Role of dietary patterns and inter-meal intervals in hypopharyngeal cancer: A case–control study from Assam, India

Methods

This case-control study was undertaken by the department of Mathematical and Computational Sciences, Physical Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Guwahati, Assam, in collaboration with Dr. B. Borooah Cancer Institute, Guwahati, Assam, India. Written informed consent was obtained from all participants, and ethical approval was granted by the Institutional Ethics Committee.

Results

Between May 2023 and August 2024, 300 eligible cases and 300 controls were enrolled in a frequency-matched design. We approached 411 potential controls, of whom 300 agreed to participate (73.0% response rate).

Socio-demographic and lifestyle characteristics of the study participants are summarised in Figure 1 and Supplementary Table. Cases and controls demonstrated similar distributions across matching variables, including administrative region, age, sex, religious affiliation, caste category, and urban/rural residence. A notable SES disparity emerged, with cases showing greater representation in lower socioeconomic strata (Fig. 1). Cases exhibited significantly higher rates of cigarette smoking, areca nut consumption, and smokeless tobacco use compared to controls (all P<0.001). As shown in Figure 1, the age distribution of cases and controls was comparable, with the highest proportion in the 50–65 yr age group (cases: 52.3%; controls: 52.7%).

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Fig. 1.

Dumbbell plot of baseline characteristics among cases and controls.

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After comprehensive multivariable adjustment for all major established risk factors (tobacco use, areca nut consumption, alcohol intake, and sociodemographic factors), habitual inter-meal intervals ≥5 hours conferred almost three-fold increased HC odds relative to intervals <4 h [Odds ratio (OR)=2.69, 95% confidence interval (CI): 1.56-4.69], whereas gaps of 4-5 h showed no significant association (OR 1.12, 95% CI: 0.66-1.88) ( Table I, Fig. 2). When analysed as a continuous variable, each one-hour increase in inter-meal interval was associated with 46% increased odds of HC (OR=1.46, 95% CI: 1.20-1.80, P<0.001), demonstrating a clear dose-response relationship. The consistency between categorical and continuous analyses strengthens causal inference. Higher roti consumption demonstrated protective effects (OR=0.48, 95% CI: 0.28-0.82) ( Table I).

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Fig. 2.

Association between inter-meal intervals and hypopharyngeal cancer risk.

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Overall vegetable intake showed no significant association, but higher intake of leafy green vegetables was strongly protective, with the highest tertile showing approximately 80% reduced risk (OR 0.21, 95% CI: 0.09-0.49). Yellow-orange vegetable intake also suggested protective effects, though borderline significant ( Table II). Total fruit consumption was inversely associated with HC, with both second and third tertiles showing significant protective effects ( Table II). For citrus fruits, the highest tertile showed 87% lower risk (OR 0.13, 95% CI: 0.05-0.32). Non-citrus fruits also reduced risk significantly (OR 0.35, 95% CI: 0.14-0.87) ( Table II).

Higher milk intake was positively associated with HC risk (OR 2.06, 95% CI: 1.22-3.52) ( Table III). Coffee consumption was inversely associated with HC (OR 0.54, 95% CI: 0.30-0.94) ( Table IV). Total meat intake demonstrated a significant increase in the second tertile (OR=1.63, 95% CI: 1.04-2.55), while red meat showed no association. Tea consumption, including type, temperature, and frequency, was not associated with HC. No associations were observed for fish, egg, lentils, smoked fish, smoked meat, bamboo shoot, split black gram lentils, or kolakhar ( Table IV).

Figure 3 presents a comprehensive visual representation of the key dietary and meal timing factors associated with HC risk identified in our study. The forest plot illustrates the magnitude and precision of associations, clearly distinguishing between protective factors (odds ratios below 1.0) and risk factors (odds ratios above 1.0). The most pronounced protective effects are demonstrated by citrus fruits in the highest tertile (OR 0.13, 95% CI: 0.05-0.32), followed closely by leafy green vegetables (OR 0.21, 95% CI: 0.09-0.49), indicating substantial risk reductions of 87% and 79%, respectively. It also reveals the concerning impact of prolonged inter-meal intervals (≥5 h), which emerged as the strongest risk factor with an odds ratio of 2.69 (95% CI: 1.56-4.69), representing a nearly three-fold increase in cancer risk.

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Fig. 3.

Forest plot of key risk and protective factors for hypopharyngeal cancer.

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Discussion

This hospital-based case-control study provides novel evidence linking prolonged inter-meal intervals to hypopharyngeal carcinoma risk in northeastern India. Habitual inter-meal intervals ≥5 h were associated with nearly three-fold higher odds of hypopharyngeal cancer, with a clear dose–response pattern, each additional hour increased risk by 46%.

