Important prognostic factors of long-term oropharyngeal carcinoma survivors in Taiwan

Oral Oncology (2004) 40 847–855

http://intl.elsevierhealth.com/journals/oron/

Important prognostic factors of long-term oropharyngeal carcinoma survivors in Taiwan Ping-Ho Chena, Ying-Chin Kob,c, Yi-Hsin Yangd, Ying-Chu Lina, Tien-Yu Shiehd, Chung-Ho Chena, Chi-Cheng Tsaia,* a

Graduate Institute of Dental Sciences, Kaohsiung Medical University, No. 100 Shin-Chuan 1st Road, Kaohsiung 807, Taiwan, ROC b National Health Research Institutes, Taiwan, ROC c Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC d Graduate Institute of Oral Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC Received 12 March 2004; accepted 17 March 2004

Available online KEYWORDS

Summary In Taiwan, a clear gender difference emerges for rates of oropharyngeal carcinoma incidence. The purpose of this study was to identify the gender differences and clinical factors associated with oropharyngeal carcinoma survival rates in Taiwan. We analyzed the 5-year survival rates of 8114 subjects diagnosed with oropharyngeal carcinoma between 1987 and 1994. The Cox proportionalhazards model identified clinical characteristics for gender according to oropharyngeal carcinoma death and all-cause death outcomes. The 5-year survival rates were significantly lower for males than females (p < 0:0001). The adjusted hazard ratio of males versus females was 1.54 (95% CI: 1.36–1.74) for oropharyngeal carcinoma death and 1.44 (95% CI: 1.31–1.58) for all-cause death. Gender and other clinical characteristics (i.e. diagnostic age, anatomic site, morphologic type, and treatment modality) play important roles in oropharyngeal carcinoma survival. We suggested that Taiwanese males have high proportion of betel quid chewing and that this is associated with the gender differences. c 2004 Elsevier Ltd. All rights reserved.

Oropharyngeal carcinoma; Gender; Survival; Cox proportionalhazards model; Hazard ratio; Betel quid chewing




Introduction Abbreviations: ASRW, age-standardized incidence rate adjusted by world population; ICD-O, international classification of disease for oncology; SCC, squamous cell carcinoma; NOS, not otherwise specified; RT, radiation therapy; CT, chemotherapy; ST, supportive care therapy * Corresponding author. Tel.: +886-7-312-1101x2154; fax: +886-7-321-0637. E-mail addresses: [email protected], hereditary@ seed.net.tw (C.-C. Tsai).




Oropharyngeal carcinoma is one of the most common carcinomas in the world, and its occurrence shows a number of geographic and demographic variations. The age-standardized incidence rate adjusted by world population (ASRW) for oropharyngeal carcinoma in the United States in 2000 was 9.32 per 100,000 males and 4.35 per 100,000

1368-8375/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2004.03.006

848 females, and the ASRW of oropharyngeal carcinoma in eastern Asia (Taiwan not included) for the same year was 2.31 per 100,000 for males and 1.13 per 100,000 for females.1 In Taiwan, the male-tofemale ratio of ASRW increased from 3:1 between 1979 and 1983 to 8:1 between 1994 and 1996.2 In 1999, the ASRW for this disease in males rose to 25.31 per 100,000, making it the fourth most prevalent carcinoma among males in Taiwan.3 Therapy usually includes a combination of surgery, radiation therapy, and conventional chemotherapy.4–8 However, 5-year survival rates of patients with oropharyngeal carcinoma are only around 50%.5;9;10 In 1998, the mortality rate of males with oropharyngeal carcinoma was 8.93 per 100,000 and 0.75 per 100,000 for females (M:F ¼ 12:1).11 Despite the wide differences found between the males and females, gender has not been analyzed in Taiwan as a predictor of survival rates of oropharyngeal carcinoma. Many factors influence survival from oropharyngeal carcinoma, including gender, diagnostic age, anatomic site, morphologic type, and treatment modality.4–6;8 Therefore, our aim was to examine survival rates for oropharyngeal carcinoma in accordance with clinical characteristics of Taiwanese subjects.

