Abstract
Background.
Head and neck cancer (HNC) is a major cause of cancer morbidity and mortality in Nepal. The study aims to investigate differences in risk factors for head and neck cancer by sex in Nepal.
Methods.
A hospital-based case-control study was conducted at the B.P. Koirala Memorial Cancer Hospital in Nepal from 2016–2018. A semi-structured questionnaire consisting of socio-demographic characteristics, dietary habits, reproductive factors, household air pollution, tobacco use (smoking and chewing), alcohol consumption, and second-hand smoking was used to collect the data. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders.
Results.
A total of 549 HNC cases (438 men and 111 women) and 601 age-matched healthy controls (479 men and 122 women) were recruited in this study. An increased risk of HNC for low education level and family income were observed among men (adjusted odds ratio (AOR) for 3rd grade and less=1.58, 95% CI=1.14–2.18; AOR for family monthly income <5000 Rupees =1.64, 95% CI 1.20–2.24). The AORs among women were higher than the men for known risk factors (AOR for smoking 1.34 (95% CI 0.96–1.86) for men, 2.94 (95% CI 1.31–6.69) for women; AOR for tobacco chewing 1.76 (95% CI 1.27–2.46) for men, 10.22 (95% CI 4.53–23.03) for women).
Conclusion.
Our results point to an effect modification by sex for HNC risk factors with high AORs observed among women.
Keywords: head and neck cancer, Nepal, tobacco smoking, chewing, alcohol drinking
Introduction
Head and neck cancer (HNC) is one of the most common cancers worldwide and is still a major public health burden in developing countries. Approximately 750,000 HNC cases and 365,000 HNC-related deaths are reported annually worldwide [1]. Most recent data (2020) from Nepal suggests HNC is a leading contributor to cancer morbidity (2,327 new cases, ranking second) and mortality (1,070 deaths, ranking fourth) [2]. Previous epidemiological studies have documented significant sex differences in cancer incidence and mortality [3–5], and have suggested that the consistently higher risk observed among men is likely due to high exposure to well-established risk factors, such as tobacco and alcohol.
A distinct male predominance in the incidence rate is also observed in HNC [6]. Previous studies reported that the associations between modifiable lifestyle factors and HNC risk varied by sex [7,8]. Tobacco and alcohol consumption are major risk factors for oral cancer, which has been well-established previously. A prospective study conducted in the United States (US) including 584 men and 175 women who developed HNC reported that the hazard ratios (HR) associated with smoking were significantly larger in women (12.96; 95% confidence interval [CI], 7.81–21.52) than in men (5.45, 95% CI, 4.22–7.05, p for interaction: <0.001) [9]. Similarly, in another prospective study in the US including 611 men and 183 women who developed HNC, the HR for consuming >3 drinks per day was significantly higher in women (2.52, 95% CI, 1.46–4.35) than in men (1.48, 95% 1.15–1.90, p for interaction: 0.0036) [10]. A meta-analysis including 40 studies has reported that secondhand smoking is a significant predictor for overall cancer in women (OR 1.25, 95% CI 1.14–1.37) and not in men (OR 1.59, 95% CI 0.91–2.77) [11]. Estrogen exposure may be protective against HNC, with some studies suggesting that the higher risks of HNC among women may be due to estrogen deficiency, menopause, or hysterectomy status [12,13].
There is a paucity of data assessing the difference in risk factors among men and women in Nepal, which has hindered the development of targeted cancer prevention campaigns among Nepalese women. Given the differences in physiology and lifestyles of both sexes [14], it would be valuable to separately identify the risk factors for HNC in men and women. Therefore, in this large-scale case-control study, we aimed to investigate risk factors of HNC, stratified by sex.
