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Surgical outcomes and prognostic factors of oral cancer associated with betel quid chewing and tobacco smoking in Taiwan
Oral Oncology 46 (2010) 276–282
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Surgical outcomes and prognostic factors of oral cancer associated with betel quid chewing and tobacco smoking in Taiwan Shyun-Yeu Liu a,b, Chin-Li Lu b, Chang-Ta Chiou c, Ching-Yu Yen a, Gwo-An Liaw d, Yi-Chun Chen e, Yu-Chi Liu f, Wei-Fan Chiang b,d,g,* a
Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Yongkang, Taiwan Department of Medical Research, Chi-Mei Medical Center, Taiwan Department of Oral and Maxillofacial Surgery, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan d Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Liouying, Taiwan e Department of Oral and Maxillofacial Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan f Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan g School of Dentistry, National Yang-Ming University, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 8 December 2009 Received in revised form 13 January 2010 Accepted 14 January 2010 Available online 6 February 2010 Keywords: Oral cancer Betel quid Occult metastasis Second primary cancer Level of nodal metastasis Tumor thickness Alcohol drinking Treatment failure Locoregional recurrence Close surveillance
s u m m a r y Oral squamous cell carcinoma (OSCC) is one of the most common cancers in geographic regions where betel quid (BQ) chewing is prevalent; OSCC is an extremely malignant neoplasm whose prognostic factors are multiple and complex. The purpose of this study was to assess clinicopathological prognostic factors and treatment outcomes in 698 consecutive OSCC patients who had undergone surgery as the primary treatment in an area with a high prevalence of both betel quid chewing and tobacco smoking. The prognostic factors were predicted using Cox’s proportional-hazards regression model, and the survival rate was calculated using Kaplan–Meier analysis. The median followup for all patients was 44 months. The 5-year cumulative overall, disease-specific, and locoregional control survival rates were 61%, 62%, and 46%, respectively. Multivariate analysis showed that the lower level of nodal metastasis, advanced stage, tumor thickness >7 mm, and treatment failures were independent risk factors of overall survival. Furthermore, history of alcohol drinking, lower level of nodal metastasis, advanced stage, poor cell differentiation, and treatment failures were independent predictors of poor disease-specific survival. However, we did not find any significant factor that affected locoregional recurrence. Due to the high frequencies of locoregional recurrence and second primary cancer, our findings emphasize that aggressive surgical excision, adjuvant treatments according to clinicopathological prognostic factors and close surveillance are important to the survival of OSCC patients in an area with a high prevalence of betel quid chewing and tobacco smoking. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Oral and pharyngeal cancers are common and identified as significant public health threats worldwide; their incidence and mortality vary by region. Oral squamous cell carcinoma (OSCC) is the most common subtype. The management of OSCC varies considerably, but the standard procedure remains local excision, with or without neck dissection, and then adjuvant radiotherapy depending on the risk factors. Supplemental adjuvant chemotherapy is occasionally used to improve locoregional and distant control. Despite recent therapeutic developments, the 5-year survival rate for
* Corresponding author. Address: Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Liouying. 201, Taikang Village, Liouying, Tainan 735, Taiwan. Tel.: +886 6 6226999x73158. E-mail address: [email protected] (W.-F. Chiang). 1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2010.01.008
persons with OSCC is unfavorable. In recent decades, genomic and proteomic markers have been developed to predict which cases of OSCC will have unfavorable outcomes. These markers are also used as targets for treatment. The clinicopathological prognostic factors of OSCC are still important for clinicians for delineating the aggressiveness of specific instances of the disease and for determining appropriate postoperative therapies. Betel quid (BQ) was declared a group 1 carcinogen by the International Agency for Research on Cancer.1 Taiwan has a high prevalence of BQ chewing and a high incidence of OSCC.2 In Taiwan, OSCC patients usually have habits of BQ chewing, tobacco smoking, and alcohol drinking, all of which have a synergistic effect on oral carcinogenesis.3,4 Few studies have been done on the surgical outcomes and prognostic factors in southern Taiwan. Chi-Mei Medical Center is one of the tertiary referral centers for OSCC in this region. Therefore, we were interested in the clinicopathological factors
S.-Y. Liu et al. / Oral Oncology 46 (2010) 276–282
that affect the OSCC survival rate in this high-prevalence BQ chewing area. Materials and methods Patients and treatment After the protocol had been approved by the institutional review broad, we retrospectively studied the medical records of 698 consecutive patients who had been diagnosed with OSCC and had undergone surgery as a primary treatment from January 1995 through December 2005. Patients who initially showed distant metastasis were excluded. All the tumors were excised with at least 1-cm safe margins. Except for patients who showed poor compliance or compromised systemic conditions, all patients underwent concurrent neck dissection to examine regional lymph node metastasis (RLNM). Patients were referred for radiotherapy and ranged from 60 to 65 Grey with or without chemotherapy within 6 weeks post-surgery, depending on the risk factors. Using the modified protocol,5 our patients were asked to visit clinic every 2 weeks in the first year following treatments, every month in the second year, and then every 3 months until the fifth year. There were at least 2 years of followup for each patient until the endpoint of this study, December 2008. Descriptive analysis was done on 17 clinicopathological variables (Table 1). The patient delay means the duration between the onset of symptoms and the date of clinic visit for definite diagnosis. Synchronous second primary cancer in the oral cavity (OSPC) was judged using previously published guidelines.6,7 A microscope was used to maximally measure tumor thickness perpendicularly from the surface of the tumor to its deepest extent, excluding the keratin coat. Except for tumor thickness and length of hospital stay, information for all variables was obtained for all patients (Table 1). Statistical analysis Cumulative survival rates, from the day of admission to the day of withdrawal or to the endpoint of this study, were calculated using the Kaplan–Meier analysis. These rates reflect the probability of death attributed to all causes (cumulative overall survival; COS), deaths attributed only to OSCC (cumulative disease-specific survival; CDSS), or tumor recurrence in the oral cavity or neck region or both (cumulative locoregional control; CLRC). The differences between subgroups were examined using the log-rank test. The independent prognostic factors for survival were assessed using Cox’s proportional-hazards regression model. In the present study, patients who did not come for followup for the full 2 years were considered to have died of OSCC, therapeutic complications, or intercurrent disease less than 2 years after the primary surgery. The optimal cutoff thickness for RLNM and survival was selected using both receiver operating characteristic (ROC) analysis and univariate analysis for every millimeter of cutoff thickness. SPSS 17.0 (SPSS Institute, Chicago, IL) was used for the analysis. Statistical significance was set at P < 0.05. Results Clinicopathological characteristics The male/female ratio was 20.8. The median age was 49 years (range, 23–84 years). The largest age group was 40–49 years, followed by 50–59. Most patients had a history of tobacco smoking (87.2%) and BQ chewing (83.9%). The most common length of hos-
