboratory of Oncology in Southern China, Cancer Center, ; and c Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 14 October 2012 Received in revised form 14 May 2013 Accepted 7 August 2013 Available online 7 September 2013 Keywords: Matched-pair analysis Nasopharyngeal carcinoma Prognostic factor Radiotherapy Smoking Smoking index
a b s t r a c t Background and Purpose: To evaluate the effect of smoking on prognosis of male nasopharyngeal carcinoma by comparing the treatment outcomes between smokers and non-smokers. Materials and Methods: A total of 2450 nasopharyngeal carcinoma patients were enrolled, including 1865 male patients. Matching was performed between smokers and non-smokers in male patients according to age, UICC clinical stage, T stage, N stage and treatment. Survival outcomes were compared using Kaplan– Meier analysis and Cox regression. Smoking index was calculated by multiplying cigarette packs per day and smoked time (year). Results: In male patients, smokers had significantly lower 5-year overall survival (70.1% vs. 77.5%, P < 0.001) and locoregional recurrent free survival (76.8% vs.82.4%, P = 0.002) compared with non-smokers. Matched-pair analysis showed that smokers kept a high risk of death compared with non-smokers (HR = 2.316, P < 0.001). High degree of smoking index (>15 pack-years) had a poor effect on overall survival (HR = 1.225, P = 0.016). When smoking index was more than 45 and 60 pack-years, the risk for death increased to 1.498 and 1.899 fold compared with non-smokers (P = 0.040, 0.001), respectively. Conclusions: Smoking was a poor prognostic factor for male nasopharyngeal carcinoma. The heavier the patients smoked, the poorer prognosis they suffered. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 110 (2014) 409–415
Nasopharyngeal carcinoma (NPC) presents a high incidence in Southern China and Southeast Asia [1–4]. Smoking, as a non-viral personal factor, was significantly associated with a 2 to 3 fold higher incidence of NPC than non-smoking in a dose-dependent manner [5–9]. In the past decade, great effort had been made in exploring the relationship between tobacco and prognosis of head and neck cancer (HNC) [10–12]. A prospective study, involving 115 advanced HNC patients receiving radiotherapy, reported that smoking during radiation would lead to a lower complete response and overall survival rate [13]. Matched-pair studies concerning head and neck cancer also found that smoking, both before diagnosis and during the treatment could lead to a poor outcome [14,15]. However, rare study specifically focused on the impact of smoking on prognosis in NPC patients. Therefore, in this study, a large database of NPC patients in our center was involved to investigate whether smoking had any effect on prognosis. Moreover, matchedpair analysis between non-smokers and smokers was used to assess the real impact and quantity analysis of ascending smoking in-
⇑ Corresponding author. Address: 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China. E-mail address: [email protected] (Y.-F. Xia). 1 These authors contributed equally to this work. 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.08.003
dex (SI) was performed to dig out the trend and threshold between smoking and prognosis of NPC. Materials and methods Patient populations This work had been approved by the ethics committees of Sun Yat-Sen University Cancer Center (SYSUCC). The medical records of 2820 patients newly diagnosed with NPC without distant metastasis in SYSUCC from November of 2000 to December of 2004 were reviewed. All patients received radical radiotherapy and completed the prescribed course of treatment. The exclusion criteria included: (1) lost follow-up within 5 years from diagnosis, (2) lack of the record of smoking habits. A total of 2450 patients were enrolled. The information on smoking habits of patients, containing smoking status, packs of cigarettes/day, years that the patient had smoked and years since smoking cessation, was collected by physicians at entry and by nurses during hospitalization at SYSUCC. Only the records from physicians and nurses were consistent, they were considered credible. Smokers were identified as those who said ‘‘yes’’ when asked ‘‘smoking/smoked or not’’. Patients who said ‘‘no’’ were considered as non-smokers. Patient information on smoking cessation defined the smoker as either [14,16,17]: (1) Current smokers, who did not quit before
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presentation, (2) Long-term quitters, who quit longer than 1 year, (3) Recent quitters, who quit no longer than 1 year. Karnofsky Performance Status Scale (KPS) was used to evaluate general performance of patients [18].
