Correlation analysis between age, severity, and social determinant with anemia and electrolyte imbalance occurrences in bladder cancer population with chemoradiation treatment plan

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Introduction

Chemoradiation has become an important part of bladder cancer treatment, especially in nonresectable cases or when patient is unwilling to go through radical cystectomy [1]. The treatment is deemed a viable alternative avoiding morbidity and mortality of radical surgery and allows preservation of bladder [1]. The treatment modality would be suitable for elderly and weaker patients with lower performance score, however these specific group is also susceptible to multiple adverse effects from chemoradiation, such as anemia and electrolyte imbalances [1–5].

The natural course of bladder cancer itself showed an increased risk of anemia and electrolyte imbalance. Anemia was reported in about 30–90 % of cancer patients [6], whilst electrolyte imbalance accounts for 25–45 % and 40 % in forms of hyponatremia and hypokalemia [7, 8]. Further chemoradiation treatment may increase the impact on hemoglobin and electrolyte levels through multiple mechanisms, for instance, myelosuppression of most chemotherapy to the hemoglobin levels, hyponatremia and hypokalemia in specific platinum-based chemotherapy routinely used in bladder cancer, B₁₂ deficiency after radiotherapy that can cause anemia, vomiting and diarrhea caused by both chemoradiation that can lead to malnutrition/malabsorption causing both anemia and electrolyte imbalances, and other mechanisms currently explored and investigated [9–11]. By understanding these aggravating effects of chemoradiation in bladder cancer to anemia and electrolyte imbalance, it would be beneficial if we could stratify the risk of these adverse effect occurrences by identifying their independent risks factors.

By identifying the predisposing factors of anemia and electrolyte imbalance occurrences during chemoradiation therapy in bladder cancer, physician may closely monitor and evaluate patients with higher risk of disturbances, making early prompt treatment possible, resulting in better prognosis. This study would like to conduct an analysis for association and correlation between age, severity, and social determinant with anemia and electrolyte imbalance, specifically hyponatremia and hypokalemia in bladder cancer population with chemoradiation treatment plan.

Materials and methods

Study design

A prospective cohort study in bladder cancer patients was conducted in a tertiary referral hospital in Medan, Indonesia between year 2022–2023. Participants meeting the inclusion and exclusion criteria were included through total consecutive sampling. The following inclusion criteria were: (1) adult patient with urothelial carcinoma bladder cancer planned for chemoradiation, (2) patient with normal hemoglobin dan electrolyte level before commencing chemoradiation, (3) patient did not take diuretics for any other comorbid. Exclusion criteria were: (1) patient who were converted to surgical therapy (radical cystectomy), (2) patient who died during treatment before completing the chemoradiation. The radiation procedure encompassed full bladder irradiation to a cumulative dosage of 64–66 Gy in 2 Gy fractions utilizing 3D-CRT or IMRT techniques. The concurrent treatment regimen included weekly cisplatin (40 mg/m²), the predominant radiosensitizer utilized at our institution. Informed consent was obtained from each of the participants, and study has been approved for ethical clearance by local ethic committee.

Data collection

Baseline and follow-up examinations were conducted in Adam Malik Central Hospital. Diagnosis of bladder cancer was made by histopathological confirmation from transurethral bladder tumor resection done priorly and plan for chemoradiation was made from a careful discussion in internal oncological meeting, with consent from patients’ family confirmed beforehand. Baseline hemoglobin and electrolyte levels were taken before the meeting and commencement of chemoradiation therapy.

Predisposing factors were predetermined, including: age, severity, and social determinant. Age was presented as dichotomous data by geriatric and non-geriatric group using cut-off of 65 years old, and continuous data with mean and standard deviation. Severity was defined as cancer stadium, determined by TNM staging through abdominal contrast CT, thorax X-ray, and histopathological data. Stadium was divided into stage I, II, III, and IV according to American college of surgeon (AJCC) Cancer Staging Manual (2017). Social determinant was collected through anamnesis for total household income, categorizing income into below and above Upah minimum regional (UMR; regional minimum wage) in Medan defined as 3,624,117.00 IDR based on data from 2023, and education, categorizing into no education, elementary, junior high, high school, and above high school level. Follow up for hemoglobin and electrolyte levels were done in before every start of chemotherapy cycle and radiation therapy, determining the safety for treatment. Any occurrences of anemia, hyponatremia, and hypokalemia were recorded as positive event of adverse outcome, and the data of abnormal hemoglobin and electrolytes were collected for analysis.