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pital stay for surgical treatment was 7–14 days (56.9%). The three most common sites of major tumors were the buccal mucosa (46.5%), oral tongue (24.8%), and lower gum (11.2%). For patients with OSPC, the retromolar trigone and the lower lip were the two most common sites of the main lesion, and the buccal mucosa (40.1%) was the most common affected site of the secondary tumor. After we had examined 548 ipsilateral cervical specimens and 38 bilateral cervical specimens, pathological RLNM (pN+) presented in the specimens of 170 (29.0%) patients. The levels of RLNM were defined by the lowest level of lymph node to which the carcinoma had metastasized. Clinically occult metastasis was proved in 31 (6.1%) cervical specimens from 506 patients without RLNM (N0) clinically; all the nodes were localized at levels I–III. The sensitivity, specificity, and accuracy of the clinical nodal classification for 587 patients who had undergone neck dissection were 84%, 89%, and 88%, respectively. Tumors on the retromolar trigone and the lip mucosa were more likely to metastasize to regional lymph nodes (Table 2). A primary tumor in the floor of the mouth had the highest tendency to metastasize to the ipsilateral nodes at levels I–V and the contralateral nodes. A cutoff thickness >7 mm was not only the best value of the Youdon index in ROC analysis to predict RLNM, but it also gave both the best statistical power and the highest hazard ratio to predict poor outcomes in univariate analysis (Table 3). Outcomes The median follow up for all patients was 44 months. Localized recurrence and metachronous second primary cancers were distinguished using previously published guidelines.4,5 Patients with carcinoma of the retromolar trigone and the tongue had the highest tendency for localized recurrence and for regional recurrence with or without localized recurrence, respectively. The median duration of local recurrence was 10 months (range, 1–88 months). Twenty-nine pathological N0 patients had regional recurrence without local recurrence within 2 years, which was defined as pathological occult metastasis (median duration, 8 months; range, 1–40 months). The overall occult metastasis rate was 9.2%: 31 cases of clinical occult metastasis, regional recurrence in seven observed cN0 necks, and 29 pathological occult metastases. Except for four patients with pathological occult metastasis, all occult metastasis was limited to the ipsilateral nodes at levels I–III and contralateral nodes at level I–III. The median duration for regional recurrence in ipsilateral level I–III nodes was 7 months (range, 1–40 months), in ipsilateral level I–V nodes 3 months (range, 1–7 months), and in contralateral nodes 6 months (range, 1–77 months). Prognostic factors The median followup period was 44 months (range, 9–156 months). The 5-year COS, CDSS, and CLRC of all patients were 61%, 62%, and 46%, respectively (Fig. 1). The 5-year COS, CDSS, and CLRC for different clinicopathological variables are listed in Table 1. All pathological variables were significantly correlated with all survivals. In the clinical variables, patients with a history of alcohol drinking, carcinoma of the retromolar trigone, long hospital stays, or distant metastasis during followup had significantly worse COS and CDSS, and those with multiple primary cancers and carcinoma of the retromolar trigone had a significantly worse CLRC. Using Cox’s proportional-hazards regression model, the significant independent predictors of overall survival and diseasespecific survival are shown in Table 4; however, we did not find any significant variable for locoregional control.
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Table 1 Kaplan–Meier survival analyses for clinicopathological parameters. Variables
n (%)
5-year COS rate % (SE)
Gender Male Female Diagnostic age 0–39 years 40–49 years 50–59 years 60–69 years P70 years Diagnosis delay 61 month 63 months 66 months 612 months >12 months Tobacco smokinga No Yes Betel quid chewinga No Yes Alcohol drinkinga No Yes Synchronous SPC No Yes Site of main tumor Buccal mucosa Oral tongue Lower gum Retromolar trigone Floor of mouth Upper gum and palate Lip mucosa Length of hospital stayb 67 days 7–14 days >14 days Surgical modalities Excision Excision and ND T classification T1–T3 T4 N classification N0 N1 and N2a N2b N2c and N3 Levels of nodal metastasisc No metastasis Ipsilateral level I–III Ipsilateral level I–V Contralateral side Stage Stage I Stage II Stage III Stage IV Grade of differentiation Well Moderately Poorly Tumor thicknessd 67 mm >7 mm Treatment failure No Localized Regional Locoregional Distant metastasis
5-year CDSS rate P-value
% (SE)
0.811 666 (95.4) 32 (4.6)
62 (2) 61 (10)
114 (16.3) 242 (34.7) 199 (28.5) 105 (15.1) 38 (5.4)
69 58 63 64 59
(5) (3) (4) (5) (9)
127 (18.2) 261 (37.4) 142 (20.3) 63 (9.0) 105 (15.1)
59 61 57 68 74
(5) (3) (5) (6) (5)
89 (12.8) 609 (87.2)
56 (6) 63 (2)
112 (16.1) 586 (83.9)
69 (5) 61 (2)
430 (61.6) 268 (38.4)
65 (3) 58 (3)
558 (80.0) 140 (20.0)
62 (2) 60 (4)
325 (46.5) 173 (24.8) 78 (11.2) 34 (4.9) 23 (3.3) 25 (3.6) 40 (5.7)
65 62 61 26 66 52 71
39 (7.0) 315 (56.9) 200 (36.1)
72 (8) 67 (3) 54 (4)
111 (15.9) 587 (84.1)
69 (5) 61 (2)
527 (76.0) 171 (24.0)
70 (2) 38 (4)
522 (74.8) 66 (9.5) 96 (13.7) 14 (2.0)
72 43 24 50
(2) (7) (5) (13)
416 (70.9) 150 (25.5) 11 (1.9) 10 (1.7)
72 33 25 46
(2) (5) (13) (15)
182 (26.1) 190 (27.2) 93 (13.3) 233 (33.4)
82 76 58 36
(4) (3) (6) (4)
410 (58.8) 253 (36.2) 35 (5.0)
67 (3) 56 (4) 36 (10)
219 (40.0) 328 (60.0)
80 (3) 51 (3)
353 (50.6) 181 (25.9) 77 (11.0) 44 (6.3) 26 (3.7)
95 (1) 41 (4) 27 (6) 13 (6) 9 (6)
5-year CLRC rate P-value
63 (2) 61 (10) 0.523 (5) (4) (4) (5) (9)
61 62 58 69 75
(5) (4) (5) (7) (5)
46 (2) 39 (11) 0.543 49 41 49 45 49
(5) (4) (6) (6) (9)
43 46 40 49 53
(5) (4) (5) (7) (6)
0.245
0.236
0.244
0.164 57 (6) 64 (2)
0.088
0.357 40 (6) 47 (2)
0.081 70 (5) 62 (2)
0.021
0.305 50 (6) 45 (2)
0.012 66 (3) 59 (3)
0.291
0.267 46 (3) 45 (4)
0.338 63 (2) 63 (4)
0.022
0.071 46 (3) 43 (5)
0.023 66 63 63 27 69 52 72
(3) (4) (6) (11) (12) (11) (8)
<0.001
0.013 46 45 52 23 70 44 46
(3) (5) (6) (8) (11) (11) (9)
0.003 74 (8) 67 (3) 56 (4)
0.078
0.154 55 (10) 49 (4) 44 (4)
0.033 71 (5) 62 (2)
<0.001
0.323 49 (5) 45 (2)
<0.001 71 (2) 39 (4)
<0.001
<0.001 51 (3) 29 (4)
<0.001 73 44 25 50
(2) (7) (5) (14)
73 33 18 50
(2) (5) (12) (16)
84 77 58 37
(4) (3) (6) (4)
<0.001
<0.001 52 (3) 33 (8) 19 (5) NA
<0.001
<0.001
<0.001 52 (3) 25 (4) NA NA
<0.001
<0.001
<0.001 64 53 34 29
(4) (4) (6) (4)
<0.001 69 (3) 57 (4) 34 (10)
<0.001
0.008 48 (3) 44 (4) 35 (12)
<0.001 81 (3) 52 (3)
<0.001
<0.001 60 (4) 38 (3)
<0.001 100 41 (4) 27 (6) 13 (6) 9 (6)
P-value 0.901
0.518 69 59 64 66 60
0.327
(3) (4) (6) (10) (12) (11) (7)
% (SE)
0.674
NA NA NA NA NA NA
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S.-Y. Liu et al. / Oral Oncology 46 (2010) 276–282 Table 1 (continued) Variables
n (%)
5-year COS rate % (SE)
Second primary cancer
17 (2.5)
5-year CDSS rate P-value
% (SE)
81 (10)
5-year CLRC rate P-value
81 (10)
% (SE)
P-value
NA
COS, cumulative overall survival; CDSS, cumulative disease-specific survival; CLRC, cumulative locoregional control; SPC, second primary cancer; ND, neck dissection; NA, not applicable. a The risk of the oral habit was classified as positive if the patient kept it for at least 2 years. b Statistically analyzed 584 patients who had information of length of hospital stay. c Statistically analyzed 587 patients who had undergone neck dissection. d Statistically analyzed 574 patients who had information of tumor thickness.