Study design The flowchart of our study design is shown in Fig. 1. We first analyzed the impact of smoking on outcome in the all 2450 patients. Given female smokers were few (5 females), we took only male patients (1865) into analysis to eliminate the confounding of gender. In order to balance other prognostic factors and validate the real association between smoking and outcomes in male NPC, we performed 1 to 1 match between smokers and non-smokers based on randomization pairing principle for matched-pair analysis. Matching was preformed according to age (±5 years), UICC clinical stage, T stage, N stage and treatment (radiotherapy or chemoradiotherapy). Finally, we got 363 pair matched patients. Smoking quantity was evaluated by smoking index (SI), which was calculated by multiplying cigarette packs/day and years that the patient had smoked. A pack contained 20 cigarettes, and 1 pack-year was defined as the equivalent of smoking one pack of cigarettes per day for 1 year [16,19].The receiver operating characteristic (ROC) curve based on data of male patients indicated a best cut-off value of 15.5 pack-year (the sensitivity was 46.8% and the specificity was 65.4%) to divide NPC patients into low degree of SI (615 pack-years) and high degree of SI (>15 pack-years) groups, with an area of 0.577 (95% CI 0.549–0.605; P < 0.001). Furthermore, an interval of 15 pack-years divided the patients as a series of ascending SI groups: (1) SI = 0 pack-year; n = 697; (2) 0 < SI 6 15 pack-years; n = 447; (3) 15 < SI 6 30 pack-years; n = 464; (4) 30 < SI 6 45 pack-years; n = 144; (5) 45 < SI 6 60 pack-years; n = 61; (6) SI > 60 pack-years; n = 52. The ROC curve was also used to determine the best threshold difference value of age, with a
cut-off value of 49.5 year-old (the sensitivity was 54.5% and the specificity was 65.6%). Treatment Radiotherapy alone was given for the early stage cases, and radiotherapy combined with chemotherapy was given for the advanced stage cases. All patients were treated with radiotherapy with high energy 6-8 MV X-ray by linear accelerator. Isocenter radiation by face-neck joint field with low melting point lead block was used, and the radiation field included the skull base, nasopharynx and neck. Face-neck joint field and lower cervical anterior tangent field were irradiated, firstly, with anterior nasal field added when the nasal cavity had been invaded, to a dose of 36 Gy, and then followed by bilateral preauricular fields plus anterior tangent field to a total dose of 60 to 78 Gy. Chemotherapy included induction chemotherapy, concomitant chemotherapy, and adjuvant chemotherapy. Chemotherapy regimen was mainly cisplatin (DDP) plus 5-fluorourac(5-FU) for 1 to 3 cycles. Follow-up Patients were evaluated by phone and out-patient clinic followup. The follow-up mainly included recurrence, distant metastasis and survival status. All recurrence and distant metastasis were confirmed by pathological examination and/or imaging. The last date of follow-up was February 2011. The follow-up time was at least 5 years. Endpoints and statistical analysis The primary endpoint was death and the secondary endpoints were recurrence and metastasis. Overall survival (OS) time was defined as time from diagnosis to death from any cause. Locoregional recurrent free survival (LRFS) time was defined as time to the first
Fig. 1. Flowchart of study design. NPC = nasopharyngeal carcinoma, pts = patients, UICC = International Union Against Cancer, SI = smoking index.
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occurrence of tumor growth at the primary site or regional lymph nodes and death from the primary cancer without a documented site of recurrence or metastasis. Distant metastasis free survival (DMFS) time was defined as time to the first occurrence of distant failure during follow-up. Outcomes analyses were compared by the Kaplan–Meier method. Pair-wise comparisons were performed with two-sided log-rank test. Factors associated with outcomes or matched factors were evaluated by the Pearson v2 test and Fisher’s exact test to detect significant differences between smokers and nonsmokers in the whole population and male patient population. Multivariable analysis and matched-pair analysis were performed by Cox regression in backward conditioned method with corresponding hazard ratio (HR), 95% confidence interval (95% CI) and P value estimated. The covariates entering into the multivariable analysis included gender, age, UICC T stage, N stage, and treatment. All tests were two tailed, with a probability (P) value of less than 0.05 considered statistically significant. Statistical analyses were performed by Statistical Product and Service Solutions (SPSS) software, version 17.0.