Subjects and methods Study data Hospital-based cancer registry data were obtained from the Taiwan Cancer Registry Annual Report established by the National Health Department in 1979. Data were collected from diagnoses of oropharyngeal carcinoma reported to the Health Department between 1987 and 1994 (N ¼ 8850). Survival days were determined by active follow-up based on verification of vital status for subjects until December 31, 2000. We excluded patients with uncertain identification numbers (n ¼ 2), birth dates (n ¼ 5), resident areas (n ¼ 65), survival days (n ¼ 26), and those diagnosed with no histopathological confirmation (n ¼ 638). Thus, 8114 eligible subjects were included for analysis in the study.

Descriptive variable characteristics The collected data included the following: gender, resident area, diagnostic age, anatomic site, morphologic type, course of treatment, date of death, and cause of death. Subjects were grouped into three communities according to their area of

P.-H. Chen et al. residence: aborigine, Hakka, or Fukkien.12 Oropharyngeal carcinoma data were coded according to the first edition of the International Classification of Disease for Oncology (ICD-O) on topographic site. These anatomic sites included malignant carcinoma of the lip (T140), tongue (T141), gum (T143), floor of the mouth (T144), other unspecified parts of the mouth (T145), oropharynx (T146), hypopharynx (T148), and other sites (T149). Morphologic types were broadly grouped into general histological categories according to the ICD-O coding system. These categories were carcinoma not otherwise specified (NOS) (M8010, M8012–8022), verrucous carcinoma (M8051), squamous cell carcinoma (SCC: M8052–8082), adenocarcinoma (M8140–8580), lymphoma (M9590–9723), and other carcinoma. The treatment modalities were as follows: surgery alone, radiation therapy (RT) alone, chemotherapy (CT) alone, surgery + RT, surgery + CT, RT + CT, surgery + RT + CT, supportive care therapy (ST) alone, other complex therapy (including hormonal or traditional Chinese herbal medicine therapy), and unknown therapy.

Statistical analysis After finding no significant differences in survival rates between the three groups, we combined gum, mouth floor, and other unspecified parts of the mouth sites into the mouth group (T143–145). Oropharyngeal carcinoma death and all-cause death were treated as two different outcomes for the purposes of the study. For oropharyngeal carcinoma survival analysis, deaths with codes T140–149 (except for T142 and T147) were classified as deaths due to oropharyngeal carcinoma, and subjects who died of other causes or were still alive were considered censored observations. Preliminary frequency distributions according to clinical characteristics for each gender were compared by v2 test. Survival days after diagnosis were estimated by Kaplan-Meier methods; 5-year survival rates are presented. Survival curves differed significantly for each outcome of clinical factors by gender with log-rank test. After log–log survival plots were used to verify the proportion hazard assumptions for each predictor; the Cox proportional-hazards model was applied to estimate their contributions. Adjusted multiple variables of diagnostic age, resident area, anatomic site, morphologic type, and therapeutic choice were used to assess the hazard ratio of relationship for oropharyngeal carcinoma death and all-cause death. SAS version 8.2 statistical software was used for all analysis (SAS Institute, Inc., Cary, NC, USA).

Prognostic factors of oropharyngeal carcinoma survivors

Results Distribution of clinical characteristics A total of 8114 subjects (88% males and 12% females) were included in the survival analysis. Ninety-one percent of all subjects were Fukkien community, 6% were Hakka community, and only 3% were aboriginal community. The mean age of oropharyngeal carcinoma subjects was 54 years. The highest proportion was found in the 50–59-year age group (28%). The proportion of 40–49-year age group was 24% and the 60–69-year age group was 22%. Thirteen percent of diagnosed subjects were age 6 39 years, and 13% were age P 70 years. The most common site of oropharyngeal carcinoma was the mouth (43%), and the followings were tongue (28%), hypopharynx (15%), oropharynx (10%), lip (3%), and other sites (1%). Distributions of morphologic types were as follows: 83% subjects were proven SCC; the remainders were verrucous carcinoma (5%), adenocarcinoma (3%), lymphoma (3%), other carcinoma (3%), and carcinoma–NOS (2%). Primary treatments were surgery alone (27%), followed by unknown therapy (18%), surgery + RT (10%), CT alone (10%), RT alone (8%), surgery + CT (7%), RT + CT (6%), other complex therapy (5%), surgery + RT + CT (5%), and ST alone (4%).