Table 2 Levels and primary site of the main tumors in 185 patients with regional lymph node metastasis (RLNM). Site of main tumor
RLNM n (%)
Ipsilateral side
Contralateral side n (%)
Level I–III n (%)
Level I–V n (%)
Buccal mucosa Oral tongue Lower gum Retromolar trigone Floor of mouth Upper gum and palate Lip mucosa
79 (24.3) 39 (22.5) 19 (24.4) 14 (41.2) 8 (34.8) 3 (12.0) 14 (35.0)
72 (22.2) 34 (19.6) 16 (20.5) 13 (38.3) 4 (17.5) 3 (12.0) 11 (27.5)
5 2 1 1 1 0 2
(1.5) (1.2) (1.3) (2.9) (4.3) (0.0) (5.0)
2 3 2 0 3 0 1
(0.6) (1.7) (2.6) (0.0) (13.0) (0.0) (2.5)
Table 3 Analyses of the cutoff thicknesses for survival and tumor recurrence. Tumor thickness (mm)
62 >2 63 >3 64 >4 65 >5 66 >6 67 >7 68 >8 69 >9 610 >10
Regional lymph node metastasis YI
Overall survival
Disease-specific survival
Locoregional control
HR
YI
HR
YI
HR
YI
0.06
2.00
0.032
1.87
0.030
1.09
0.009
0.11
2.62
0.086
2.74
0.088
1.44
0.038
0.14
2.99
0.124
3.08
0.125
1.72
0.08
0.21
2.99
0.224
3.04
0.225
1.89
0.162
0.22
3.10
0.253
3.10
0.252
1.83
0.158
0.24
3.29
0.290
3.26
0.288
2.15
0.220
0.21
2.96
0.291
2.88
0.283
2.00
0.210
0.22
2.98
0.295
2.88
0.286
2.04
0.217
0.20
3.15
0.297
3.13
0.290
2.13
0.190
HR, hazard ratio after multivariate analysis; YI, Youdon index after receiver operating characteristic analysis.
Discussion Traditionally, OSCC was thought to be a disease occurring most frequently in the sixth and seventh decades of life and to be rare in the young (<40 years old). Recently, the incidence of OSCC in this population has risen in Western countries, but it is still low.8,9 In Taiwan, OSCC is the most common cancer in the young male population; it may be associated with the age at which young Taiwanese males begin chewing BQ and smoking tobacco: somewhere between 12 and 15 years.10,11 The effect of age on prognosis is still controversial. Age was not a significant predictor for outcome in this study, which may be attributable to similar rates of BQ chewing and tobacco smoking between age groups (data not shown). BQ chewing, tobacco smoking, and alcohol drinking are not only risk habits for oral carcinogenesis3; they also have strong effects on patient morbidity, tumor recurrence, second primary tumor, and
mortality.4,12–14 Although our study showed that alcohol drinking was the only independent risk habit affecting survival, we cannot disregard the high prevalence of tobacco smoking and BQ chewing in our patients; therefore, ceasing all risk habits has become an important part of the treatment of OSCC. The resumption rate of oral risk habits after OSCC treatment is high and is a significant prognostic factor.15 For patients who undergo successful medical treatment, clinicians should not only keep close surveillance on their recovery, but they should also dissuade them from keeping or resuming all of these risk habits. RLNM is a well-known negative prognostic factor for OSCC, and it decreases the survival rate by 50%.16,17 Managing a cN+ patient usually requires multiple treatment modalities and close surveillance; however, there is still controversy over the management of cN0 patients.16,17 Compared with the 20–40% clinical occult metastasis reported in previous studies,18 we found a lower
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Figure 1 Cumulative survival curves for overall survival (A), disease-specific survival (B), and locoregional control (C).
incidence rate in our patients, and all of their metastatic nodes were limited to levels I–III. Our previous results19 also that showed 95.3% of the sentinel lymph nodes were localized in the ipsilateral region at levels I–III. The 6th edition of the American Joint Committee on Cancer (AJCC) staging system suggested that the level of nodal metastasis should be recorded; however, it is still not included in the consideration of stage. As in a previous study,20 our patients with lower, posterior, or both cervical tumor metastases had the worse outcomes. Under our surgical regimens for cN0 patients, there were similar incidences of regional recurrence between patients given a supraomohyoid neck dissection (7.4%) and those given a modified radical neck dissection (9.9%), which agrees with other series.21–23 It is reasonable to support supraomohyoid neck dissection as a primary treatment for cN0 patients for the early detection of occult metastasis and the planning of subsequent adjuvant treatments.24 Except for T4 tumors, the maximal diameter is the only parameter used to classify local tumors. Because tumors can spread in different planes to invade the surrounding structures, diameter alone cannot completely express the overall aggressiveness of a given tumor. Although many studies have reported that tumor thickness rather than maximal diameter may have a greater effect on
the risk of RLNM, locoregional recurrence, and mortality, there is still controversy over the critical cutoff thickness range of 2– 10 mm.25 The significant cutoff thickness of 7 mm for RLNM and mortality in our study was within the 6–10 mm range reported by two other large-scale studies.26,27 Estimating tumor thickness by inspection and palpation is unreliable, and punch biopsy also has limitations for evaluating tumor thickness.28 Ultrasonography and magnetic resonance imaging are useful for preoperatively assessing tumors, and they correlate well with histological assessments.29–31 If imaging studies are not available, a frozen surgical specimen is an alternative measuring method. It is necessary to design a prospective study on the cutoff values for the different assessments. Thereafter, clinicians could have a powerful parameter to predict whether cN0 patients will benefit from elective neck dissection, detection of micrometastasis, and close surveillance. The reported32,33 surgical complication rate in OSCC patients is 50%; the most frequent complication is infection. Surgical complication, an indicator of unfavorable outcome, is defined as a development arising during or after surgery.32 Because the severity of complications is difficult to quantify, some objective assessment scales to predict postoperative morbidities have been proposed32,34; however, they are complicated to use. The length of
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S.-Y. Liu et al. / Oral Oncology 46 (2010) 276–282 Table 4 Multivariate analyses of independent predictors for overall survival and disease-specific survival. Variables
Overall survival HR (95% CI)
Disease-specific Survival P-value
Alcohol drinking No Yes
HR (95% CI)
P-value
Reference 1.31 (1.0–1.7)
0.048
Levels of nodal metastasis No metastasis Ipsilateral level I–III Ipsilateral level I–V Contralateral side
Reference 1.46 (1.0–2.2) 2.96 (1.4–6.2) 2.86 (1.2–7.0)
0.052 0.004 0.021
Reference 1.49 (1.1–2.1) 3.43 (1.7–7.1) 2.62 (1.0–6.8)
0.021 0.001 0.047
Stage I and II III and IV
Reference 2.13 (1.4–3.3)
0.001
Reference 1.76 (1.3–2.5)
0.001
Reference 1.18 (0.9–1.6) 2.14 (1.3–3.6)
0.248 0.005
Reference 48.95 (9.8–243.8) 114.24 (28.2–463.1) 148.80 (36.1–613.5) 195.74 (46.9–817.3) 225.15 (52.6–964.0)
<0.001 <0.001 <0.001 <0.001 <0.001
Differentiation Well Moderately Poorly Tumor thickness 67 mm >7 mm
Reference 1.59 (1.1–2.3)
0.019
Treatment failure No Second primary cancer Localized Regional Locoregional Distant
Reference 1.43 (0.2–10.9) 11.79 (6.7–20.9) 14.74 (7.9–27.6) 19.64 (10.7–37.5) 19.68 (9.6–40.4)
0.733 <0.001 <0.001 <0.001 <0.001
HR, hazard ratio; CI, confidence interval.