Results Demographics The baseline characteristics of the whole patients, male patients and matched-pair male patients are listed in Table 1. Gender and age proportion were significantly different in total patients and male patients with P < 0.001. No statistically different distribution existed in matched-pair patients. Due to most pathological types of the whole patients were undifferentiated non-keratinizing carcinoma (86.7%), we did not list pathological types in the baseline table. The KPS was mostly 90 scores (90.4%), and others were 80 (9.2%) or 100 (0.4%). The distribution of KPS was balanced between smokers and non-smokers. Details of smoking status in male patients are shown in Table 2. Survival analysis of smoking or not In the whole patients In 2450 patients, 421 smokers and 339 non-smokers died. OS rates of 1, 3, and 5 years for smokers and non-smokers were
Table 1 Characteristics of patients. Characteristics
Total patients (N = 2450)
Male patients (N = 1865)
Matched-pair male patients (N = 726)
Non-smokers n (%)
Smokers n (%)
P
Non-smokers n (%)
Smokers n (%)
Gender Male Female
697 (54.6) 580 (45.4)
1168 (99.6) 5 (0.4)
<0.001
697 (100) 0 (0)
1168 (100) 0 (0)
Age (year) <50 P50
891 (69.8) 386 (30.2)
611 (52.1) 562 (47.9)
<0.001
490 (70.3) 207 (29.7)
609 (52.1) 559 (47.9)
UICC clinical stage I 68 (5.3) IIa 17 (1.3) IIb 459 (35.9) III 515 (40.3) IVa 176 (13.8) IVb 42 (3.3)
59 (5.0) 8 (0.7) 380 (32.4) 471 (40.2) 207 (17.6) 48 (4.1)
0.038
37 (5.3) 7 (1.0) 249 (35.7) 277 (39.7) 100 (14.3) 27 (3.9)
UICC T stage T1 T2a T2b T3 T4
216 (16.9) 48 (3.8) 488 (38.2) 342 (26.8) 183 (14.3)
180 (15.3) 29 (2.5) 467 (39.8) 284 (24.2) 213 (18.2)
0.020
UICC N stage N0 N1 N2 N3a N3b
357 (28.0) 513 (40.2) 365 (28.6) 4 (0.3) 38 (3.0)
284 (24.2) 468 (39.9) 373 (31.8) 4 (0.3) 44 (3.8)
Treatment RT CRT
594 (46.5) 683 (53.5)
501 (42.7) 672 (57.3)
P
Non-smokers n (%)
Smokers n (%)
P
363 (100.0) 0 (0.0)
363 (100.0) 0 (0.0)
—
<0.001
253 (69.7) 110 (30.3)
250 (68.9) 113 (31.1)
—
59 (5.1) 8 (0.7) 379 (32.4) 468 (40.1) 206 (17.6) 48 (4.1)
0.422
24 (6.6) 0 (0.0) 144 (39.7) 159 (43.8) 31 (8.5) 5 (1.4)
24 (6.6) 0 (0.0) 144 (39.7) 159 (43.8) 31 (8.5) 5 (1.4)
—
132 (18.9) 26 (3.7) 259 (37.2) 175 (25.1) 105 (15.1)
180 (15.4) 29 (2.5) 466 (39.9) 281 (24.1) 212 (18.2)
0.060
75 (20.7) 3 (0.8) 157 (43.3) 97 (26.7) 31 (8.5)
75 (20.7) 3 (0.8) 157 (43.3) 97 (26.7) 31 (8.5)
—
0.165
204 (29.3) 271 (38.9) 195 (28.0) 3 (0.4) 24 (3.4)
282 (24.1) 466 (39.9) 372 (31.8) 4 (0.3) 44 (3.8)
0.142
97 (26.7) 157 (43.3) 104 (28.7) 0 (0.0) 5 (1.4)
97 (26.7) 157 (43.3) 104 (28.7) 0 (0.0) 5 (1.4)
—
0.058
329 (47.2) 368 (52.8)
498 (42.6) 670 (57.4)
0.055
179 (49.3) 184 (50.7)
179 (49.3) 184 (50.7)
—
—
UICC = International Union Against Cancer; RT = radiotherapy; CRT = chemo radiotherapy. The cut-off value of age was 49.5 year-old (11–78 year-old, mean 46.3 year-old, median 46 year-old, standard deviation 11.7 year-old). P < 0.05 was considered statistically significant.