Relationship of clinical factors by gender Table 1 shows that the number of diagnosed males was predominantly higher than diagnosed females in the 40–49-year age group. Regarding area of residence, the number of diagnosed females was higher in aboriginal and Hakka communities, but lower in the Fukkien community. By anatomic sites, tongue and oropharynx carcinoma were more common among females than males. Males also had a higher percentage of mouth and hypopharynx carcinoma than females. Males with SCC had significantly higher percentage than females. It is noteworthy that females had more adenocarcinoma and lymphoma than males. Gender differences in received treatment modality were also noted. Females tended to accept surgery alone more frequently than males.

Five-year survival rates and hazard ratio of gender for oropharyngeal carcinoma death and all-cause death During the follow-up study period, a total of 3447 (42%) subjects died from oropharyngeal carcinoma. The average rate for all-causes of death

849

during the study period was 69% (3447 + 2120 ¼ 5567 subjects died). The observational 5-year specific rate of survival for oropharyngeal carcinoma was 55.6% (53.3% for males, 71.1% for females). Overall, the 5-year survival rate for allcause of death was 39.3% (37.3% for males and 53.6% for females). Males had a significantly lower survival curve (p < 0:0001) than females (Fig. 1). The hazard ratio, adjusted for diagnostic ages, residence areas, anatomic sites morphological types, and treatment modalities, are shown in Table 2. For oropharyngeal carcinoma death, the crude hazard ratio of males was 1.85 (95% CI, 1.64–2.09). After adjusting all clinical variables, males had significantly higher risks of death than females (HR ¼ 1.54; 95% CI, 1.36–1.74). In all-cause death, the adjusted hazard ratios of males also had significantly poorer (HR ¼ 1.26; 95% CI, 1.14–1.39) prognosis than females.

Five-year survival rates of oropharyngeal carcinoma death for each gender Table 3 represents the survival rate of diagnosed subjects for each age group. Except for the age group P 70 years, males had a lower survival rate than females (p < 0:0001). In Hakka and Fukkien communities, males had significantly lower survival rates than females. Based on lip, tongue, mouth, and oropharynx locations, statistical differences were noted between genders. Males exhibited significantly lower survival rates than females. The SCC and Carcinoma, NOS of males presented significantly lower survival rates than females. Statistical survival estimates for treatment modalities also revealed gender differences. Except for modalities of surgery + RT + CT and ST alone, survival rates were significantly higher for females than for males.

Five-year survival rates of all-cause death for each gender Table 3 indicates that the 5-year survival estimates for females were higher than males in all diagnostic age groups except for the age group of subjects 70 years or older (p < 0:0001). Regarding area of residence, only females from the Fukkien community had higher survival rates than males (p < 0:0001). Comparing anatomic sites (including lip, tongue, mouth, and oropharynx), the results showed that males had a significantly lower survival rate. Males with SCC and adenocarcinoma had a significantly lower survival rate than females with SCC and adenocarcinoma. Except for

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P.-H. Chen et al.

