Introduction

Bladder cancer is one of the most commonly diagnosed cancers in the world [1]. However, various studies have reported on marked international variation in incidence and mortality rates in bladder carcinoma [1,2,3]. The highest incidence is seen in European countries but has been decreasing in recent years [4]. Tobacco use has been attributed as the most important risk factor in European nations, and the decline in its use is thought to account for the falling rates [5].

Bladder cancer is more frequently diagnosed in older subgroups of the population, and in groups of lower socioeconomic status [1]. Mortality rates are lower in Europe and North America, potentially due to early diagnosis and treatment [1,2,3,4,5].

This retrospective review is the first to offer the Irish perspective of bladder carcinoma incidence using data from the National Cancer Registry of Ireland. We aim to offer a comprehensive analysis of incidence rates, mortality, and potential risk factors in the Irish population over two decades.

Methods

We collected all data on histologically confirmed primary carcinoma of the bladder according to the International Statistical Classification of Disease and Related Health Problems 10th revision (ICD-10) from the database of the National Cancer Registry of Ireland (NCRI) from 1994 to 2015. The data collected includes the demographics of the patient (sex, age, HSE region), smoking history, treatment received at 1 year, months of survival and some histological data. Further data was collected from the NCRI regarding incidence and survival.

The NCRI has been collecting data on all cancer cases in Ireland since 1994, covering a current population of 4.7 million [6]. Age standardised rates (ASR) per 100,000 person-years and annual percentage change were provided by the NCRI and used for incidence data [7]. This data was reviewed and analysed using Excel to show treatment and survival trends as well as potential contributing factors: socioeconomic and smoking status etc. ANOVA and Kruskal-Wallis tests were used to compare outcomes amongst these groups and to establish if these relationships were significant.

Survival data was collected in two ways by NCRI: alive at most recent follow-up and months of survival since diagnosis. Grading of malignancy was recorded at time of initial diagnosis, and the 1973 World Health Organization grading system was used.

Stage was recorded using the TNM 5th edition criteria. The treatment received was recorded by the NCRI under five headings [7]. These treatments were defined by the NCRI as follows: Chemotherapy refers to patients who received chemotherapy within 12 months of diagnosis date. There was no data available regarding timing or type of chemotherapy (intravesical, neoadjuvant etc.). Medical oncology refers to treatment aimed at tumour destruction or slowing tumour growth more than 12 months from diagnosis date. Surgical treatment was defined as tumour-directed surgery or related destructive treatment within 12 months (or 1 month before) from the date of diagnosis. Radiotherapy received within 12 months of diagnosis was also recorded.

Patients were broken down by location using the Health Service Executive regional breakdown which divides Ireland into four areas: Dublin north, Dublin and Mid Leinster, South and West [7]. Socioeconomic status was described using the Pobal Deprivation index, with region 1 being the least deprived and region 5 being the most deprived [7].

Results

Incidence

Trends

From 1994 to 2015, there were 9656 cases of bladder cancer in Ireland. Overall, the incidence has decreased, as seen in Fig. 1.

Fig. 1
figure 1

Overall incidence of bladder cancer in Ireland 1994–2015

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By gender

The majority of cases (71%, n = 6848 cases) occurred in men. There was an average of 193 cases per annum in women and 479 per annum in men. During this period, it was the fourth most common cancer in men and the ninth most common chance in women accounting for 3.1% and 1.4% of new cancer cases respectively. Figure 1 shows the downtrending incidence in both sexes over the period; there was an annual percentage change of − 2.9% in men and − 2.6% in women.

By age

The incidence of bladder cancer increased with increasing age and was most common in the over 85 age group, as in Fig. 2.

Fig. 2
figure 2

Age specific incidence of bladder cancer in Ireland 1994–2015

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Risk factors

Fifty percent of men had a recorded smoking history and 35% of women. Of those with a smoking history, the majority lay in deprivation index 4 and 5 (57%).

Geography

Throughout this period, the majority of cases occurred in Dublin Mid Leinster (DML) at 27% (Table 1). The lowest proportion was in Dublin North East.

Table 1 Breakdown by region
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Pathology

There was limited data available regarding pathology. Seventeen per cent were grade 1, 22% were grade 2, 40% were grade 3 and 22% had no recorded grade (Fig. 3). Ninety-five per cent of patients were recorded as having urothelial pathology, which includes squamous cell carcinoma. Two per cent were recorded as adenocarcinoma, and 3% as “other.” Tables 1 and 2 show the mean grade recorded by the socio-economic subgroup, and the mean grade did not vary by deprivation index or region as seen in Tables 1 and 2. All were recorded to have a mean of 2.3–2.4 regardless of region or socio-economic status. Figures 4 and 5 show the breakdown of grade by region and social status.