Table 2 Detailed information of smoking status in male patients. Smoking status
N
SI/pack-year Range (median)
High degree/n
Quit time/year Range (median)
Non-smokers Smokers Current smokers Recent quitters Long-term quitters
697 1168 876 124 168
0 0.08–125 (20) 0.08–125 (20) 0.25–100 (20) 0.5–120 (10)
0 721 582 71 70
0 0 0 0.01–1 (0.42) 1.1–30 (6)
SI = Smoking Index; High degree: smoking index > 15.5 pack-years.
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96.1% and 97.3% (P = 0.080); 80.5% and 86.8% (P < 0.001); 70.2% and 79.0% (P < 0.001) respectively. LRFS rates of 1, 3, and 5 years for smokers and non-smokers were 96.8% and 97.4% (P = 0.333); 84.7% and 89.7% (P < 0.001); 76.8% and 83.9% (P < 0.001) respectively. No statistical difference existed in 5-year DMFS (93.4% vs. 94.7%, P = 0.161). Univariable analyses showed that male, age P 50 years, UICC T3/T4, N2/N3, and chemoradiotherapy were associated with a lower OS rate (all, P < 0.001). In a multivariate analysis involving smoking and above factors, smoking was unexpectedly excluded
from the Cox model (HR 1.152, P = 0.104), partly due to the imbalance of sex proportion between two groups (seen in Table 1). In male patients In 1865 male patients, 420 smokers and 198 non-smokers died. OS rates of 1, 3, and 5 year for smokers and non-smokers were 96.1% and 97.3% (P = 0.167); 80.5% and 85.9% (P = 0.002); 70.1% and 77.5% (P < 0.001), respectively. 5-year OS rate and LRFS rate of smokers were significantly lower than those of non-smokers (Fig. 2a and b), while no statistical difference existed in 5-year
Fig. 2. Survival analyses of smoking or not: overall survival (OS) curve and locoregional free survival (LRFS) curve of male patients and matched-pair male patient populations are shown respectively. Corresponding rates, P values and the number of patients at risk at time points have been presented. N = non-smokers, S = smokers. P < 0.05 was considered statistically significant.
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Table 3 Univariable and multivariable analyses of overall survival in man patients. Characteristics
Multivariable⁄
Univariable
Smoking Quantity
Smoking Rate (%)
P
Age (year) <50 P50
74.4 56.0
<0.001
UICC T stage T1–T2 T3–T4
71.3 60.5
UICC N stage N0–N1 N2–N3 Treatment RT CRT
95% CI
P
1 2.028
Reference 1.729–2.378
<0.001
<0.001
1 1.366
Reference 1.160–1.610
70.2 60.4
<0.001
1 1.430
72.2 62.6
<0.001
Smoking/smoking quantity Noa/low degreeb 71.6a/71.2b Yesa/high degreeb 64.0a/59.9b
<0.001/<0.001b
HR
HR
95% CI
P
1 1.913
Reference 1.619–2.259
<0.001
<0.001
1 1.357
Reference 1.152–1.600
<0.001
Reference 1.208–1.694
<0.001
1 1.425
Reference 1.203–1.688
<0.001
1 1.287
Reference 1.077–1.538
0.006
1 1.286
Reference 1.076–1.537
0.006
1a 1.146a
Referencea 0.964–1.362a
0.121a
1b 1.225b
Referenceb 1.038–1.445b
0.016b
RT = radiotherapy; CRT = chemoradiotherapy; HR = hazard ratio; 95% CI = 95% confidence interval; NS = not significant. ⁄Multivariate analysis alternatively involved smoking or smoking quantity as candidate factors. Smoking quantity was assessed by smoking index with a cut-off value of 15.5 pack-years. P < 0.05 was considered statistically significant. Upper label ‘‘a’’ represents smoking, and upper label ‘‘b’’ represents smoking quantity.