Table 1 Characteristics of oropharyngeal carcinoma subjects at time of diagnosis by gender in 1987–1994 Males (N ¼ 7115) N (%)a

Females (N ¼ 999) N (%)a

Diagnostic age (years) 6 39 40–49 50–59 60–69 P 70

880 1779 2016 1564 876

179 140 221 257 202

Resident area Aboriginal community Hakka community Fukkien community

Characteristics

(12) (25) (28) (22) (12)

p-Value

(18) (14) (22) (26) (20)

\0.0001

205 (3) 422 (6) 6488 (91)

61 (6) 82 (8) 856 (86)

\0.0001

Anatomic site Lip Tongue Mouth Oropharynx Hypopharynx Other

236 (3) 1913 (27) 3096 (44) 645 (9) 1168 (16) 57 (1)

47 (5) 351 (35) 387 (39) 140 (14) 52 (5) 22 (2)

\0.0001

Morphologic type SCC Verrucous carcinoma Adenocarcinoma Carcinoma, NOS Lymphoma Other carcinoma

6111 (86) 350 (5) 146 (2) 132 (2) 180 (3) 196 (3)

647 (65) 25 (3) 132 (13) 35 (4) 93 (9) 67 (7)

\0.0001

Treatment modality Surgery alone RT alone CT alone Surgery + RT Surgery + CT RT + CT Surgery + RT + CT ST alone Other complex therapy Unknown therapy

1861 (26) 543 (8) 751 (11) 723 (10) 519 (7) 433 (6) 358 (5) 257 (4) 362 (5) 1308 (18)

306 (31) 80 (8) 77 (8) 109 (11) 78 (8) 58 (6) 33 (3) 40 (4) 34 (3) 184 (18)

0.0025

SCC: squamous cell carcinoma; NOS: not otherwise specified; RT: radiation therapy; CT: chemotherapy; ST: supportive care therapy. a May not total 100% due to rounding.

surgery + RT + CT and ST alone, males had a significantly lower survival rate for treatment modalities than females.

Contribution of clinical characteristics for oropharyngeal carcinoma death Table 4 summarizes the adjusted multivariate hazard ratios of clinical characteristics for oropharyngeal carcinoma death for both genders. Males aged 40–49 years were at significantly higher risk of death than those aged 39 years or younger.

The increased risk of death was significant for males and females aged 70 years or older. Regarding area of residence, no significant differences in gender were found. The results showed that anatomic sites were significant predictors of survival for both genders. Tongue (HR ¼ 1.21; 95% CI, 1.04–1.41) and mouth (HR ¼ 1.16; 95% CI, 1.01–1.34) carcinomas of males were at an increased risk of death compared to oropharynx carcinomas. Among males, risk of death for lip carcinomas was significantly lower than for oropharynx carcinomas (HR ¼ 0.76; 95% CI, 0.59–0.99). Among females, risk of death for lip

Prognostic factors of oropharyngeal carcinoma survivors 1.0 Oropharyngeal carcinoma survival 0.9

Survival Distribution Function

0.8

Females

0.7 0.6 0.5 0.4 0.3

Males

0.2

Survival distribution

0.1 0.0 0

500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500

LIFE (days) 1.0 All-cause survival

0.9

Survival Distribution Function

0.8 0.7 0.6

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carcinomas was lower than for oropharynx carcinomas, but not statistically significant (HR ¼ 0.36; 95% CI, 0.12–1.09). Compared with oropharynx, tongue and mouth carcinomas among females were at significantly higher risk of death (HR ¼ 2.10, 1.81, respectively). The morphologic types of oropharyngeal carcinoma death showed that males with lymphoma, verrucous carcinoma, adenocarcinoma, and other carcinoma (HR ¼ 0.05, 0.43, 0.43, 0.60, respectively) were at lower risks of death than SCC. The risk of death for females was significantly lower for lymphoma (HR ¼ 0.03) and adenocarcinoma (HR ¼ 0.49) than for SCC. The data showed a significant improvement of prognosis for males treated by surgery alone (HR ¼ 0.37; 95% CI, 0.33–0.43) rather than CT alone. Surgery + CT and surgery + RT also showed similar results (HR ¼ 0.54, 0.66, respectively). However, RT + CT had a significant deleterious effect (HR ¼ 1.30; 95% CI, 1.11–1.53) on males. For females, the hazard ratio of surgery alone, surgery + RT, surgery + CT, and unknown therapy also showed significantly improved prognoses compared to CT alone.