hospital stay has been significantly associated with complications.32,35 In our analysis, length of hospital stay also significantly affected survival but was not an independent predictor for survival or recurrence. Compared with the 5-year COS (range, 56–83%) and 5-year CDSS (range, 74–87%) of OSCC patients underwent surgical treatment in the recent studies, our study showed a similar 5-year COS but a lower 5-year CDSS in the BQ-associated OSCC patients.36,37 The main reason may be a higher incidence of treatment failure. According to previously published studies, locoregional recurrence is the most common treatment failure for OSCC patients without BQ chewing, and the outcomes of salvage therapy are poor (range, 15–37%).38–40 The relatively poor 5-year CLRC in our BQassociated OSCC patients could be the major reason for their lower 5-year DSS.41 Although one study suggested a shorter period of followup because the benefits are limited, some studies indicate OSCC patients have a better survival rate if the recurrent tumor can be detected in an early stage and treated by salvage surgery.5,37,42 A close followup protocol is important for the BQ-associated OSCC patients, not only to detect locoregional recurrence, but also to find second primary cancer. The risk of metachronous second primary cancer in the upper aerodigestive tract and lungs has a 20-year cumulative risk of 36%, particularly in patients who continue to smoke tobacco and drink alcohol.43 The 19.9% incidence of synchronous second primary cancer in our patients was higher than in other studies,43,44 which might be due to the high prevalence of risk habits in our patients. Our patients with localized recurrence exhibited a 41% 5-year COS, higher than patients in previous studies.27,36,37,44 Furthermore, the 5-year COS of patients with localized recurrence may be camouflaged by metachronous second primary cancer. The outcomes for patients with localized recurrence may be reasonably estimated after excluding metachronous second primary cancers by using molecular analysis of the tumors and the genetically altered mucosal field in between.45 Although we adopted a close followup protocol, patients with regional failure, including regional
and locoregional recurrence still had a poor 5-year COS, however within 20% to 33% reported in previous studies.46,47 The poor prognoses of patients with regional failure were due to widely disseminated tumors in more than 50% of the patients. In addition to close surveillance, more accurate, noninvasive, and early diagnostic techniques for tumor recurrence are needed. In conclusion, alcohol drinking, lower levels of nodal metastasis, advanced stage, poor cell differentiation, large tumor thickness, and treatment failure were poor prognostic factors for this patient population with high rate of betel quid chewing and tobacco smoking. Due to the prevalence of locoregional recurrence and second primary cancer, aggressive surgical excision and close surveillance may be the optimal policy for BQ-associated OSCC. Conflicts of interest statement None declared. Acknowledgements This work was supported in part by Chi-Mei Medical Center (CMFHR9358) and National Science Council, Taiwan (NSC 972314-B-384-003-MY3). References 1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Betelquid and areca-nut chewing and some areca-nutderived nitrosamines. IARC Monogr Eval Carcinog Risks Hum 2004;85(1):11-18. 2. Yang YH, Chen HR, Tseng CH, et al. Prevalence rates of areca/betel quid chewing in counties of Taiwan. Taiwan J Oral Med Health Sci 2002;18(1):1–16. 3. Shiu MN, Chen TH. Impact of betel quid, tobacco and alcohol on three-stage disease natural history of oral leukoplakia and cancer: implication for prevention of oral cancer. Eur J Cancer Prev 2004;13(1):39–45. 4. Lee JJ, Jeng JH, Wang HM, Chang HH, Chiang CP, Kuo YS, et al. Univariate and multivariate analysis of prognostic significance of betel quid chewing in squamous cell carcinoma of buccal mucosa in Taiwan. J Surg Oncol 2005;91(1):41–7.