DMFS (93.3% vs. 94.5%, P = 0.280). Univariable and multivariable analyses of OS are listed in Table 3. In a multivariable analysis, smoking did not show a significant difference, which may be caused by the imbalance of covariates between the two groups with more strength than smoking in predicting prognosis (such as age). In matched-pair male patients In 726 paired patients, 155 smokers and 84 non-smokers died. OS rates of 1, 3, and 5 year for smokers and non-smokers were 94.8% vs. 97.8% (P = 0.032); 77.7% vs. 89.5% (P < 0.001); 64.7% vs. 81.5% (P < 0.001), respectively. Smokers have significantly lower 5-year OS (Fig. 2c), LRFS (Fig. 2d), and DMFS (93.9% vs. 97.5%, P = 0.017) rates than non-smokers. We defined pairs in which each patient experienced the same event as concordant, and pairs in which one patient experienced an event and the other did not as discordant. For the endpoint of OS, there were 50 concordant pairs in which both smokers and non-smokers died, 105 discordant pairs in which smoker died and non-smoker did not, and 34 discordant pairs in which nonsmoker died and smokers did not. Stratified Cox regression showed smoking had a significant risk of OS (HR = 2.316; 95% CI, 1.697 to 3.159; P < 0.001). In male patients regarding quitters Survival rates and comparisons of 5-year OS, LRFS, and DMFS for non-smokers, current smokers, recent quitters and long-term quitters are presented in Supplementary material, Table 1. Quitters (long/recent) and current smokers had unfavorable 5-year OS and LRFS compared with non-smokers, while no differences existed among long-term quitters, recent quitters and current smokers. Survival analysis of smoking quantity in male NPC patients Low degree of SI group vs. high degree of SI group There were 1144 patients in low degree of SI group and 721 patients in high degree of SI group among male patients. In a univariate analysis, low degree of SI group presented to have higher 5-year OS (Fig. 3a) and LRFS (75.3% vs. 81.1%, P = 0.002) rates compared with high degree of SI group, while no
statistical difference in 5-year DMFS was observed (92.6% vs. 94.5%, P = 0.107). In a multivariable analysis, smoking quantity remained in the Cox regression model as an independent risk factor (HR = 1.225, P = 0.016) together with age, UICC T, N stage and treatment (Table 3). Ascending SI groups OS data of six SI groups are labeled in Fig. 3b. In a univariate analysis, a significantly lower OS rate and LRFS rate were observed from the third group (64.4%, P = 0.007; 72.8%, P = 0.024) to the sixth group (40.4%, P < 0.001; 59.6%, P < 0.001) compared with the first group (71.6%; 78.6%), while no significant difference was found for DMFS (P = 0.333, data not shown). In a multivariate OS analysis adjusted for age, UICC T and N stage, and treatment, no statistically significant difference appeared except in the fifth group (HR = 1.498, P = 0.040) and the sixth group (HR = 1.899, P = 0.001) compared with the first group (Fig. 3b). An increasing trend of death risk was observed along with the ascending smoking index. Accumulated smokers vs. recent smokers Survival analyses of 5-year OS, LRFS and DMFS were carried out in patients who smoked 10 (n = 159), 20 (n = 217), 30 (n = 182), and 40 (n = 99) pack-years, respectively (Supplementary material, Fig. 1). No significant differences were obtained between accumulated smokers and recent smokers with the same amount of packyears. Discussion Our study showed that smoking poorly impacts the prognosis of male NPC patients treated by radiotherapy (HR = 2.316, P < 0.001; matched-pair analysis). Quitting could not change the survival outcomes if the patient had smoked ever. Quantity analysis showed that, for male patients, high degree of SI group had a 1.225 fold hazard ratio of death risk compared with low degree of SI group (P = 0.016). Further analysis indicated that the impact of smoking quantity on prognosis was mainly caused by heavy smoking (SI > 45 pack-years). And with the ascending of the smoking index, the risk of death increased in male NPC. There was no advantage
