Total Fluid Intake and the Risk of Recurrence in Patients With Non-Muscle Invasive Bladder Cancer: A Prospective Cohort Study

The bladder cancer prognosis programme

This study is part of the Bladder Cancer Prognosis Programme (BCPP), a prospective cohort study in the West Midlands region of England. Details of the cohort have been published previously [9]. Briefly, during the enrolment period (December 2005–October 2011), a total of 1,550 male and female patients (age ≥18 years) were enrolled based on abnormal cystoscopic findings suggestive of bladder cancer. Transurethral resection of the primary bladder tumour (TURBT) was followed by cytoscopic surveillance. Optimal additional treatment comprised intravesical chemotherapy with mitomycin C within 24 hours of TURBT and/or a course of further mitomycin C or intravesical BCG, as per contemporary European Association of Urology guidelines. Bladder cancer recurrence was defined as the new occurrence of a non-muscle invasive bladder cancer (stage Ta, T1, or pTis) at the same or at a different site as the initial primary bladder tumour and excluding recurrence identified at the first check cystoscopy. Written informed consent was obtained from all participants. The study protocol was approved by the Nottingham Research Ethics Committee (06/MRE04/65) and registered on ClinicalTrials.gov (NCT00553566).

Data collection

Around the time of diagnosis, just prior to, or just post TURBT, data on medical history, socio-demographics, quality of life, and health-related lifestyle (including dietary intake) were collected by a trained research nurse using semi-structured face-to-face interviews and a questionnaire. The research nurse and patient went through the questionnaire page by page. Patients were asked about habitual dietary intake over the previous year. The developed version of the food-frequency questionnaire (FFQ) aims to assess the dietary intake, by asking the participants to report the frequency of consumption of approximately 16-line items over the last year. More specifically, the frequency of fluid intake from beverages asked in the questionnaire consisted of six levels: never or less than once per month, one to three times per month, once a week, two to four times per week, five to six times per week, or at least once per day. For each drink, a measure size was provided (e.g. cup, (small) glass, pub measure (2.5cl), or (half) pint glass). The frequency of intake of each beverage was multiplied by their measure size to calculate the millilitres of fluids consumed per day. Total fluid intake was computed as the sum of servings of all beverages in the questionnaire: wine-champagne, fortified wine, beer, cider, spirits, liqueurs, coffee, tea, hot chocolate, soup, ovaltine-horlicks, fizzy pop, pure fruit juice, fruit squash, milk, and water. Total alcohol intake included alcoholic beverages only: wine-champagne, fortified wine, beer, cider, spirits, and liqueurs. Repeated fluid intake from beverages was collected through a postal follow-up questionnaire one year after diagnosis.

Exclusion criteria

A total of 244 participants with no evidence of a bladder tumour (T0), patients who had a tumour that could not be assessed (Tx) (n = 116), who had muscle invasive bladder cancer (MIBC) (n = 275), who received no TURBT (n = 16), who had radiotherapy (on suspicion of MIBC) (n = 8), who had incomplete data on tumour characteristics (e.g. stage, grade, size, multiplicity) (n = 53) and smoking (n = 94), and had missing data on pre-diagnosis fluid intake (n = 28), were all excluded from this study (Fig. 1). The final analysis for fluid intake over the year before diagnosis comprised 716 patients. More than a third of these 716 patients did not complete a follow-up questionnaire one year after diagnosis (n = 278) or developed a recurrence of bladder cancer before completing the follow-up questionnaire (n = 59). Therefore, a total of 379 patients remained for investigating the association between fluid intake over the year after diagnosis and bladder cancer recurrence.

Fig.1

Flow diagram of patients selection, with exclusion criteria.

Statistical analysis

According to the UK government recommendations on eating healthy and achieving a balanced diet, anybody living in a maritime climate should consume at least 1,200 mL of fluids from drinks a day [10]. Patients were divided into three groups: a group with an intake of 250 mL –850 mL of total fluid per day, a group consuming 850 mL –1,200 mL of total fluid per day, or a group with a total intake of more than the recommended 1,200 mL of fluid per day. Patients became at risk for a recurrence of bladder cancer from the date of TURBT and remained at risk until the earliest occurrence of a recurrence, cystectomy, death, the most recent surveillance cystoscopy, or study end (five years post-TURBT). Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (95% C.I.) of developing a first recurrence of bladder cancer in relation to total fluid intake, total alcohol intake, and individual beverages. To identify possibly influential outliers in total fluid and alcohol intake, Cook’s Distance was used. The association of fluid intake with recurrent bladder cancer was examined in both crude and multivariate models. Confounders were considered a priori based on known prognostic factors for NMIBC recurrence from the European Association of Urology guidelines and included: age at diagnosis (continuous) [11], sex (male/female) [12], smoking status (never/former/current smoker) [13], and tumour characteristics including stage (pTa/pT1/pTis), grade (1/2/3), size of largest tumour (diameter <3 cm/≥3 cm), and tumour multiplicity (1/>1) [14–16].