Contribution of clinical characteristics for all-cause death

Females 0.5 0.4 0.3 0.2 Males

0.1 0.0 0

500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500

LIFE (days)

Figure 1 Survival days for gender according to oropharyngeal carcinoma death (N ¼ 3447) and all-cause death (N ¼ 5567) were the endpoints (p < 0:0001).

For both genders, apparent risk trends increased for all-cause death were correlated with increasing diagnostic age (Table 4). Regarding residence area, no disparity between males and females was noted. Males and females with lip carcinoma had significantly better prognoses. Tongue and mouth carcinoma showed a reduced risk of death among males, but an increased risk of death was found among females. The influence of morphologic types (adenocarcinoma and lymphoma) on deaths was significant for both genders. Subjects were treated by surgery alone, surgery + RT, and surgery + CT

Table 2 Crude and adjusted hazard ratio for males versus females according to oropharyngeal carcinoma death and all-cause death

Crude hazard ratios Adjusted hazard ratios Adjusted for diagnostic age, residence area Above plus anatomic site Above plus morphological type Above plus treatment modality HR: hazard ratio; CI ¼ confidence interval. a Male-to-female ratio. * Statistical significance (p < 0:0001).

Oropharyngeal carcinoma death (N ¼ 3447) M:Fa HR (95% CI)

All-cause death (N ¼ 5567) M:Fa HR (95% CI)

1.85 (1.64–2.09)

1.58 (1.44–1.72)

1.83 1.80 1.56 1.54

(1.62–2.06) (1.60–2.04) (1.38–1.77) (1.36–1.74)

1.60 1.55 1.45 1.44

(1.46–1.75) (1.41–1.69) (1.32–1.58) (1.31–1.58)

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Table 3 Five-year survival rates of oropharyngeal carcinoma death and all-cause death by gender Characteristics

Oropharyngeal carcinoma death (%) (N ¼ 3447)

All-cause death (%) (N ¼ 5567)

p-Valuea

Males

Females

80.9 75.6 73.4 71.2 54.0

\0.0001 \0.0001 \0.0001 \0.0001 0.3289

46.7 38.2 38.3 35.8 26.5

67.0 59.3 58.8 55.6 29.2

\0.0001 \0.0001 \0.0001 \0.0001 0.2168

58.9 58.3 52.9

60.0 74.9 71.5

0.4673 0.0031 \0.0001

40.0 40.5 37.0

42.6 48.8 54.8

0.1776 0.0568 \0.0001

Anatomic site Lip Tongue Mouth Oropharynx Hypopharynx Other

71.4 50.0 53.1 57.6 53.7 71.0

93.4 63.4 70.9 87.2 60.1 74.6

0.0003 \0.0001 \0.0001 \0.0001 0.2417 0.6545

58.5 39.9 40.3 30.4 24.9 33.3

87.2 53.3 52.7 56.4 30.8 36.4

0.0011 \0.0001 \0.0001 \0.0001 0.1242 0.5866

Morphological type SCC Verrucous carcinoma Adenocarcinoma Carcinoma, NOS Lymphoma Other carcinoma

49.3 81.2 81.5 58.8 96.3 67.9

62.8 74.7 87.7 79.5 98.8 78.8

\0.0001 0.8263 0.1234 0.0298 0.2330 0.0606

34.5 71.4 58.2 35.6 47.2 41.3

49.5 68.0 72.0 48.6 51.6 56.7

\0.0001 0.7227 0.0271 0.0609 0.1521 0.0603

Treatment modality Surgery alone RT alone CT alone Surgery + RT Surgery + CT RT + CT Surgery + RT + CT ST alone Other complex therapy Unknown therapy