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Fig. 3. Survival analyses of smoking quantity in male patients: (a) was overall survival (OS) curve of male patients. Corresponding rates, P value and the number of patients at risk at time points have been presented. The male patients were divided into two groups by smoking index cut-off value 15.5 pack-year obtained from ROC curve: low degree of SI group (615 pack-years) and high degree of SI group (>15 pack-years). L = low degree of smoking index group, H = high degree of smoking index group; (b) was a boxplot figure about hazard ratio (HR) of six ascending SI groups. The HR values and 95% confident interval were labeled on the right side of boxplot. The sample size (n), the number of patients dead (D) in six SI groups and the P values of the last five groups compared with the first groups are displayed below the X-axis (smoking index). P < 0.05 was considered statistically significant.
for patients who had accumulated several pack-years compared to recent smokers with the same amount of pack-years. Previous reports had indicated smoking was a poor prognostic factor for head and neck cancer [11,12]. K. Kian Ang et al. [17,19] had reported that tobacco smoking was a risk factor for prognosis of oropharyngeal cancer and the risk of death increased by 1% per pack-year, then further established risk-of-death categories model based on HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. However, such systematic study of NPC was rare. Only two studies specifically focused on the impact of smoking on NPC. Fu Min et al., in his study of 347 NPC patients receiving conformal radiotherapy, found that a smoking habit was associated with a higher locoregional failure [20]. A large-sample prospective study conducted by Weihua Jia further showed that current
smokers had significantly 1.88-fold mortality risk in comparison with never smokers, and the patients smoked more than 25 pack-years had nearly two fold risk of death compared with who did not. Nevertheless, gender was excluded in multivariate analysis due to its colinearity with smoking in their study, which might confound the real impact of smoking [21]. In our study, we specifically analyze prognostic impact of smoking in male NPC patients and found that high degree of SI group, rather than smoking status, was an independent prognostic risk factor for male NPC (HR = 1.225, P = 0.016). Moreover, the heavier the patients smoked, the poorer the prognosis they suffered. However, whether smoking cessation had a favor for survival was far from conclusive. Kristen B. Pytynia et al. [14] showed 2year OS rates were similar between former and current smokers. But, Allen M. Chen et al. [10] showed that active smokers who continued to smoke during radiotherapy had significantly lower 5-year OS and LRFS compared with former smokers. In addition, Sonia A. Duffy et al. [12] showed current and former smokers both had significant associations with poor survival compared with never smokers. While, an analysis by K. Kian Ang et al. [17] presented that former smokers had no significant difference with never smokers for OS. In our study, the results presented that both current smokers and quitters had poorer survival than never smokers, and no significant differences existed between quitters and current smokers. Although matched-pair analysis had been commonly applied in investigating the effect of smoking in HNC before due to its advantages in minimizing the confounding effect of covariates [10,14,15], no previous matched-pair analyses in NPC were reported. After matching for age, gender, treatment modality, T stage, and N stage, our result revealed that smoking poorly impacts the prognosis of male NPC patients treated by radiotherapy (HR = 2.316), which was consistent with the study involving 50 matched-pair HNC patients, in which Ptynia et al. showed that smoking was significantly associated with three fold risk of cancer-specific mortality and tumor recurrence. Several hypotheses have been proposed attempting to explain why smokers have unfavorable prognosis. One of the possible mechanisms involves hypoxia [13,22–24]. Cigarette smoking is associated with increased blood carboxyhemoglobin