Statistical analysis

Subject characteristics acquired from the data collection were presented in summary table. Statistical analysis was done in two parts. (1) Association between predisposing factors as categorical data with the occurrences of anemia, hyponatremia, and hypokalemia were made. Bivariate analyses were done using Chi-square test and multivariate analysis for variables with bivariate p result <0,1 were continued for multiple regression analysis using backward stepwise approach, omitting possible predetermined confounding, presented in OR and 95 % confidence interval. (2) Linear correlation between the predisposing factors in numerical data with hemoglobin, sodium, and potassium level were made using Pearson correlation test, presented in Pearson correlation coefficient (r). All statistical analyses were made using IBM SPSS Statistics, v.23.

Results

About 30 patients included in the study 60 % were male and 40 % were female. Mean ± SD age were 66.8 ± 8.23 years old, severity of bladder cancer was mostly stage IV (60 %), and most patients had total household income under UMR (83.3 %) with income of 2.000.000,00 (1.000.000,00–8.000.000,00) IDR. Education was mostly at elementary level (40 %) and below elementary level (23.3 %). Sample characteristics is presented in Table 1. Baseline median hemoglobin level was 11.1 (10.20–13.10) g/dL, median sodium level was 138 (136–140) mEq/L, and median potassium level was 4.2 (3.9–4.7) mEq/L. Anemia occurs in 66.7 % of patients during chemoradiation, while hyponatremia and hypokalemia occurs in 50 % and 36.7 % of patients respectively. Follow-up median hemoglobin level in reported anemia were 8.3 (5.9–9.8) g/dL, median sodium level in reported hyponatremia were 127 (118–132) mEq/L, median potassium level in reported hypokalemia were 2.9 (2.7–3.3) mEq/L.

 

Table 1. Study characteristics

Таблица 1. Характеристики пациентов, включенных в исследование

Characteristics Характеристика	Value Значение
Age, years1 Возраст, лет1	66.8	8.23 (51–79)
Age group, n (%): Возрастная группа, n (%): non-geriatric нестарческая geriatric старческая	10 (33.3) 20 (66.7)
Sex, n (%): Пол, n (%): male мужской female женский	18 (60) 12 (40)
Stadium, n (%): Стадия, n (%): 3 4	12 (40) 18 (60)
Household income2 (IDR) Общий семейный доход2 (IDR)	2,000,000.00 (1,000,000.00–8,000,000.00)
Economic level, n (%): Экономический уровень, n (%): under UMR ниже РПМ above UMR выше РПМ	25 (83.3) 5 (16.7)
Education, n (%): Образование, n (%): no education без образования elementary начальное junior high среднее high-school старшая школа beyond high school высшее	7 (23.3) 12 (40) 5 (16.7) 3 (10) 3 (10)
Baseline laboratory level2: Исходный уровень показателя2: Hb Na K	11.1 (10.20–13.10) 138 (136–140) 4.2 (3.9–4.7)
Anemia on chemoradiation, n (%) Анемия в ходе химиолучевой терапии, n (%)	20 (66.7)
Hb level2 Уровень гемоглобина2	8.3 (5.9–9.8)
Hiponatremia on chemoradiation, n (%) Гипонатриемия в ходе химиолучевой терапии, n (%)	15 (50)
Na level2 Уровень натрия2	127 (118–132)
Hipokalemia on chemoradiation, n (%) Гипокалиемия в ходе химиолучевой терапии, n (%)	11 (36.7)
K level2 Уровень калия2	2.9 (2.7–3.3)
1Age is presented as mean and median. 2Household income and laboratorium results are presented in median (min–max). Note. Household income are presented in Indonesian rupiah (IDR). UMR – regional minimum wage. 1Возраст представлен как среднее и медиана. 2Уровень дохода и лабораторные показатели представлены как медиана (мин–макс). Примечание. Общий семейный доход представлен в индонезийских рупиях (IDR). РПМ – региональный прожиточный минимум.