73.0 41.1 44.2 52.8 61.6 32.1 34.9 41.1 40.7 46.5

84.1 65.3 61.5 69.6 77.8 48.1 51.6 55.7 60.2 68.3

\0.0001 0.0013 0.0203 0.0012 0.0026 0.0074 0.0535 0.1155 0.0371 \0.0001

60.4 21.7 27.6 37.5 46.4 20.3 24.3 23.7 25.7 27.9

70.3 38.8 37.7 60.6 61.5 32.8 39.4 37.5 47.1 45.1

\0.0001 0.0009 0.0398 \0.0001 0.0015 0.0244 0.0701 0.0544 0.0040 \0.0001

All subjects

53.3

71.1

\0.0001

37.3

53.6

\0.0001

Males

Females

Diagnostic age (years) 6 39 40–49 50–59 60–69 P 70

57.1 50.5 52.9 55.4 52.7

Residence area Aboriginal community Hakka community Fukkien community

p-Valuea

SCC: squamous cell carcinoma; NOS: not otherwise specified; RT: radiation therapy; CT: chemotherapy; ST: supportive care therapy. a Log-rank test.

significantly reduced the risk of death for both males and females. Conversely, only males treated by RT + CT showed significant higher risks than those treated by CT alone.

Discussion Observational 5-year oropharyngeal carcinoma specific survival rate was 55.6%, and all-cause

specific survival rate was 39.3% in the present study. Several previous studies have reported the 5-year survival rates for oropharyngeal carcinoma subjects as 50%,5;6;9;10 whereas others have reported lower rates ranged from 30% to 36%.4;8 Previous investigations have also indicated that male survival rates for oropharyngeal carcinoma are lower.6;9;10 However, reports in other countries showed better survival rates for males or displayed similar survival rates for both males and

Prognostic factors of oropharyngeal carcinoma survivors

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Table 4 Multivariate proportional-hazard ratio for oropharyngeal carcinoma death and all-cause death by gender Oropharyngeal carcinoma death (N ¼ 3447)

All-cause death (N ¼ 5567)

Males HR (95% CI)

Females HR (95% CI)

Males HR (95% CI)

Females HR (95% CI)

Diagnostic age (years) 6 39 40–49 50–59 60–69 P 70

1.00 1.14 1.04 1.06 1.20

1.00 1.05 1.37 1.46 2.55

1.00 1.22 1.18 1.34 1.71

1.00 1.31 1.53 1.66 3.40

Resident area Fukkien community Aboriginal community Hakka community

1.00 – 0.84 (0.68–1.05) 0.92 (0.79–1.08)

1.00 – 0.96 (0.61–1.52) 0.68 (0.42–1.11)

1.00 – 0.88 (0.74–1.04) 0.96 (0.85–1.08)

1.00 – 1.03 (0.73–1.46) 1.01 (0.74–1.37)

Anatomic site Oropharynx Lip Tongue Mouth Hypopharynx Other

1.00 0.76 1.21 1.16 0.91 0.62

– (0.59–0.99) (1.04–1.41) (1.01–1.34) (0.77–1.07) (0.35–1.12)

1.00 0.36 2.10 1.81 1.51 1.14

– (0.12–1.09) (1.23–3.58) (1.05–3.10) (0.74–3.05) (0.37–3.49)

1.00 0.63 0.88 0.90 1.04 0.97

– (0.51–0.77) (0.78–0.98) (0.81–1.00) (0.93–1.17) (0.70–1.35)

1.00 0.45 1.23 1.33 1.48 1.61

– (0.25–0.82) (0.89–1.71) (0.97–1.83) (0.96–2.30) (0.88–2.93)

Morphologic type SCC Verrusous carcinoma Adenocarcinoma Carcinoma, NOS Lymphoma Other carcinoma

1.00 0.43 0.43 0.76 0.05 0.60

– (0.35–0.53) (0.30–0.60) (0.58–1.00) (0.02–0.12) (0.46–0.77)

1.00 0.76 0.49 0.59 0.03 0.84

– (0.35–1.63) (0.31–0.77) (0.26–1.35) (0.00–0.18) (0.48–1.47)

1.00 0.50 0.61 0.89 0.54 0.81

– (0.42–0.59) (0.48–0.76) (0.73–1.09) (0.44–0.66) (0.68–0.97)