concentrations, which will cause a leftward shift of the hemoglobin-oxygen dissociation curve [25]. A study in 2008 by Fortin A et al. [24] reported that combined exposure of smoking during the radiation and antioxidant vitamin would increase the rate of long-term mortality and recurrence among HNC. A recent prospective study by Overgaard J et al. also supported the hypothesis of hypoxia [16]. Their study indicated that the negative impact of smoking in loco-regional control of radiotherapy could be explained by a rise of carboxyhemoglobin in smokers. A rise of carboxyhemoglobin reduced oxygen supply to tumor and influenced the efficacy of radiation therapy. They also confirmed a lower survival rate of patients with hypoxia tumor than that of patients with non-hypoxia tumor using hypoxia image in HNC [26] and pointed out the potential use of imaging to help improve clinical outcome to radiotherapy [27]. Another potential immunological mechanism may be associated with nature killer (NK) cell. Cigarette smoking suppresses NK cell activation and attenuate NK cytotoxic lymphocyte (CTL) activity, which can further influence tumor microenvironment, accelerate tumor progression and metastasis and increase tumor burden. Effects above were mainly based on the impairment of NK celldependent tumor immune surveillance, including the decreased release of anti-tumor factor and the weakened ability of binding and attacking pathogenic cells in mitosis [28–31]. Our study had several advantages. Firstly, we reviewed a large population of NPC patients (n = 2450), including 1865 male NPC patients, of a single center which can decrease the treatment skill
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bias from multicenter. Secondly, we performed a 1 to 1 match-pair analysis (n = 363 pairs) between non-smokers and smokers in male NPC to assess the real impact of smoking on survival. Lastly, we further carried out a quantity analysis of ascending smoking index (SI) to reveal the trend and threshold between smoking and prognosis of male NPC. Based on above reasons, our results were more powerful. The limitations of our study are related to its retrospective nature. We only chose six factors for matching. Factors such as alcohol consumption and weight were not matched and might influence treatment outcomes. Regardless, our study provide both clinicians and patients with tangible evidence supporting the role of smoking in poor prognosis, particularly with respect to heavy smoking (SI > 45 pack-years), and also provide guidance for individual treatment of nasopharyngeal carcinoma. Further studies are needed to clarify the molecular differences between smokers and non-smokers with NPC and the effect of smoking on metastasis site and competing mortality. Conflicts of interest and informed consent The authors have declared no conflicts of interest. Informed consent was obtained. Acknowledgement This work was supported by the Hi-Tech Research and Development Program of China (Grant number 2006AA02Z4B4). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2013. 08.003. References [1] Chan AT, Teo PM, Johnson PJ. Nasopharyngeal carcinoma. Ann Oncol 2002;13:1007–15. [2] Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 2002;12:421–9. [3] Brennan B. Nasopharyngeal carcinoma. Orphanet J Rare Dis 2006;1:23. [4] Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:1765–77. [5] Abdulamir AS, Hafidh RR, Abdulmuhaimen N, Abubakar F, Abbas KA. The distinctive profile of risk factors of nasopharyngeal carcinoma in comparison with other head and neck cancer types. BMC Public Health 2008;8:400. [6] Jia WH, Qin HD. Non-viral environmental risk factors for nasopharyngeal carcinoma: a systematic review. Semin Cancer Biol 2012;22:117–26. [7] Hsu WL, Chen JY, Chien YC, et al. Independent effect of EBV and cigarette smoking on nasopharyngeal carcinoma: a 20-year follow-up study on 9,622 males without family history in Taiwan. Cancer Epidemiol Biomarkers Prev 2009;18:1218–26. [8] Feng BJ, Khyatti M, Ben-Ayoub W, et al. Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa. Br J Cancer 2009;101:1207–12.
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