Methods
We conducted a hospital-based case-control study at the B.P. Koirala Memorial Cancer Hospital (BPKMCH), located in the Chitwan district of central Nepal, from April 2016 to July 2018. BPKMCH is a tertiary cancer care treatment facility and a public national cancer hospital with a capacity of 450 beds. There is no universal health insurance system in Nepal. Most of patients pay their health care costs out of pocket. The government of Nepal provides up to 100,000 Nepalese Rupees (about 756 USD) to every cancer patient for cancer treatment. Details on the study design have been previously described [15]. In brief, this study included HNC cases who were 18 years of age or older and residents of Nepal for at least 5 years. The cases were recruited within three months after the initial cancer diagnosis of oral cavity, oropharynx, hypopharynx, and larynx. Cancers of the salivary gland (including parotid glands), nasopharynx, and thyroid were not included in this study. Hospital-based controls were selected and matched by age (±5 years), sex, race/ethnicity, and residential area. The inclusion criteria for the controls were (1) cancer-free, (2) older than 18 years of age, and (3) hospital visitors (excluding cases’ relatives) or patients for regular screening.
Using a structured questionnaire, trained staff members conducted face-to-face interviews to collect information on socio-demographic characteristics, medical history, residential history, reproductive factors, dietary history, household air pollution, and a detailed history of tobacco smoking, chewing habits, and alcohol consumption. Household air pollution was measured by the “level of smokiness in house from cooking” in the questionnaire. A high level of household air pollution was defined as “much smokiness caused by cooking and enough to irritate eyes”. The medium level was defined as “much smokiness caused by cooking although not enough to irritate eyes”, and the low level was defined as “some smokiness caused by cooking “, “None, cooking done indoors but little smoke “, and “None, outdoor cooking”. Birth control for women was measured by the question “Have you ever used any kind of birth control during your life?”. The study was approved by the Nepal Health Research Council and the Institutional Review Boards at the University of Utah. Written informed consent was obtained from the participant prior interview.
Statistical analysis
Data analysis was performed using SAS, version 9.4 (SAS Institute, Cary, NC). Chi-square tests were used to compare the distribution of demographic characteristics between cases and controls. Unconditional logistic regression was used to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). Age, education, residence, income, ethnicity/race, smoking, chewing tobacco, and alcohol were included in the logistic regression models. P values for the joint effects were estimated between exposures of interest and sex on the risk of HNC. We performed sensitivity analyses by adding secondhand smoking (yes/no), dietary factors (frequency per week of red meat, fish, and vegetable consumption, continuous), and household air pollution (high/medium/low) as additional confounders in the models above. Potential confounding factors were chosen a priori based on the three properties of confounders determined by causal diagrams [16]. A p-value of less than 0.05 was considered statistically significant.
Results
A total of 549 HNC cases (N of men=438, N of women=111) and 601 age-matched healthy controls (N of men=479, N of women=122) were recruited in this study (Table 1 and Supplemental Table 1). The most common age group in both sexes was 50 to 59 years. More cases were from Madhesi ethnic group in both sexes. A higher proportion of men with HNC were from the plain region compared to women with HNC (p=0.039, Table 1). In the control group, men from the plain region were more likely to have chewing habits (p <0.001) and less likely to drink alcohol (p=0.012) compared to men from the hill and the mountain regions (data not shown). Women from the plain region were less likely to smoke tobacco compared to women from the hill and mountain regions (p=0.031, data not shown). Men with HNC had higher education compared to women with HNC (p<0.001). Oral cavity was the most common site in HNC (Table 1).
Table 1.