Fig. 3
figure 3

Overall grade breakdown

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Table 2 Breakdown by Deprivation Index
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Fig. 4
figure 4

Overall stage breakdown

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Fig. 5
figure 5

Grade distribution by Region (% of Total Region

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Stage

The majority of patients were stage 1 (27.3%) or stage 2 (17.4%). A total of 5.8% of patients were stage 3, 9.4% were stage 4, 7% were stage 0a and 0.3% were 0is. A total of 32.8% of patients had no stage recorded (Fig. 6). The mean stage did not vary by demographic region or by socioeconomic status (Tables 1 and 2).

Fig. 6
figure 6

Grade distribution by socio-economic status (% of deprivation score)

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Survival outcomes

Age

The survival decreased with increasing age; the median survival in patients over the age of 80 years was 11 months (0–250 months), in the 60–80 year age groups was 42 months (0–251 months), 40–60 years was 102 months (0–251 months) and in the < 40 year age group was 111.5 months (0–251 months). The difference between the age groups was significant statistically p = 0.000 (Kruskal-Wallis).

Gender

Thirty-eight percent of women were alive at the most recent follow-up, compared with 42% of men. The median survival in women of 30 months (0–251 months) was significantly lower than in men of 36 months (0–251 months) (p = 0.000, ANOVA).

Socio-economic status

As seen in Table 2, the survival outcomes worsen with increasing levels of deprivation. Only 35% of index 5 was alive at the most recent follow-up compared with 41% in index 1. However, these differences were not significant statistically (p = 0.453, Kruskal-Wallis). The median survival in deprivation index 1 was 40 months, and this reduced to 35 months in index 5. Of note, smoking was more common in patients of lower socioeconomic status, with 51% of index 5 being smokers compared with 36% in index 1.

Demographic region

Dublin Mid Leinster and the West had the highest portion of patients alive at the most recent follow up (Table 1). The Dublin Mid Leinster region had the highest number of patients alive at the most recent follow-up at 28%. The South had the lowest number of patients alive at the most recent follow-up (22%). The median survival was not significantly different in the regions and ranged from 32 months (South) to 39 months (West) (p = 0.804 Kruskal-Wallis).

Grade

As expected, the higher the grade, the worse the survival outcomes (Table 3), with only 31.6% of patients with high grade disease being alive at the most recent follow-up. The median survival was significantly higher in grade 1 bladder cancer (92 months), compared with grade 2 (63 months and grade 3 (18 months) bladder cancer (p = 0.001 Kruskal-Wallis).

Table 3 Grade and relationship to survival outcomes
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Stage

Table 4 details the relationship between survival outcomes and stage. A higher stage was also associated with worse survival, the median survival ranging from 6.5 months (stage 4), 15 months (stage 3), 25 months (stage 3), 66 months (stage 2), 86 months (stage 0a) to 57 months in stage (0is), the differences being statistically significant (p = 0.000, ANOVA).

Table 4 Stage and relationship to survival outcomes
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Risk factors

The median survival in smokers 47 months (0–251 months) was significantly worse compared with non-smokers 37 months (0–251 months) (p = 0.000 ANOVA).

Treatment

The NCRI record the treatment received at 1 year from diagnosis. A total of 7093 (73.5%) patients had surgical treatment, 1539 (15.5%) had chemotherapy, 1612 (16.%) were referred to medical oncology and 131 (1.4%) had radiotherapy. Dual treatment with chemotherapy and surgery was received by 1351 patients (14%). Chemotherapy refers to patients who received chemotherapy within 12 months of diagnosis date, medical oncology refers to treatment aimed at tumour destruction or slowing tumour growth administered more than 12 months after diagnosis date.

Discussion

Incidence

There is marked international variation in the incidence and mortality of bladder cancer as shown by a European Association of Urology Review in 2013 [5]. This 10-year review showed high incidence in North America with an age standardised rate of 12 and Southern Europe of 11.2. The lowest rates were seen in middle Africa of 0.8, with a global ASR of 5.3. NCRI data shows that the ASR in women is 4.4 and in men 13.0.

The EAU review showed that incidence rates in all of Northern and Western Europe were decreasing, with a 1.5 annual percentage decrease in Ireland [5]. Our review looks at a longer 21-year period and sees a greater APC change over a prolonged period (− 2.9 in men, − 2.6 in women). This is a stark difference to Eastern and Southern Europe where many countries saw an increasing incidence; for example, Croatia saw a 4.8 annual percentage increase.

When we compare our incidence to that of our closest neighbours, there is some interesting variation. The 2015 UK statistics show an ASR of 9 in women and 28 in men [8]. The Irish incidence is lower, and this could be due to changing trends in smoking.

Survival

Overall

Irish treatment rates and survival outcomes are good over this period. Irish mortality rates continue to decline with a 2008 EAU paper stating that Ireland has some of the lowest mortality rates in Europe at < 4/100,000 [4].

Gender

Our data shows a statistically significant survival difference by gender; with a rate of 2.2 deaths per 100,000 per annum in women and 6.4 in men, compared with 14.5 in men and 5.0 in women in the UK [8]. This survival difference has been noted in international data with contributing factors identified including the sex steroid hormone pathway, metabolic enzyme activity and gender disparity in the work up of haematuria [9]. Women are more likely to have haematuria attributed to benign causes such as urinary tract infections; thus, they are more likely to have advanced disease at time of diagnosis [9].