Our study strongly supports the protective role of fruits and vegetables against HC. The protective effects observed for both citrus and non-citrus fruits in the highest consumption tertiles align with findings from other Indian populations and international studies on head and neck cancer.^24-26 The remarkable protective effect of leafy green vegetables and yellow/orange vegetables aligns with their high content of folate, carotenoids, and various phytonutrients. ^27,28 The consumption of citrus fruits and fresh tomatoes was associated with reduced risks of oral cavity cancer in previous head and neck cancer studies, supporting our findings regarding the protective effects of specific fruit categories. ^29,30 The dose-response relationship observed strengthens evidence for causality. ²⁷ The protective mechanisms likely involve multiple pathways, including antioxidant activity, enhancement of DNA repair mechanisms, modulation of carcinogen metabolism, and anti-inflammatory effects. ³¹

The positive association between milk consumption and risk of hypopharyngeal cancer contrasts with some international studies but may reflect specific patterns of milk consumption, processing methods, or population-specific factors in this region. ³² This finding requires careful interpretation and further investigation, as it may be confounded by unmeasured lifestyle or dietary factors associated with higher milk consumption in this population. ³³ Inverse association of Coffee consumption with risk of hypopharyngeal cancer is consistent with meta-analytic evidence for approximately 25-30% lower risk of oral/pharyngeal cancers among higher coffee consumers. ^34,35 The protective effect of roti consumption may reflect higher dietary fibre and lower glycaemic characteristics typical of some whole-wheat flatbreads. ³⁶

Although direct comparisons are limited due to the novelty of analysing inter-meal intervals, converging chrononutrition studies indicate that eating timing patterns relate to elevated cancer risk at other sites. ^37,38 The hypopharynx’s anatomical proximity to both upper digestive and respiratory tracts makes it particularly susceptible to chemical irritation from gastroesophageal reflux, which may be exacerbated by irregular eating patterns. In this population, where areca nut chewing is highly prevalent. The practice of consuming areca nut without meals during prolonged intervals may further worsen acid reflux and mucosal irritation. ^17,18

This study has several strengths. We employed prospective recruitment of newly diagnosed cases, ensuring systematic enrolment and standardised data collection at a high-volume tertiary cancer centre serving as the regional referral hub. Recruiting cases before treatment initiation ensured high-quality data and avoided biases typically associated with retrospective record reviews. Frequency matching and systematic adjustment for major confounders, including tobacco use, areca nut consumption, alcohol intake, and socioeconomic status, strengthen result reliability. Our study design also ensured to minimise reverse causation concerns. All cases were enrolled at diagnosis prior to treatment initiation, and dietary assessment captured lifelong habitual patterns established before symptom onset. This temporal sequence of lifelong dietary habits preceding cancer development supports a potential causal interpretation rather than disease-related dietary changes.

Several limitations warrant consideration. While patient recruitment was prospective, dietary assessment was necessarily retrospective, relying on participants’ recall of habitual patterns. We attempted to minimise recall bias by focusing on long-standing dietary and meal-timing habits rather than recent intake and by enrolling cases immediately after diagnosis, before treatment initiation; nevertheless, some degree of recall error is inherent to this approach. As a hospital-based case-control study, potential selection bias exists, although our prospective recruitment and frequency matching help minimise this concern. Residual confounding from unmeasured factors such as specific cooking methods, gastroesophageal reflux severity, genetic susceptibility, and Human Papillomavirus infection status cannot be completely ruled out.

Dietary epidemiology has inherent limitations, and the associations observed in case–control studies should be interpreted with caution. Although our findings align with evidence from large prospective studies and the WCRF/AICR Expert Report supporting a protective role of fruits and vegetables in head and neck cancer, causality cannot be inferred. ^10,39-41 These results should therefore be viewed as hypothesis-generating and warrant confirmation in prospective studies. While large, long-term prospective cohort studies are the gold standard for establishing causality in nutritional epidemiology, they are particularly challenging for rare cancers such as HC, where accruing adequate numbers would require extremely large populations and decades of follow-up. In such contexts, case control studies remain an appropriate and widely used approach, offering a practical and informative design where a prospective cohort study would require thousands of participants and decades of follow up, an undertaking currently not feasible in our setting. The monograph “Epidemiologic research of rare cancers: trends, resources, and challenges” argues that rare cancers pose serious obstacles to prospective cohort research due to difficulty in recruiting sufficient numbers, and highlights the value of case–control and other observational designs. ⁴² Modern research continues to validate this approach: for instance, a recent hospital-based case–control study in Nepal included 549 head and neck cancer cases and 601 controls to identify risk factors in a context similar to ours. ⁴³

Our findings provide preliminary evidence that both dietary composition and meal-timing behaviours may contribute to the risk of hypopharyngeal cancer in this high-incidence region. The associations observed after adjustment for major confounders provide a basis for future hypothesis-driven research and for developing prevention strategies targeting multiple dietary practices.