Demographic characteristics of head and neck cancer cases in Nepal, stratified by sex
| Male cases, n(%) | Female cases, n(%) | p-value1 | |
|---|---|---|---|
| Total | 438 | 111 | |
| Age | 0.251 | ||
| <40 | 35 (8.0) | 10 (9.0) | |
| 40 to 49 | 103 (23.5) | 25 (22.5) | |
| 50 to 59 | 141 (32.2) | 46 (41.4) | |
| 60 to 69 | 129 (29.5) | 22 (19.8) | |
| ≥70 | 30 (6.8) | 8 (7.2) | |
| Ethnicity | 0.481 | ||
| Brahmin | 53 (12.1) | 17 (15.3) | |
| Chettri | 78 (17.8) | 21 (18.9) | |
| Rai | 19 (4.3) | 5 (4.5) | |
| Madhesi | 147 (33.6) | 26 (23.4) | |
| Limbu | 7 (1.6) | 3 (2.7) | |
| Magar | 39 (8.9) | 11 (9.9) | |
| Tharu | 32 (7.3) | 6 (5.4) | |
| Other | 63 (14.4) | 22 (19.8) | |
| Residential area | 0.039 | ||
| Plain | 319 (72.8) | 68 (61.3) | |
| Hill | 109 (24.9) | 41 (36.9) | |
| Mountain | 10 (2.3) | 2 (1.8) | |
| Education | <0.001 | ||
| <= 3rd grade | 240 (54.8) | 94 (84.7) | |
| > 3rd grade | 198 (45.2) | 17 (15.3) | |
| Family monthly income (Rupees) | 0.8467 | ||
| >= 5000 | 182 (41.6) | 45 (40.5) | |
| < 5000 | 256 (58.4) | 66 (59.5) | |
| Cancer site | 0.101 | ||
| Oral cavity | 286 (65.3) | 67 (60.4) | |
| Oropharynx | 44 (10.0) | 8 (7.2) | |
| Hypopharynx | 40 (9.1) | 7 (6.3) | |
| Larynx | 59 (13.5) | 26 (23.4) | |
| Oral cavity-oropharynx-hypopharynx not otherwise specified | 9 (2.1) | 3 (2.7) |
p-value for chi-square test
Men with a lower education level (3rd grade and less) had an increased risk of HNC (AOR 1.58, 95% CI 1.14–2.18) compared to those with >3rd grade. Such association was not observed in women (AOR 1.12, 95% CI 0.44–2.85). The P-value for the product term between sex and education was not statistically significant (P=0.512). Men with low family income (<5000 Rupees) had an elevated risk of HNC (AOR 1.64, 95% CI 1.20–2.24) compared to those with high income (≥5000 Rupees). Marital status was not associated with HNC risk in both sexes (Table 2). In sensitivity analysis, education, family income, and marital status were associated with increased risk of HNC among men but not women after further adjustment of secondhand smoking, dietary factors, and household air pollution (Supplementary Table 2).
Table 2.
Demographic factors and the risk of head and neck cancer in Nepal, stratified by sex
| Men | Women | P3 | |||||
|---|---|---|---|---|---|---|---|
| Cases, n(%) | Controls, n(%) | AOR (95% CI)1 | Cases, n(%) | Controls, n(%) | AOR (95% CI)1 | ||
| Education | 0.424 | ||||||
| > 3rd grade | 198 (45.2) | 315 (65.8) | Reference | 17 (15.3) | 29 (23.8) | Reference | |
| <= 3rd grade | 240 (54.8) | 164 (34.2) | 1.58 (1.14, 2.18) | 94 (84.7) | 93 (76.2) | 1.12 (0.44, 2.85) | |
| Family monthly income (Rupees) | 0.540 | ||||||
| >= 5000 | 182 (41.6) | 294 (61.4) | Reference | 45 (40.5) | 66 (54.1) | Reference | |
| < 5000 | 256 (58.4) | 185 (38.6) | 1.64 (1.20, 2.24) | 66 (59.5) | 56 (45.9) | 1.30 (0.66, 2.55) | |
| Marital status | 0.279 | ||||||
| Married | 417 (95.2) | 468 (97.7) | Reference | 96 (86.5) | 111 (91.0) | Reference | |
| Non-married2 | 21 (4.8) | 11 (2.3) | 2.25 (0.98, 5.17) | 15 (13.5) | 11 (9.0) | 0.91 (0.31, 2.67) | |
Abbreviations: AOR, adjusted odds ratio; CI, confidence interval
Adjusted for age, race/ethnicity, residential area, education levels, family monthly income, tobacco smoking (duration and frequency), chewing habits (duration and frequency), alcohol drinking (duration and frequency), where appropriate
Included unmarried, widowed, divorce/separated
P value for the product term between exposures of interest and sex
Women who ever smoked tobacco had a higher risk of HNC (AOR 2.94, 95% CI 1.31–6.59) compared to never-tobacco smokers, while this difference was not statistically significant among men (AOR 1.34, 95% CI 0.96–1.86; Table 3). The AORs for frequency and duration of smoking among women were higher than the AORs among men. We observed sex-based differences in tobacco chewing-related HNC risk (AOR 1.76 for men vs. AOR 10.22 for women). The p-value for the product term between sex and tobacco chewing was statistically significant (P<0.001). For alcohol consumption, women who consumed alcohol had 3.18 times of HNC risk (95% CI 1.06–9.53) compared to women who did not consume alcohol. The AOR for men who consumed alcohol was 1.44 (95% CI 1.02–2.05). Similar results were found when further adjusted to secondhand smoking, dietary factors, and household air pollution (Supplementary Table 3). For women, menopausal status and birth control measures were not associated with HNC risk (Table 4).