1.00 0.58 0.66 0.90 0.68 1.16

– (0.31–1.10) (0.48–0.90) (0.56–1.47) (0.47–0.98) (0.81–1.66)

Treatment modality CT alone Surgery alone RT alone Surgery + RT Surgery + CT RT + CT Surgery + RT+CT ST alone Other complex therapy Unknown therapy

1.00 0.37 0.99 0.66 0.54 1.30 1.00 1.13 0.93 0.88

– (0.33–0.43) (0.84–1.16) (0.57–0.76) (0.45–0.64) (1.11–1.53) (0.84–1.18) (0.92–1.39) (0.78–1.10) (0.78–1.00)

1.00 0.24 0.62 0.48 0.31 1.01 0.89 0.63 0.66 0.59

– (0.15–0.39) (0.36–1.07) (0.29–0.80) (0.17–0.57) (0.58–1.76) (0.47–1.68) (0.33–1.18) (0.34–1.28) (0.37–0.94)

1.00 0.43 1.00 0.65 0.60 1.15 0.92 1.12 0.91 0.98

– (0.39–0.48) (0.89–1.14) (0.58–0.73) (0.53–0.69) (1.01–1.32) (0.80–1.06) (0.96–1.32) (0.79–1.05) (0.88–1.08)

1.00 0.46 0.93 0.59 0.51 1.19 1.11 0.76 0.67 0.90

– (0.33–0.66) (0.63–1.37) (0.40–0.89) (0.32–0.80) (0.79–1.79) (0.67–1.84) (0.47–1.25) (0.39–1.16) (0.63–1.27)

Characteristics

– (1.01–1.28) (0.92–1.17) (0.93–1.20) (1.04–1.40)

– (0.65–1.70) (0.90–2.10) (0.96–2.22) (1.66–3.92)

– (1.10–1.35) (1.06–1.31) (1.20–1.48) (1.52–1.92)

– (0.92–1.87) (1.11–2.11) (1.22–2.26) (2.49–4.63)

SCC: squamous cell carcinoma; NOS: not otherwise specified; RT: radiation therapy; CT: chemotherapy; ST: supportive care therapy; HR: hazard ratio; CI: confidence interval. * Statistical significance (p < 0:05).

females.5;8;13;14 In our study, the 5-year survival rates for females were significantly higher than for males. After adjustment for clinical factors, males had a risk 1.54 and 1.44 times higher than females for oropharyngeal carcinoma death and all-cause death, respectively. However, the effect of gender on survival rates for oropharyngeal carcinoma remains unclear. In Taiwan, carcinoma researches have demonstrated that betel quid chewing might be the most important risk factor for oropharyngeal carcinoma and

the development of oral precancerous diseases.15–17 According to earlier retrospective data obtained at hospitals in southern Taiwan, withdrawing from betel quid chewing can improve survival of oropharyngeal carcinoma patients.4 In both genders, the pattern of drinking and smoking is similar, but use of betel quid has been much more common among males than among females.2;18 Because betel quid chewing can cause bad breath and unsightly red stains on the lip, females are less likely to use betel quid. A