 

Table 2 show the association between investigated predisposing factors with the occurrences of anemia, hyponatremia, and hypokalemia. Bivariate analysis showed that out of all the grouped variables, only age group were shown to have statistically significant association to anemia and hyponatremia with odds ratio (OR) of 6.9 (1.9–52.5) and 20.8 1.2–342.7) and p of 0.03 and 0.02, respectively. Multivariate analysis resulted in an adjusted OR of 6 (1.1–31.9) and 7.4 (1.2–45) and p of 0.04 and 0.03, respectively. There were no variables that had association with hypokalemia.

 

Table 2. Comparison between groups of characteristics (age group, stadium, economic level, and education) with anemia, hyponatremia and hypokalemia during chemoradiation for bladder cancer

Таблица 2. Анализ ассоциаций между характеристиками пациентов (возрастная группа, стадия заболевания, экономический уровень и образование) и развитием анемии, гипонатриемии или гипокалиемии в ходе химиолучевой терапии

Characteristics Характеристика

Anemia Анемия

Hyponatremia Гипонатриемия

Hypokalemia Гипокалиемия

n (%)

non-adjusted без поправки

adjusted с поправкой

n (%)

non-adjusted без поправки

adjusted с поправкой

n (%)

non-adjusted без поправки

adjusted с поправкой

p

OR (95 %CI) ОШ (95 % ДИ)

p

OR (95 %CI) ОШ (95 % ДИ)

p

OR (95 %CI) ОШ (95 % ДИ)

p

OR (95 %CI) ОШ (95 % ДИ)

p

OR (95 %CI) ОШ (95 % ДИ)

p

OR (95 %CI) ОШ (95 % ДИ)

Age group: Возрастная группа: non-geriatric нестарческая geriatric старческая

4 (40) 15 (80)

0.03*

1 6.9 (1.9–52.5)

0.04*

1 6 (1.1–31.9)

2 (20) 13 (65)

0.02*

1 20.8 (1.2–342.7)

0.03*

1 7.4 (1.2–45.0)

2 (20) 9 (45)

0.18

– –

N/A НД

– –

Stadium: Стадия: 3 4

8 (67) 12 (67)

1

– –

N/A НД

– –

5 (42) 10 (55)

0.45

– –

N/A НД

– –

4 (67) 7 (39)

0.76

– –

N/A НД

– –

Economic level: Экономический уровень: under UMR ниже РПМ above UMR выше РПМ

16 (64) 4 (80)

0.49

– –

N/A НД

– –

1 3 (52) 2 (40)

0.63

– –

N/A НД

– –

9 (36) 2 (40)

0.87

– –

N/A НД

– –

Education: Образование: no education без образования elementary начальное junior high среднее high-school старшая школа beyond high school высшее

5/7 (71) 8 (67) 2 (40) 2 (67) 3 (100)

0.53

– – – – –

N/A НД

– – – – –

4 (57) 6 (50) 3 (60) 0 (0) 2 (67)

0.45

– – – – –

N/A НД

– – – – –

4 (57) 5 (42) 0 (0) 0 (0) 2 (67)

0.12

– – – – –

– – – – –

*Bivariate analysis was done using χ2 test and multivariate analysis was done using logistic regression to ommit confounding (age group, stadium, economic level, and education). Statistical significance was defined as p <0.05. Note. OR – odds ratio; CI – confidence interval; UMR – regional minimum wage; N/A – not available. *Двухмерный анализ проводился с использованием χ2-критерия, многомерный анализ – с использованием логистической регрессии для исключения сопутствующих факторов (возрастная группа, стадия заболевания, экономический уровень и образование). Уровень статистической значимости p <0,05. Примечание. ОШ – отношение шансов; ДИ – доверительный интервал; РПМ – региональный прожиточный минимум; НД – данные не доступны.