Table 3.
Tobacco smoking, chewing habits, alcohol drinking, and the risk of head and neck cancer in Nepal, stratified by sex
| Men | Women | P6 | |||||
|---|---|---|---|---|---|---|---|
| Cases, n(%) | Controls, n(%) | AOR (95% CI)1,5 | Cases, n(%) | Controls, n(%) | AOR (95% CI)1,5 | ||
| Tobacco smoking 2 | |||||||
| Ever consumed | 0.063 | ||||||
| No | 127 (29.0) | 211 (44.1) | Reference | 42 (37.8) | 75 (61.5) | Reference | |
| Yes | 311 (71.0) | 268 (55.9) | 1.34 (0.96, 1.86) | 69 (62.2) | 47 (38.5) | 2.94 (1.31, 6.59) | |
| Frequency (cigarettes-equivalent/day) | 0.118 | ||||||
| 0 | 127 (29.0) | 211 (44.1) | Reference | 42 (37.8) | 75 (62.0) | Reference | |
| > 0 to 10 | 168 (38.4) | 169 (35.3) | 1.21 (0.85, 1.72) | 38 (34.2) | 33 (27.3) | 2.56 (1.08, 6.05) | |
| > 10 | 143 (32.6) | 99 (20.7) | 1.68 (1.10, 2.59) | 31 (27.9) | 13 (10.7) | 5.28 (1.71, 16.28) | |
| Duration (years) | 0.187 | ||||||
| 0 | 127 (29.0) | 211 (44.1) | Reference | 42 (37.8) | 75 (62.0) | Reference | |
| > 0 to 25 | 96 (21.9) | 136 (28.4) | 0.98 (0.67, 1.44) | 18 (16.2) | 16 (13.2) | 2.45 (0.88, 6.84) | |
| > 25 | 215 (49.1) | 132 (27.6) | 1.94 (1.30, 2.90) | 51 (45.9) | 30 (24.8) | 3.63 (1.44, 9.13) | |
| Chewing habits 3 | |||||||
| Ever consumed | <0.001 | ||||||
| No | 108 (24.7) | 174 (36.3) | Reference | 64 (57.7) | 110 (90.2) | Reference | |
| Yes | 330 (75.3) | 305 (63.7) | 1.76 (1.27, 2.46) | 47 (42.3) | 12 (9.8) | 10.22 (4.53, 23.03) | |
| Frequency (numbers/day) | <0.001 | ||||||
| 0 | 108 (25.0) | 174 (36.7) | Reference | 64 (57.7) | 110 (90.2) | Reference | |
| > 0 to 6 | 130 (30.1) | 149 (31.4) | 1.43 (0.97, 2.10) | 26 (23.4) | 10 (8.2) | 5.56 (2.28, 13.56) | |
| > 6 | 194 (44.9) | 151 (31.9) | 2.09 (1.44, 3.02) | 21 (18.9) | 2 (1.6) | 48.76 (8.53, 278.79) | |
| Duration (years) | <0.001 | ||||||
| 0 | 108 (24.9) | 174 (36.7) | Reference | 64 (57.7) | 110 (90.2) | Reference | |
| > 0 to 20 | 110 (25.4) | 137 (28.9) | 1.27 (0.85, 1.91) | 26 (23.4) | 8 (6.6) | 7.50 (2.81, 20.02) | |
| > 20 | 215 (49.7) | 163 (34.4) | 2.17 (1.51, 3.12) | 21 (18.9) | 4 (3.3) | 15.67 (4.64, 52.89) | |
| Alcohol drinking 4 | |||||||
| Ever consumed | 0.064 | ||||||
| No | 127 (29.0) | 189 (39.5) | Reference | 74 (66.7) | 106 (86.9) | Reference | |
| Yes | 311 (71.0) | 290 (60.5) | 1.44 (1.02, 2.05) | 37 (33.3) | 16 (13.1) | 3.18 (1.06, 9.53) | |
| Frequency (drinks/day) | 0.087 | ||||||
| 0 | 127 (29.1) | 189 (39.8) | Reference | 74 (67.3) | 106 (86.9) | Reference | |
| > 0 to 6 | 86 (19.7) | 138 (29.1) | 1.02 (0.68, 1.52) | 17 (15.5) | 11 (9.0) | 1.81 (0.50, 6.50) | |
| > 6 | 223 (51.1) | 148 (31.2) | 2.21 (1.46, 3.34) | 19 (17.3) | 5 (4.1) | 5.63 (1.28, 24.73) | |