854 predominant male-to-female ratio (21:1) of chewing prevalence between males (28.4%) and females (1.4%) among Kaohsiung residents was demonstrated in Taiwan.19 This could be partially explained our observed gender disparities in survival rates. In morphologic types, we found males were more likely to have SCC (86%) than females (65%), and it was often more aggressive than other carcinomas. Some reports have suggested that most cases of oral SCC are related to betel quid chewing habits.4;20 The greater prevalence of oral SCC is likely due to widespread betel quid chewing habits among males, which might partially explain the poor prognosis for males with oropharyngeal carcinoma in Taiwan. Thus, betel quid chewing habits are a very important gender difference in the probability of contracting and surviving oropharyngeal carcinoma. As for diagnostic age, some reports indicate that older age groups are at increased risk of death,5;9;14;21;22 but others indicate that younger subjects have a greater risk of death.23–25 When considering the all-cause death subjects, upward risk trends are associated with increasing age in both genders. However, when focusing on oropharyngeal carcinoma death, we found that increasing age is a significant risk factor for males and females older than 69 years. This might be due to poor tolerance of treatment, more likely to have advanced stages and belief that older subjects have poor health conditions.26 However, it is unclear why male subjects aged between 40 and 49 years are treated significantly more aggressively than females in oropharyngeal carcinoma death. In previous reports from Taiwan, the peak age of oral carcinoma occurrence has declined to 40–49 years and the age of occurrence among subjects who chewed betel quid was on 10 years younger than subjects without betel quid chewing.4 The presented study also showed that 5-year survival rates of 40–49-year age group were lowest than other groups (Table 3). These consequences might explain the higher risk of oropharyngeal death for males aged 40–49 years. In our study, the most common site of oropharyngeal carcinoma was mouth carcinomas. The higher proportion of mouth site is compatible with other countries where betel quid chewing is popular, such as India, and Papua New Guinea.27;28 The analysis of carcinoma sites revealed that, except for hypopharynx and other sites, males consistently had lower survival rates than females. For oropharyngeal carcinoma death outcome, males and females had higher risk of death for tongue and mouth carcinomas than for oropharynx carcinomas. A 15-year survival follow-up study conducted in

P.-H. Chen et al. Brazil revealed that females with mouth carcinoma (T143–145) had a 29% lower risk of death than males with mouth carcinoma, after adjusting for clinical factors.6 Previous researches have indicated that tongue carcinoma is often more aggressive than carcinoma of other sites.6;8;22 Our study showed that only males with lip carcinomas had significant lower risk of death as compared with oropharynx carcinomas. Lip carcinomas among females presented better prognosis, though not statistical significance. A number of articles have been suggested that lip carcinomas have higher survival rates.6;7;22;26;29;30 The higher survival rates for lip sites might be explained by the readily visible lesions, which can be identified and treated at an earlier stage than carcinoma of other sites. Our data indicated that adenocarcinoma and lymphoma in both genders had significant improvement in prognosis. The verrucous carcinoma had better prognosis only in males. Most clinicians consider adenocarcinoma and lymphoma to have superior long-term prognosis than SCC; other reports have also showed higher 5-year survival rates for patients with adenocarcinoma, verrucous carcinoma, and lymphoma.7–9 In the present study, surgical resection and/or chemotherapy/ radiotherapy were the main treatments for oropharyngeal carcinoma. For both death outcomes, we found a positive improved effect of surgical therapy alone for both males and females. Both genders treated with surgery + RT or surgery + CT consistently showed significant improvement. Only males treated with RT + CT had increased risk of death. Subjects who opted for early surgical intervention would have a survival advantage.4;5;8;30 Leite et al. reported that subjects treated with surgery had the highest survival rate, followed by surgery plus radiotherapy, but subjects treated with chemotherapy or radiotherapy had the worst prognosis.8 Other authors have also indicated that patients treated with radiotherapy alone had a higher risk of death than those receiving surgical treatment alone.5;30 Selected treatment modalities were primary according to carcinoma extension, but also might be decided by clinical indices (i.e. tumor size, clinical stage, distant metastasis, histological differentiation, and lymph-node involvement). Therefore, subjects who accepted surgery alone were often at an earlier clinical stage. Treatment with CT alone or RT alone might indicate that they were diagnosed in advanced stages of the disease. However, the improvements in surgery alone might have been due to differences in disease stage, rather than differences in effectiveness of treatment methods.

Prognostic factors of oropharyngeal carcinoma survivors In conclusion, our survival analysis found that gender was an important factor for oropharyngeal carcinoma death and all-cause death. The betel quid chewing is known as an important risk factor for oropharyngeal carcinoma and dramatically decreases survival rates in males with oropharyngeal carcinoma. We suggested that abstinence from betel quid chewing might enhance oropharyngeal carcinoma survival for males in Taiwan.

Acknowledgements Supported by grants NHRI-EX91-8803PL from the National Health Research Institutes and Department of Health, Taiwan, ROC.

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