 

Further analysis to evaluate whether the numerical age, severity based on stadium, household income, and education have a linear correlation with hemoglobin, sodium, and potassium value in anemia, hyponatremia, and hypokalemia were done using Pearson correlation test. Correlation analysis of age and hemoglobin level showed significant moderate correlation coefficient (r) of –0.52 (p = 0.018) indicating that the higher the age, the lower hemoglobin level in anemia during chemoradiation. Correlation analysis of household income and hemoglobin, sodium, and potassium level showed moderate-strong correlation coefficient (r) of 0.61, 0.52, and 0.69 respectively (p = 0.004, 0,04, and 0.018), indicating that the lower the household income, the lower the hemoglobin, sodium, and potassium level during chemoradiation. Furthermore, Education showed a moderate correlation (r = 0.52) and strong correlation (r = 0.63) with anemia hemoglobin level and hypokalemia potassium level, respectively. Results of the correlation analysis can be seen in Table 3.

 

Table 3. Bivariate correlation analysis between age, severity, household income, and education with hemoglobin, sodium, and potassium level in anemia, hyponatremia, and hypokalemia during chemoradiation for bladder cancer

Таблица 3. Двухмерный анализ корреляций между возрастом, тяжестью заболевания, общим семейным доходом, образованием и уровнями гемоглобина, натрия и калия при анемии, гипонатриемии и гипокалиемии в ходе химиолучевой терапии рака мочевого пузыря

Characteristics Характеристика	Anemia Hb level Уровень гемоглобина при анемии		Hyponatremia Na level Уровень натрия при гипонатриемии		Hypokalemia K level Уровень калия при гипокалиемии
	p	r-correlation coefficient Коэффициент корреляции r	p	r-correlation coefficient Коэффициент корреляции r	p	r-correlation coefficient Коэффициент корреляции r
Age Возраст	0.018*	– 0.52	0.11	– .0.27	0.75	0.11
Severity Тяжесть заболевания	0.86	– 0.42	0.93	0.02	0.86	– 0.06
Household income Общий семейный доход	0.004*	0.61	0.04*	0.52	0.018*	0.69
Education Образование	0.017*	0.52	0.15	0.39	0.038*	0.63
*Statistical significance was defined as p <0.05. Note. r coefficient were analyzed using Pearson test. *Уровень статистической значимости p <0,05. Примечание. Коэффициент корреляции r рассчитан по методу Пирсона.

 

Discussion

Chemoradiation has been a highly accepted treatment modality in bladder cancer, especially in unresectable patients and those who opted out from radical surgery [1].Albeit its routine utilization, adverse events such as anemia and electrolyte imbalance occurring due to the therapy are likely to occur, sometimes complicating the course of therapy for the physician [1, 6–12]. To our knowledge, our study is the first to analyze the linear correlation between potential predisposing factors as such age, severity, and social determinant with the levels of hemoglobin, sodium, and potassium in anemia and electrolyte imbalance during chemoradiation therapy. We found that age had a linear correlation with hemoglobin level in anemia patients given chemoradiation, where the older the patient the higher the risk lower hemoglobin level of anemia. We also found that social determinants such as household income and education had linear correlation with hemoglobin level in anemia and electrolyte level in electrolyte imbalance patient given chemoradiation.

Similar to previous publications [13–15], we found a robust number of patients (66.7 %) who develop anemia given the four cycle of gemcitabine and cisplatin chemotherapy as well as radiation therapy of 68 Gy. Past literature has demonstrated that platinum-based chemotherapy (carboplatin and cisplatin) is very myelosuppressive, and additional therapy would incur higher severity of anemia after therapy [13, 16–19]. In addition, as previously reported by past literatures anemia is one of a frequent adverse event of radiotherapy, occurring in 16–30 % of the patients, suggested by its myelosuppressive effect [20]. Our study investigated further into predisposing factor analysis by both categorical analysis and correlation analysis for the occurrence of anemia in chemoradiation. We found out that only geriatric group were more at risk to develop anemia when categorized into groups with an adjusted OR of 6 (1.1–31.9). Furthermore, correlation analysis showed that the higher the age of the patient, the more likely that the patient have more severe anemia with lower hemoglobin level due to chemoradiation. Although when categorized into group based on their household income by UMR and education level no statistical difference were found, correlation analyses showed contrasting result. There were significant moderate-strong correlations between the number of household income and education level with the level of hemoglobin in the anemia patients. Our study showed that the higher the household income and education level, the better the hemoglobin level in these anemia patient post chemoradiation.