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28. de Visscher JG, Schaapveld M, Grond AJ, van der Waal I. Relationship of tumor thickness in punch biopsy and subsequent surgical specimens in stage I squamous cell carcinoma of the lower lip. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88(2):141–4. 29. Shintani S, Yoshihama Y, Ueyama Y, Terakado N, Kamei S, Fijimoto Y, et al. The usefulness of intraoral ultrasonography in the evaluation of oral cancer. Int J Oral Maxillofac Surg 2001;30(2):139–43. 30. Songra AK, Ng SY, Farthing P, Hutchison IL, Bradley PF. Observation of tumour thickness and resection margin at surgical excision of primary oral squamous cell carcinoma—assessment by ultrasound. Int J Oral Maxillofac Surg 2006;35(4):324–31. 31. Lam P, Au-Yeung KM, Cheng PW, Wei WI, Yuen AP, Trendell-Smith N, et al. Correlating MRI and histologic tumor thickness in the assessment of oral tongue cancer. AJR Am J Roentgenol 2004;182(3):803–8. 32. de Melo GM, Ribeiro KC, Kowalski LP, Deheinzelin D. Risk factors for postoperative complications in oral cancer and their prognostic implications. Arch Otolaryngol Head Neck Surg 2001;127(7):828–33. 33. Kowalski LP, Alcantara PS, Magrin J, Parise Jr O. A case control study on complications and survival in elderly patients undergoing major head and neck surgery. Am J Surg 1994;168(5):485–90. 34. de Cássia Braga Ribeiro K, Kowalski LP. APACHE II, POSSUM, and ASA scores and the risk of perioperative complications in patients with oral or oropharyngeal cancer. Arch Otolaryngol Head Neck Surg 2003;129(7):739–45. 35. Penel N, Mallet Y, Roussel-Delvallez M, Lefebvre JL, Yazdanpanah Y. Factors determining length of the postoperative hospital stay after major head and neck cancer surgery. Oral Oncol 2008;44(6):555–62. 36. Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Salvage therapy in relapsed squamous cell carcinoma of the oral cavity: how and when? Cancer 2008;112(1):94–103. 37. Arduino PG, Carrozzo M, Chiecchio A, Broccoletti R, Tirone F, Borra E, et al. Clinical and histopathologic independent prognostic factors in oral squamous cell carcinoma: a retrospective study of 334 cases. J Oral Maxillofac Surg 2008;66(8):1570–9. 38. Koo BS, Lim YC, Lee JS, Choi EC. Recurrence and salvage treatment of squamous cell carcinoma of the oral cavity. Oral Oncol 2006;42(10):789–94. 39. Liu SA, Wong YK, Lin JC, Poon CK, Tung KC, Tsai WC. Impact of recurrence interval on survival of oral cavity squamous cell carcinoma patients after local relapse. Otolaryngol Head Neck Surg 2007;136(1):112–8. 40. Rogers SN, Brown JS, Wooglar JA, Lowe D, Magennis P, Shaw RJ, et al. Survival following primary surgery for oral cancer. Oral Oncol 2009;45(3):201–11. 41. Eckardt A, Barth EL, Kokemueller H, Wegener G. Recurrent carcinoma of the head and neck: treatment strategies and survival analysis in a 20-year period. Oral Oncol 2004;40(4):427–32. 42. Schwartz GJ, Mehta RH, Wenig BL, Shaligram C, Portugal LG. Salvage treatment for recurrent squamous cell carcinoma of the oral cavity. Head Neck 2000;22(1):34–41. 43. Chuang SC, Scelo G, Tonita JM, Tamaro S, Jonasson JG, Kliewer EV, et al. Risk of second primary cancer among patients with head and neck cancers: a pooled analysis of 13 cancer registries. Int J Cancer 2008;123(10):2390–6. 44. Liao CT, Kang CJ, Chang JT, Wang HM, Ng SH, Hsueh C, et al. Survival of second and multiple primary tumors in patients with oral cavity squamous cell carcinoma in the betel quid chewing area. Oral Oncol 2007;43(8):811–9. 45. Braakhuis BJ, Tabor MP, Leemans CR, van der Waal I, Snow GB, Brakenhoff RH. Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 2002;24(2):198–206. 46. Nathanson A, Agren K, Biorklund A, Lind MG, Andréason L, Anniko M, et al. Evaluation of some prognostic factors in small squamous cell carcinoma of the mobile tongue: a multicenter study in Sweden. Head Neck 1989;11(5): 387–92. 47. Pearlman NW. Treatment outcome in recurrent head and neck cancer. Arch Surg 1979;114(1):39–42.
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Surgical outcomes and prognostic factors of oral cancer associated with betel quid chewing and tobacco smoking in Taiwan Shyun-Yeu Liu a,b, Chin-Li Lu b, Chang-Ta Chiou c, Ching-Yu Yen a, Gwo-An Liaw d, Yi-Chun Chen e, Yu-Chi Liu f, Wei-Fan Chiang b,d,g,* a
Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Yongkang, Taiwan Department of Medical Research, Chi-Mei Medical Center, Taiwan Department of Oral and Maxillofacial Surgery, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan d Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Liouying, Taiwan e Department of Oral and Maxillofacial Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan f Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan g School of Dentistry, National Yang-Ming University, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 8 December 2009 Received in revised form 13 January 2010 Accepted 14 January 2010 Available online 6 February 2010 Keywords: Oral cancer Betel quid Occult metastasis Second primary cancer Level of nodal metastasis Tumor thickness Alcohol drinking Treatment failure Locoregional recurrence Close surveillance
s u m m a r y Oral squamous cell carcinoma (OSCC) is one of the most common cancers in geographic regions where betel quid (BQ) chewing is prevalent; OSCC is an extremely malignant neoplasm whose prognostic factors are multiple and complex. The purpose of this study was to assess clinicopathological prognostic factors and treatment outcomes in 698 consecutive OSCC patients who had undergone surgery as the primary treatment in an area with a high prevalence of both betel quid chewing and tobacco smoking. The prognostic factors were predicted using Cox’s proportional-hazards regression model, and the survival rate was calculated using Kaplan–Meier analysis. The median followup for all patients was 44 months. The 5-year cumulative overall, disease-specific, and locoregional control survival rates were 61%, 62%, and 46%, respectively. Multivariate analysis showed that the lower level of nodal metastasis, advanced stage, tumor thickness >7 mm, and treatment failures were independent risk factors of overall survival. Furthermore, history of alcohol drinking, lower level of nodal metastasis, advanced stage, poor cell differentiation, and treatment failures were independent predictors of poor disease-specific survival. However, we did not find any significant factor that affected locoregional recurrence. Due to the high frequencies of locoregional recurrence and second primary cancer, our findings emphasize that aggressive surgical excision, adjuvant treatments according to clinicopathological prognostic factors and close surveillance are important to the survival of OSCC patients in an area with a high prevalence of betel quid chewing and tobacco smoking. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Oral and pharyngeal cancers are common and identified as significant public health threats worldwide; their incidence and mortality vary by region. Oral squamous cell carcinoma (OSCC) is the most common subtype. The management of OSCC varies considerably, but the standard procedure remains local excision, with or without neck dissection, and then adjuvant radiotherapy depending on the risk factors. Supplemental adjuvant chemotherapy is occasionally used to improve locoregional and distant control. Despite recent therapeutic developments, the 5-year survival rate for
* Corresponding author. Address: Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Liouying. 201, Taikang Village, Liouying, Tainan 735, Taiwan. Tel.: +886 6 6226999x73158. E-mail address: [email protected] (W.-F. Chiang). 1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2010.01.008