| Duration (years) | 0.101 | ||||||
| 0 | 127 (29.0) | 189 (39.6) | Reference | 74 (66.7) | 106 (86.9) | Reference | |
| > 0 to 20 | 83 (18.9) | 125 (26.2) | 1.10 (0.72, 1.68) | 8 (7.2) | 8 (6.6) | 1.06 (0.26, 4.33) | |
| > 20 | 228 (52.1) | 163 (34.2) | 1.82 (1.22, 2.70) | 29 (26.1) | 8 (6.6) | 8.69 (2.04, 37.10) | |
Abbreviations: OR, adjusted odds ratio; CI, confidence interval
Adjusted for age, race/ethnicity, residential area, education levels, family monthly income
Additionally adjusted for chewing habits (duration and frequency), alcohol drinking (duration and frequency)
Additionally adjusted for tobacco smoking (duration and frequency), alcohol drinking (duration and frequency)
Additionally adjusted for tobacco smoking (duration and frequency), chewing habits (duration and frequency)
P for trend < 0.05 for duration and frequency of tobacco smoking, chewing habits, and alcohol drinking
P value for the product term between exposures of interest and sex
Table 4.
Reproductive factors and the risk of head and neck cancer among women in Nepal
| Cases, n(%) | Controls, n(%) | AOR (95% CI)1 | |
|---|---|---|---|
| Menopause 2 | |||
| No | 26 (23.6) | 50 (41.7) | Reference |
| Yes | 84 (76.4) | 70 (58.3) | 2.11 (0.86, 5.15) |
| Birth control 2 | |||
| Did not use | 84 (75.7) | 92 (77.3) | Reference |
| Used | 27 (24.3) | 27 (22.7) | 1.47 (0.60, 3.56) |
Abbreviations: AOR, adjusted odds ratio; CI, confidence interval
Adjusted for age, race/ethnicity, residential area, education levels, family monthly income, tobacco smoking (duration and frequency), chewing habits (duration and frequency), alcohol drinking (duration and frequency), where appropriate
Missing menopause status: 1 case, 2 controls; missing birth control use: 3 controls
Discussion
The differences among men and women in the major risk factors of HNC were rarely addressed in the studies conducted in Nepal. A higher incidence of HNC is reported among men than women in Nepal due to the higher prevalence of known risk factors such as tobacco use and alcohol in men [17,18]. In the current study, marital status was not associated with HNC development in both men and women. The previous case-control study reported that marital status was not associated with the risk of oral cancer [19]. Similar to our finding, the educational level among women was not associated with HNC risk in the study conducted in Italy and Switzerland [20]. Although estrogen may decrease the risk of HNC, we did not observe an association between menopause status and HNC risk. Contraceptive pill use was not associated with HNC risk among women, similar to the previous studies [12,13].