Electrolyte imbalance were found in a moderately high number of patients in our study, in a form of hyponatremia (50 %) and hypokalemia (33.7 %). The result is in accordance to literature made by B. Oronsky et al. [10] and Pi et al. [21] literatures indicated that renal wasting and GI losses may contribute in impaired reabsorption of sodium and potassium, resulting in electrolyte imbalances. Furthermore, since vomiting and diarrhea are also common in platinum-based therapy, these might exacerbate the electrolyte imbalance [21]. As reported by A. Ayoola et al. [22]. radiation can lead to syndrome of inappropriate secretion of antidiuretic hormone. The excess release of antidiuretic hormone can result in hyponatremia [22]. Our study also showed that geriatric patients were more at risk of hyponatremia with adjusted OR of 7.4 (1.2–45.0). Further correlation analyses showed that there are moderate-strong correlations between the number of household income and education level with the level of electrolytes in the hyponatremia and hypokalemia patients. Our study showed that the higher the household income and education level, the better the electrolyte levels in these patients.

Age is a known independent risk factor for both anemia and electrolyte imbalance. Anemia in older patient is very complex as nutritional deficiency, hormonal changes, increased consumption of erythrocytes, and chronic inflammation may all have exacerbated the decrease in hemoglobin level in anemia [3, 4, 6]. For electrolyte imbalance, older people have impaired thirst perception, decreased glomerular filtration rate, alteration in hormone level, decreased of urinary concentrating ability, and inadequate food and drink intake [5]. These pathophysiological changes may eventually aggravate the myelosuppressive of chemoradiation, leading to higher risk of having electrolyte imbalance. In our study however, although geriatric group are more susceptible for hyponatremia, the number of age did not have linear correlation with the sodium level in hyponatremia.

As suggested by, N. Daniels et al. [23] and S. S. Coughlin et al. [24] social determinants such as income and education may influence the risk of multiple adverse health outcomes in cancer therapy [24]. They suggested that low-income families may not have access to health-care, housing, or transportation and are more likely to postpone medical care and underuse medicine due to prioritizing more on their basic need, as simple as daily meal, resulting in lack of supplementation and bad health seeking behavior. Low-income family are also at risk of having less nutrient in their food and having less exposure to hemoglobin increasing food [24]. Low education would also aggravate the condition, as lack in education would make the patient deprioritize, and worse neglecting, their health [25, 26]. Lack of awareness and health seeking behavior is associated with low level of education, thus may aggravate the impact of chemoradiation on anemia and electrolyte imbalance [23–26].

Our study is limited to a low number of participants. Further good quality controlled prospective study with high number of samples should be done to ensure the quality of the result. Since the condition is very multifactorial, identification of other possible confounding is important to ensure the result would be reliable omitting potential external influences.

Conclusion

Our study showed that age and social determinants are predisposing factors of anemia and electrolyte imbalance in chemoradiation for bladder cancer and have a linear correlation with the abnormal level of hemoglobin and electrolytes after treatment.

About the authors

G. P. Siregar

Universitas Sumatera Utara

Author for correspondence.
Email: ginandaputrasiregar4@gmail.com
ORCID iD: 0000-0001-8991-9707

Division of Urology, Department of Surgery, Faculty of Medicine

Indonesia, Medan

I. I. Purtantyo

Universitas Indonesia

Email: rmhkiip@ucl.ac.uk

Department of Urology, Faculty of Medicine

Indonesia, Jakarta

S. M. Warli

Universitas Sumatera Utara

Email: warli@usu.ac.id

Division of Urology, Department of Surgery, Faculty of Medicine

Indonesia, Medan

D. D. Kadar

Universitas Sumatera Utara

Email: dhira303@yahoo.com

Division of Urology, Department of Surgery, Faculty of Medicine

Indonesia, Medan

F. F. Prapiska

Universitas Sumatera Utara

Email: fauriski@gmail.com

Division of Urology, Department of Surgery, Faculty of Medicine

Indonesia, Medan

References

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