persons with OSCC is unfavorable. In recent decades, genomic and proteomic markers have been developed to predict which cases of OSCC will have unfavorable outcomes. These markers are also used as targets for treatment. The clinicopathological prognostic factors of OSCC are still important for clinicians for delineating the aggressiveness of specific instances of the disease and for determining appropriate postoperative therapies. Betel quid (BQ) was declared a group 1 carcinogen by the International Agency for Research on Cancer.1 Taiwan has a high prevalence of BQ chewing and a high incidence of OSCC.2 In Taiwan, OSCC patients usually have habits of BQ chewing, tobacco smoking, and alcohol drinking, all of which have a synergistic effect on oral carcinogenesis.3,4 Few studies have been done on the surgical outcomes and prognostic factors in southern Taiwan. Chi-Mei Medical Center is one of the tertiary referral centers for OSCC in this region. Therefore, we were interested in the clinicopathological factors
S.-Y. Liu et al. / Oral Oncology 46 (2010) 276–282
that affect the OSCC survival rate in this high-prevalence BQ chewing area. Materials and methods Patients and treatment After the protocol had been approved by the institutional review broad, we retrospectively studied the medical records of 698 consecutive patients who had been diagnosed with OSCC and had undergone surgery as a primary treatment from January 1995 through December 2005. Patients who initially showed distant metastasis were excluded. All the tumors were excised with at least 1-cm safe margins. Except for patients who showed poor compliance or compromised systemic conditions, all patients underwent concurrent neck dissection to examine regional lymph node metastasis (RLNM). Patients were referred for radiotherapy and ranged from 60 to 65 Grey with or without chemotherapy within 6 weeks post-surgery, depending on the risk factors. Using the modified protocol,5 our patients were asked to visit clinic every 2 weeks in the first year following treatments, every month in the second year, and then every 3 months until the fifth year. There were at least 2 years of followup for each patient until the endpoint of this study, December 2008. Descriptive analysis was done on 17 clinicopathological variables (Table 1). The patient delay means the duration between the onset of symptoms and the date of clinic visit for definite diagnosis. Synchronous second primary cancer in the oral cavity (OSPC) was judged using previously published guidelines.6,7 A microscope was used to maximally measure tumor thickness perpendicularly from the surface of the tumor to its deepest extent, excluding the keratin coat. Except for tumor thickness and length of hospital stay, information for all variables was obtained for all patients (Table 1). Statistical analysis Cumulative survival rates, from the day of admission to the day of withdrawal or to the endpoint of this study, were calculated using the Kaplan–Meier analysis. These rates reflect the probability of death attributed to all causes (cumulative overall survival; COS), deaths attributed only to OSCC (cumulative disease-specific survival; CDSS), or tumor recurrence in the oral cavity or neck region or both (cumulative locoregional control; CLRC). The differences between subgroups were examined using the log-rank test. The independent prognostic factors for survival were assessed using Cox’s proportional-hazards regression model. In the present study, patients who did not come for followup for the full 2 years were considered to have died of OSCC, therapeutic complications, or intercurrent disease less than 2 years after the primary surgery. The optimal cutoff thickness for RLNM and survival was selected using both receiver operating characteristic (ROC) analysis and univariate analysis for every millimeter of cutoff thickness. SPSS 17.0 (SPSS Institute, Chicago, IL) was used for the analysis. Statistical significance was set at P < 0.05. Results Clinicopathological characteristics The male/female ratio was 20.8. The median age was 49 years (range, 23–84 years). The largest age group was 40–49 years, followed by 50–59. Most patients had a history of tobacco smoking (87.2%) and BQ chewing (83.9%). The most common length of hos-
277
pital stay for surgical treatment was 7–14 days (56.9%). The three most common sites of major tumors were the buccal mucosa (46.5%), oral tongue (24.8%), and lower gum (11.2%). For patients with OSPC, the retromolar trigone and the lower lip were the two most common sites of the main lesion, and the buccal mucosa (40.1%) was the most common affected site of the secondary tumor. After we had examined 548 ipsilateral cervical specimens and 38 bilateral cervical specimens, pathological RLNM (pN+) presented in the specimens of 170 (29.0%) patients. The levels of RLNM were defined by the lowest level of lymph node to which the carcinoma had metastasized. Clinically occult metastasis was proved in 31 (6.1%) cervical specimens from 506 patients without RLNM (N0) clinically; all the nodes were localized at levels I–III. The sensitivity, specificity, and accuracy of the clinical nodal classification for 587 patients who had undergone neck dissection were 84%, 89%, and 88%, respectively. Tumors on the retromolar trigone and the lip mucosa were more likely to metastasize to regional lymph nodes (Table 2). A primary tumor in the floor of the mouth had the highest tendency to metastasize to the ipsilateral nodes at levels I–V and the contralateral nodes. A cutoff thickness >7 mm was not only the best value of the Youdon index in ROC analysis to predict RLNM, but it also gave both the best statistical power and the highest hazard ratio to predict poor outcomes in univariate analysis (Table 3). Outcomes The median follow up for all patients was 44 months. Localized recurrence and metachronous second primary cancers were distinguished using previously published guidelines.4,5 Patients with carcinoma of the retromolar trigone and the tongue had the highest tendency for localized recurrence and for regional recurrence with or without localized recurrence, respectively. The median duration of local recurrence was 10 months (range, 1–88 months). Twenty-nine pathological N0 patients had regional recurrence without local recurrence within 2 years, which was defined as pathological occult metastasis (median duration, 8 months; range, 1–40 months). The overall occult metastasis rate was 9.2%: 31 cases of clinical occult metastasis, regional recurrence in seven observed cN0 necks, and 29 pathological occult metastases. Except for four patients with pathological occult metastasis, all occult metastasis was limited to the ipsilateral nodes at levels I–III and contralateral nodes at level I–III. The median duration for regional recurrence in ipsilateral level I–III nodes was 7 months (range, 1–40 months), in ipsilateral level I–V nodes 3 months (range, 1–7 months), and in contralateral nodes 6 months (range, 1–77 months). Prognostic factors The median followup period was 44 months (range, 9–156 months). The 5-year COS, CDSS, and CLRC of all patients were 61%, 62%, and 46%, respectively (Fig. 1). The 5-year COS, CDSS, and CLRC for different clinicopathological variables are listed in Table 1. All pathological variables were significantly correlated with all survivals. In the clinical variables, patients with a history of alcohol drinking, carcinoma of the retromolar trigone, long hospital stays, or distant metastasis during followup had significantly worse COS and CDSS, and those with multiple primary cancers and carcinoma of the retromolar trigone had a significantly worse CLRC. Using Cox’s proportional-hazards regression model, the significant independent predictors of overall survival and diseasespecific survival are shown in Table 4; however, we did not find any significant variable for locoregional control.