The AOR of HNC for tobacco smoking was almost double in women compared to men (AOR: 2.94 vs. 1.34, respectively). The distribution of tobacco smoking was different between men and women. About 55.9% of men and 38.5% of women in controls self-reported as tobacco smokers. Thus, the different baseline risks for men and women could contribute to the difference between AORs. In the previous study, the prevalence of smoking among men was higher than that of smoking among women in Nepal (27.0% vs. 10.3%) [21]. Similarly, the AOR of HNC for chewing habits was approximately six times higher among the women compared to the men (AOR: 10.22 vs. 1.76, respectively). It could be partially due to the low percentage of chewers among female controls (9.8% vs. 63.7%). Based on a previous study, the prevalence of smokeless tobacco was six times higher among men than women in Nepal (31.3% vs. 4.8%) [21]. The sex differences in oral cancer risk were reported in previous studies [22–24]. In our study, the odds for alcohol consumption was much higher among women than men (AOR: 3.18 vs. 1.44, respectively). Based on a separate study, the national prevalence of alcohol consumption was four times higher among men than women (28% vs 7.1%) [21].
This case-control study confirms that tobacco use and alcohol consumption are the major risk factors for both sexes. This study highlights the difference in HNC risk for tobacco chewing was modified by sex. A previous study reported that Nepalese women have low health-seeking behavior than men [25], which can further complicate the disease. This will likely influence the survival rate negatively in women and hence influence the mortality rate. Efforts should be made to raise awareness, HNC screening, and proper implementation of tobacco and alcohol control policies taking into consideration the sex-specific risk behaviors in the community. There is a further need for prospective population-based studies to prove the relationship.
The main limitation of this study is that we recruited cases and controls from one hospital and hence the findings may not be generalizable. However, BPKMCH is the largest cancer hospital in Nepal that treats the majority of cancer cases. We were not able to estimate the risk of HNC by subsite due to the limited sample size. Further studies are needed to assess risk factors for HNC by subsite. The number of cases was quite low for some of the female subgroups evidenced by wide CIs. The sample size among women was limited in the analysis for the duration and frequency of tobacco smoking, chewing habits, and alcohol drinking. Women may underreport the consumption of tobacco, and alcohol because it is socially unacceptable among women in the Nepalese community. The association between HNC risk and these consumptions may be underestimated because we expected both cases and controls may underreport their consumption. Recall bias may occur because HNC cases may over-recall the consumption of tobacco smoking, chewing habits, and alcohol drinking.
Conclusion
Though the incidence of HNC is higher among men, women are vulnerable to HNC. Sex plays a role as an effect modifier in HNC. Hence, attention among women should be taken to consider sex for increasing awareness, health-seeking behaviors, and other control strategies of HNC.
Supplementary Material
Highlights.
Effect modification by sex for HNC risk factors was observed.
The risk of HNC for tobacco smoking was almost double in women compared to men.
Men had higher prevalence for known risk factors of HNC compared to women.
Acknowledgements
This work was supported by a grant from the NIH 3P30 CA042014-26S6.
Footnotes
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Conflict of interest
All authors declare no conflicts of interest.
CRediT authorship contribution statement
Guarantors of integrity of entire study, C.C. and M.H.; study concepts/study design or data acquisition or data analysis/interpretation, G.S., C.C., A.S., M.H.; manuscript drafting or manuscript revision for important intellectual content, G.S., C.C., A.S., M.H.; approval of final version of submitted manuscript, G.S., C.C., C.B.P., D.K.G., B.S., A.S., M.H.; agrees to ensure any questions related to the work are appropriately resolved, G.S., C.C., C.B.P., D.K.G., B.S., A.S., M.H.; literature research, G.S.; statistical analysis, C.C.; and manuscript editing, G.S., C.C., A.S., M.H.
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