Stage

Irish survival rates reflect international data, with a higher stage associated with worse survival outcomes. For example, data from the UK shows a 1-year survival rate of 94% in stage I disease and 33% at stage IV [8]. Patients with carcinoma in situ (stage 0is) patients had a worse survival than stage 0a and stage 2 patients. A Mayo Clinic review of 0is cases showed an all-cause survival of 55% at 10 years [10].

Risk factors

We saw a statistically significant worse survival in smokers compared with non-smokers. This is reflected internationally with a 2016 meta-analysis demonstrating that any smoking history sees higher mortality than those who never smoked [11].

Management

The majority of patients received treatment within 1 year; however, the recorded rates of patients receiving surgery and chemotherapy appear low at only 15%. We would expect this to be higher given that the standard treatment would be resection and intravesical chemotherapy for all non muscle invasive bladder cancer [11]. A 2006 Lancet paper showed that the majority of cases of bladder cancer in the USA are not correctly managed [12]. The excellent patient outcomes in our review show that this is not the case in Ireland. Nonetheless, the lack of treatment data available from the NCRI suggests it is not adequately recorded.

Contributing risk factors

Age

Bladder cancer is a disease of older populations, and the incidence in Ireland increases with age. In our review, the majority of Irish cases were seen in both men and women over the age of 70.

Gender

International studies have shown that women are diagnosed at a later stage and tend to have shorter survival, and this was reflected in our study [9].

Smoking

Bladder cancer in Ireland predominantly affects smokers. The prevalence of smokers in Ireland has decreased from 28.28% in 2003 to 19.53% in 2014, and this may account for the falling incidence [13].

Socio-economic status

Irish research has also shown that smoking is more common in patients of lower socioeconomic status, and there was a higher smoking prevalence in the more deprived patients in this cohort [13]. Lower survival rates were also seen in patients with higher deprivation scores.

Occupational exposure

The data available does not give details on potential occupation exposure to carcinogens which are well-described risk factors for bladder cancer [5]. This data is not collected by the NCRI; thus, we are unable to comment on the associations between the same in the Irish population.

Regional breakdown

Dublin Mid Leinster had the highest number of cases; this is the most densely populated area of Ireland, and thus, this would be an expected finding. The lowest case number was in Dublin North. The trend of increased incidence in smokers and lower-income patients was reflected through the regions. However, survival was best in Dublin Mid Leinster despite it having the second highest proportion of smokers. Knowledge of these regional variations should allow for efficient service planning and development of one-stop haematuria clinics which have been described under the new model for care for urology and in EAU guidelines [11]. Further, benefit for resource planning would be gained by breakdown by hospital network or centre, but this is beyond the realms of the data collected by NCRI.

The NHS in Scotland published guidelines in 2014 that gave specific criteria that bladder cancer centres should strive to include the number of cystectomies per centre per annum and time to treatment [1].Currently, there are no such Irish guidelines or key performance indicators that allow centres to compare their data or benchmark their outcomes.

Limitations

The major limitation to this study is that the data available from NCRI is incomplete, with large volumes of essential information unavailable. This is likely due to limitations of data recording and information provided to NCRI. There was a lack of pathology data available, with a large proportion of patients having no pathology available and no detailed breakdown of tumour subtype. This prevented detailed analysis of the relationship between disease pathology and risk factors, treatment and survival. The grading system for bladder cancer has gone through various revisions in the 21-year period we analysed, and this could alter the limited grading data available [12]. Subsequently, we were unable to make any meaningful analysis of different risk factor subgroups, such as outcomes in the pT1G3 cohort. These details would allow a more detailed analysis of important relationships between tumour biology and outcomes in the Irish population.

Furthermore, there was minimal management and treatment data captured, only giving treatment subtype at 1 year. Specifically, there was no data available on variant subtypes, the timing and type of chemotherapy the patients received or if any patients had received immunotherapy.

There is no doubt that the NCRI provides an essential and excellent resource for healthcare professionals and those involved in planning healthcare provision and service allocation. However, the data collected is missing key information and does not always allow detailed analysis of patient outcomes. Further review is needed to ensure that the detailed and complete information regarding tumour subtypes, pathology, treatment type, patient demographics and detailed geographical information is recorded accurately to facilitate comprehensive record keeping.

Conclusions

The overall incidence of bladder cancer in Ireland has fallen, in line with reducing smoking rates. Our data reflects international trends in incidence, survival and contributing risk factors [1,2,3,4,5]. Bladder cancer continues to affect patients of increasing age and lower socio-economic status predominantly, and these cohorts see worse survival outcomes.

This is the first review to provide a detailed analysis of bladder cancer in Ireland and will allow for service planning as the drive to improve outcomes for all regions continues. However, there are large volumes of data unavailable or missing which limits our ability to make meaningful analysis of outcomes in relation to treatment type, tumour subtypes or hospital network.