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Table 1 Kaplan–Meier survival analyses for clinicopathological parameters. Variables
n (%)
5-year COS rate % (SE)
Gender Male Female Diagnostic age 0–39 years 40–49 years 50–59 years 60–69 years P70 years Diagnosis delay 61 month 63 months 66 months 612 months >12 months Tobacco smokinga No Yes Betel quid chewinga No Yes Alcohol drinkinga No Yes Synchronous SPC No Yes Site of main tumor Buccal mucosa Oral tongue Lower gum Retromolar trigone Floor of mouth Upper gum and palate Lip mucosa Length of hospital stayb 67 days 7–14 days >14 days Surgical modalities Excision Excision and ND T classification T1–T3 T4 N classification N0 N1 and N2a N2b N2c and N3 Levels of nodal metastasisc No metastasis Ipsilateral level I–III Ipsilateral level I–V Contralateral side Stage Stage I Stage II Stage III Stage IV Grade of differentiation Well Moderately Poorly Tumor thicknessd 67 mm >7 mm Treatment failure No Localized Regional Locoregional Distant metastasis
5-year CDSS rate P-value
% (SE)
0.811 666 (95.4) 32 (4.6)
62 (2) 61 (10)
114 (16.3) 242 (34.7) 199 (28.5) 105 (15.1) 38 (5.4)
69 58 63 64 59
(5) (3) (4) (5) (9)
127 (18.2) 261 (37.4) 142 (20.3) 63 (9.0) 105 (15.1)
59 61 57 68 74
(5) (3) (5) (6) (5)
89 (12.8) 609 (87.2)
56 (6) 63 (2)
112 (16.1) 586 (83.9)
69 (5) 61 (2)
430 (61.6) 268 (38.4)
65 (3) 58 (3)
558 (80.0) 140 (20.0)
62 (2) 60 (4)
325 (46.5) 173 (24.8) 78 (11.2) 34 (4.9) 23 (3.3) 25 (3.6) 40 (5.7)
65 62 61 26 66 52 71
39 (7.0) 315 (56.9) 200 (36.1)
72 (8) 67 (3) 54 (4)
111 (15.9) 587 (84.1)
69 (5) 61 (2)
527 (76.0) 171 (24.0)
70 (2) 38 (4)
522 (74.8) 66 (9.5) 96 (13.7) 14 (2.0)
72 43 24 50
(2) (7) (5) (13)
416 (70.9) 150 (25.5) 11 (1.9) 10 (1.7)
72 33 25 46
(2) (5) (13) (15)
182 (26.1) 190 (27.2) 93 (13.3) 233 (33.4)
82 76 58 36
(4) (3) (6) (4)
410 (58.8) 253 (36.2) 35 (5.0)
67 (3) 56 (4) 36 (10)
219 (40.0) 328 (60.0)
80 (3) 51 (3)
353 (50.6) 181 (25.9) 77 (11.0) 44 (6.3) 26 (3.7)
95 (1) 41 (4) 27 (6) 13 (6) 9 (6)
5-year CLRC rate P-value
63 (2) 61 (10) 0.523 (5) (4) (4) (5) (9)
61 62 58 69 75
(5) (4) (5) (7) (5)
46 (2) 39 (11) 0.543 49 41 49 45 49
(5) (4) (6) (6) (9)
43 46 40 49 53
(5) (4) (5) (7) (6)
0.245
0.236
0.244
0.164 57 (6) 64 (2)
0.088
0.357 40 (6) 47 (2)
0.081 70 (5) 62 (2)
0.021
0.305 50 (6) 45 (2)
0.012 66 (3) 59 (3)
0.291
0.267 46 (3) 45 (4)
0.338 63 (2) 63 (4)
0.022
0.071 46 (3) 43 (5)
0.023 66 63 63 27 69 52 72
(3) (4) (6) (11) (12) (11) (8)
<0.001
0.013 46 45 52 23 70 44 46
(3) (5) (6) (8) (11) (11) (9)
0.003 74 (8) 67 (3) 56 (4)
0.078
0.154 55 (10) 49 (4) 44 (4)
0.033 71 (5) 62 (2)
<0.001
0.323 49 (5) 45 (2)
<0.001 71 (2) 39 (4)
<0.001
<0.001 51 (3) 29 (4)
<0.001 73 44 25 50
(2) (7) (5) (14)
73 33 18 50
(2) (5) (12) (16)
84 77 58 37
(4) (3) (6) (4)
<0.001
<0.001 52 (3) 33 (8) 19 (5) NA
<0.001
<0.001
<0.001 52 (3) 25 (4) NA NA
<0.001
<0.001
<0.001 64 53 34 29
(4) (4) (6) (4)
<0.001 69 (3) 57 (4) 34 (10)
<0.001
0.008 48 (3) 44 (4) 35 (12)
<0.001 81 (3) 52 (3)
<0.001
<0.001 60 (4) 38 (3)
<0.001 100 41 (4) 27 (6) 13 (6) 9 (6)
P-value 0.901
0.518 69 59 64 66 60
0.327
(3) (4) (6) (10) (12) (11) (7)
% (SE)
0.674
NA NA NA NA NA NA
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S.-Y. Liu et al. / Oral Oncology 46 (2010) 276–282 Table 1 (continued) Variables
n (%)
5-year COS rate % (SE)
Second primary cancer
17 (2.5)
5-year CDSS rate P-value
% (SE)
81 (10)
5-year CLRC rate P-value
81 (10)
% (SE)
P-value
NA
COS, cumulative overall survival; CDSS, cumulative disease-specific survival; CLRC, cumulative locoregional control; SPC, second primary cancer; ND, neck dissection; NA, not applicable. a The risk of the oral habit was classified as positive if the patient kept it for at least 2 years. b Statistically analyzed 584 patients who had information of length of hospital stay. c Statistically analyzed 587 patients who had undergone neck dissection. d Statistically analyzed 574 patients who had information of tumor thickness.
Table 2 Levels and primary site of the main tumors in 185 patients with regional lymph node metastasis (RLNM). Site of main tumor
RLNM n (%)
Ipsilateral side
Contralateral side n (%)
Level I–III n (%)
Level I–V n (%)
Buccal mucosa Oral tongue Lower gum Retromolar trigone Floor of mouth Upper gum and palate Lip mucosa
79 (24.3) 39 (22.5) 19 (24.4) 14 (41.2) 8 (34.8) 3 (12.0) 14 (35.0)
72 (22.2) 34 (19.6) 16 (20.5) 13 (38.3) 4 (17.5) 3 (12.0) 11 (27.5)
5 2 1 1 1 0 2
(1.5) (1.2) (1.3) (2.9) (4.3) (0.0) (5.0)
2 3 2 0 3 0 1
(0.6) (1.7) (2.6) (0.0) (13.0) (0.0) (2.5)
Table 3 Analyses of the cutoff thicknesses for survival and tumor recurrence. Tumor thickness (mm)
62 >2 63 >3 64 >4 65 >5 66 >6 67 >7 68 >8 69 >9 610 >10
Regional lymph node metastasis YI
Overall survival
Disease-specific survival
Locoregional control
HR
YI
HR
YI
HR
YI
0.06
2.00
0.032
1.87
0.030
1.09
0.009
0.11
2.62
0.086
2.74
0.088
1.44
0.038
0.14
2.99
0.124
3.08
0.125
1.72
0.08
0.21
2.99
0.224
3.04
0.225
1.89
0.162
0.22
3.10
0.253
3.10
0.252
1.83
0.158
0.24
3.29
0.290
3.26
0.288
2.15
0.220
0.21
2.96
0.291
2.88
0.283
2.00
0.210
0.22
2.98
0.295
2.88
0.286
2.04
0.217
0.20
3.15
0.297
3.13
0.290
2.13
0.190
HR, hazard ratio after multivariate analysis; YI, Youdon index after receiver operating characteristic analysis.
Discussion Traditionally, OSCC was thought to be a disease occurring most frequently in the sixth and seventh decades of life and to be rare in the young (<40 years old). Recently, the incidence of OSCC in this population has risen in Western countries, but it is still low.8,9 In Taiwan, OSCC is the most common cancer in the young male population; it may be associated with the age at which young Taiwanese males begin chewing BQ and smoking tobacco: somewhere between 12 and 15 years.10,11 The effect of age on prognosis is still controversial. Age was not a significant predictor for outcome in this study, which may be attributable to similar rates of BQ chewing and tobacco smoking between age groups (data not shown). BQ chewing, tobacco smoking, and alcohol drinking are not only risk habits for oral carcinogenesis3; they also have strong effects on patient morbidity, tumor recurrence, second primary tumor, and
mortality.4,12–14 Although our study showed that alcohol drinking was the only independent risk habit affecting survival, we cannot disregard the high prevalence of tobacco smoking and BQ chewing in our patients; therefore, ceasing all risk habits has become an important part of the treatment of OSCC. The resumption rate of oral risk habits after OSCC treatment is high and is a significant prognostic factor.15 For patients who undergo successful medical treatment, clinicians should not only keep close surveillance on their recovery, but they should also dissuade them from keeping or resuming all of these risk habits. RLNM is a well-known negative prognostic factor for OSCC, and it decreases the survival rate by 50%.16,17 Managing a cN+ patient usually requires multiple treatment modalities and close surveillance; however, there is still controversy over the management of cN0 patients.16,17 Compared with the 20–40% clinical occult metastasis reported in previous studies,18 we found a lower
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Figure 1 Cumulative survival curves for overall survival (A), disease-specific survival (B), and locoregional control (C).