Conditional risk set modelling was applied to investigate time to each recurrent event and analysis time was reset at each event [17]. For this analysis, re-resection of tumours (yes/no) was added as a confounder. The proportional hazards assumption was checked in all models using Schoenfeld residuals [18]. Cumulative incidence functions (CIF) accounting for competing risks (death and cystectomy) were made [19]. These models are conditional as the failure times are conditional on the occurrence of the prior recurrence, i.e. a second recurrence cannot occur before the first recurrence. P-values were 2-sided with a significance level of 0.05. All statistical analyses were performed using Stata softwareversion 14.

Baseline characteristics and number of recurrences

During 2,025 person-years of follow-up (mean (SD) follow-up 3.7 (1.5) years), 238 (33%) of the 716 NMIBC patients developed one or more recurrences of bladder cancer. More specifically, 80 (34%) of these 238 patients developed a second recurrence, 35 (15%) a third recurrence, 17 (8%) a fourth recurrence, five (3%) a fifth recurrence, two (1%) a sixth recurrence, and one (1%) a seventh recurrence. Patient characteristics at diagnosis and initial treatment are presented in Table 1. The median age at diagnosis was 71 years and most patients were male (80%), Caucasian (97%), and current or former smokers (86%). The average intake of fluid was relatively evenly distributed between patients who had a recurrence of bladder cancer and those who had not (mean total fluid intake 1,087 mL per day and 1,103 mL per day, respectively).

Total fluid intake and bladder cancer recurrence

Table 2 presents HRs with corresponding 95% C.I. for total fluid intake over the year before diagnosis from beverages and time to a first bladder cancer recurrence and multiple bladder cancer recurrences among 716 NMIBC patients. Total fluid intake the year before diagnosis did not affect the recurrence of a first bladder tumour (HR = 0.98, 95% C.I. 0.70–1.38, p = 0.91) when adjusted for age, sex, smoking status, stage, grade, and tumour size and multiplicity. The association between total fluid intake the year before diagnosis and time to multiple recurrences showed similar results (HR = 1.01, 95% C.I. 0.87–1.19, p = 0.85) when adjusted for the same confounders and tumour re-resection (second transurethral resection).

Table 3 presents the results for the remaining 379 NMIBC patients on total fluid intake after diagnosis –no significant associations were observed between total fluid intake and the development of a first bladder cancer recurrence (HR = 0.91; 95% C.I. 0.60–1.37, p = 0.65) or multiple recurrences (HR = 1.06; 95% C.I. 0.89–1.26, p = 0.54) when corrected for known prognostic factors for NMIBC recurrence provided in the European Association of Urology guidelines (including age, sex, smoking status, tumour characteristics and tumour re-resection).

Total alcohol and individual beverages intake and bladder cancer recurrence

Results of the Cox proportional hazard models predicting the development of recurrence based on total alcohol intake and individual beverages can be found in the online supplementary file (Tables S1–S8). Among 716 NMIBC patients, total alcohol intake before diagnosis (highest intakes >125 mL versus lowest intakes 0 mL) was not associated with a first bladder tumour (HR = 0.97; 95% CI 0.70–1.36) in the most extensive model (adjusted for age, sex, smoking status, stage, grade, and tumour size and multiplicity) (Table S1). Similar results were found for total alcohol intake prior to a diagnosis of bladder cancer and multiple recurrences of bladder cancer (HR = 0.97; 95% CI 0.84–1.11) when corrected for the same confounders as in the time to a first recurrence analysis plus re-resection of a bladder tumour (Table S2).

None of the individual alcoholic beverages including beer, cider, wine/champagne, fortified wine, spirits or liqueurs consumed prior to bladder cancer diagnosis influenced the risk of developing a first or multiple recurrences of bladder cancer when comparing the highest frequency of intake ‘at least 1 per day’ versus the lowest frequency of intake /never/less than 1 per month’ (Tables S1–S2). The warm beverages coffee, tea, hot chocolate, ovaltine/horlicks and soup were also investigated. No associations were found when comparing the frequencies of these warm beverages (at least one per day versus never/less than 1 per month before diagnosis) and a first or multiple recurrences of bladder cancer (Tables S3–S4). In addition, pre-diagnosis consumption of the cold beverages milk, water, fizzy pop, pure fruit juice, and fruit squash/cordial, did not affect the development of one or multiple recurrences of bladder cancer when comparing the highest versus the lowest frequency intakes.

Among the 379 NMIBC that remained for analyses one year after a diagnosis of bladder cancer, total alcohol intake was not associated with a first recurrence (HR = 1,01; 95% CI 0.65–1.58) or multiple recurrences (HR = 1,05; 95% CI 0.88–1.25) (Tables S5–S6). Consumption of alcoholic beverages one year after a diagnosis of bladder cancer was not related to the development of bladder cancer recurrences (Tables S5–S6). Finally, no associations were found for usual warm and hot non-alcoholic beverages consumption and one or more recurrence of bladder cancer (Tables S7–S8).