incidence rate in our patients, and all of their metastatic nodes were limited to levels I–III. Our previous results19 also that showed 95.3% of the sentinel lymph nodes were localized in the ipsilateral region at levels I–III. The 6th edition of the American Joint Committee on Cancer (AJCC) staging system suggested that the level of nodal metastasis should be recorded; however, it is still not included in the consideration of stage. As in a previous study,20 our patients with lower, posterior, or both cervical tumor metastases had the worse outcomes. Under our surgical regimens for cN0 patients, there were similar incidences of regional recurrence between patients given a supraomohyoid neck dissection (7.4%) and those given a modified radical neck dissection (9.9%), which agrees with other series.21–23 It is reasonable to support supraomohyoid neck dissection as a primary treatment for cN0 patients for the early detection of occult metastasis and the planning of subsequent adjuvant treatments.24 Except for T4 tumors, the maximal diameter is the only parameter used to classify local tumors. Because tumors can spread in different planes to invade the surrounding structures, diameter alone cannot completely express the overall aggressiveness of a given tumor. Although many studies have reported that tumor thickness rather than maximal diameter may have a greater effect on
the risk of RLNM, locoregional recurrence, and mortality, there is still controversy over the critical cutoff thickness range of 2– 10 mm.25 The significant cutoff thickness of 7 mm for RLNM and mortality in our study was within the 6–10 mm range reported by two other large-scale studies.26,27 Estimating tumor thickness by inspection and palpation is unreliable, and punch biopsy also has limitations for evaluating tumor thickness.28 Ultrasonography and magnetic resonance imaging are useful for preoperatively assessing tumors, and they correlate well with histological assessments.29–31 If imaging studies are not available, a frozen surgical specimen is an alternative measuring method. It is necessary to design a prospective study on the cutoff values for the different assessments. Thereafter, clinicians could have a powerful parameter to predict whether cN0 patients will benefit from elective neck dissection, detection of micrometastasis, and close surveillance. The reported32,33 surgical complication rate in OSCC patients is 50%; the most frequent complication is infection. Surgical complication, an indicator of unfavorable outcome, is defined as a development arising during or after surgery.32 Because the severity of complications is difficult to quantify, some objective assessment scales to predict postoperative morbidities have been proposed32,34; however, they are complicated to use. The length of
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S.-Y. Liu et al. / Oral Oncology 46 (2010) 276–282 Table 4 Multivariate analyses of independent predictors for overall survival and disease-specific survival. Variables
Overall survival HR (95% CI)
Disease-specific Survival P-value
Alcohol drinking No Yes
HR (95% CI)
P-value
Reference 1.31 (1.0–1.7)
0.048
Levels of nodal metastasis No metastasis Ipsilateral level I–III Ipsilateral level I–V Contralateral side
Reference 1.46 (1.0–2.2) 2.96 (1.4–6.2) 2.86 (1.2–7.0)
0.052 0.004 0.021
Reference 1.49 (1.1–2.1) 3.43 (1.7–7.1) 2.62 (1.0–6.8)
0.021 0.001 0.047
Stage I and II III and IV
Reference 2.13 (1.4–3.3)
0.001
Reference 1.76 (1.3–2.5)
0.001
Reference 1.18 (0.9–1.6) 2.14 (1.3–3.6)
0.248 0.005
Reference 48.95 (9.8–243.8) 114.24 (28.2–463.1) 148.80 (36.1–613.5) 195.74 (46.9–817.3) 225.15 (52.6–964.0)
<0.001 <0.001 <0.001 <0.001 <0.001
Differentiation Well Moderately Poorly Tumor thickness 67 mm >7 mm
Reference 1.59 (1.1–2.3)
0.019
Treatment failure No Second primary cancer Localized Regional Locoregional Distant
Reference 1.43 (0.2–10.9) 11.79 (6.7–20.9) 14.74 (7.9–27.6) 19.64 (10.7–37.5) 19.68 (9.6–40.4)
0.733 <0.001 <0.001 <0.001 <0.001
HR, hazard ratio; CI, confidence interval.
hospital stay has been significantly associated with complications.32,35 In our analysis, length of hospital stay also significantly affected survival but was not an independent predictor for survival or recurrence. Compared with the 5-year COS (range, 56–83%) and 5-year CDSS (range, 74–87%) of OSCC patients underwent surgical treatment in the recent studies, our study showed a similar 5-year COS but a lower 5-year CDSS in the BQ-associated OSCC patients.36,37 The main reason may be a higher incidence of treatment failure. According to previously published studies, locoregional recurrence is the most common treatment failure for OSCC patients without BQ chewing, and the outcomes of salvage therapy are poor (range, 15–37%).38–40 The relatively poor 5-year CLRC in our BQassociated OSCC patients could be the major reason for their lower 5-year DSS.41 Although one study suggested a shorter period of followup because the benefits are limited, some studies indicate OSCC patients have a better survival rate if the recurrent tumor can be detected in an early stage and treated by salvage surgery.5,37,42 A close followup protocol is important for the BQ-associated OSCC patients, not only to detect locoregional recurrence, but also to find second primary cancer. The risk of metachronous second primary cancer in the upper aerodigestive tract and lungs has a 20-year cumulative risk of 36%, particularly in patients who continue to smoke tobacco and drink alcohol.43 The 19.9% incidence of synchronous second primary cancer in our patients was higher than in other studies,43,44 which might be due to the high prevalence of risk habits in our patients. Our patients with localized recurrence exhibited a 41% 5-year COS, higher than patients in previous studies.27,36,37,44 Furthermore, the 5-year COS of patients with localized recurrence may be camouflaged by metachronous second primary cancer. The outcomes for patients with localized recurrence may be reasonably estimated after excluding metachronous second primary cancers by using molecular analysis of the tumors and the genetically altered mucosal field in between.45 Although we adopted a close followup protocol, patients with regional failure, including regional
and locoregional recurrence still had a poor 5-year COS, however within 20% to 33% reported in previous studies.46,47 The poor prognoses of patients with regional failure were due to widely disseminated tumors in more than 50% of the patients. In addition to close surveillance, more accurate, noninvasive, and early diagnostic techniques for tumor recurrence are needed. In conclusion, alcohol drinking, lower levels of nodal metastasis, advanced stage, poor cell differentiation, large tumor thickness, and treatment failure were poor prognostic factors for this patient population with high rate of betel quid chewing and tobacco smoking. Due to the prevalence of locoregional recurrence and second primary cancer, aggressive surgical excision and close surveillance may be the optimal policy for BQ-associated OSCC. Conflicts of interest statement None declared. Acknowledgements This work was supported in part by Chi-Mei Medical Center (CMFHR9358) and National Science Council, Taiwan (NSC 972314-B-384-003-MY3). References 1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Betelquid and areca-nut chewing and some areca-nutderived nitrosamines. IARC Monogr Eval Carcinog Risks Hum 2004;85(1):11-18. 2. Yang YH, Chen HR, Tseng CH, et al. Prevalence rates of areca/betel quid chewing in counties of Taiwan. Taiwan J Oral Med Health Sci 2002;18(1):1–16. 3. Shiu MN, Chen TH. Impact of betel quid, tobacco and alcohol on three-stage disease natural history of oral leukoplakia and cancer: implication for prevention of oral cancer. Eur J Cancer Prev 2004;13(1):39–45. 4. Lee JJ, Jeng JH, Wang HM, Chang HH, Chiang CP, Kuo YS, et al. Univariate and multivariate analysis of prognostic significance of betel quid chewing in squamous cell carcinoma of buccal mucosa in Taiwan. J Surg Oncol 2005;91(1):41–7.
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