INTRODUCTION:

One of the principal aims of anticancer drug development is to improve efficacy and reduce toxicity through greater tumor specificity¹. The use of platinum drugs has contributed to increases in the long-term survival of cancer. Unfortunately, platinum agents have adverse effects including ototoxicity and associated permanent hearing loss². The effect of hearing loss in young children is significant and can influence speech and language development, educational achievement, and social-emotional development³.

Platinum ototoxicity is typically manifested as bilateral high-frequency sensorineural hearing loss. With continued administration and increasing cumulative dose, the hearing loss tends to increase in severity and progressively spreads to affect hearing atlower frequencies⁴. Ototoxicity probably is caused by damage to the organ of Corti by cisplatin, including the destruction of auditory sensory cells, and is manifested as hearing loss and/or tinnitus in the high-frequency range (beyond 4 kHz)⁵. Cisplatin accumulates in the kidneys, and the nephrotoxic effect of cisplatin is proportional to the amount of drug accumulated^{6, 7}.

The aim of the present study was to assess the nephrotoxicity and ototoxicity of weekly cisplatin therapy in cancer patients.

MATERIALS AND METHODS:

Study site and Study Design:

This study was carried out in chemotherapy ward, department of radiotherapy, Government General Hospital, Kakinada for the duration of 6 months. This prospective cross-sectional study was designed to implement a mixed methods approach. It is an approach that includes a combination of elements from the qualitative and quantitative approach in a single study. This study employed an explanatory study design which includes the collection and analysis of the quantitative data followed by qualitative data collection and analysis. The main reason for the use of this method is for depth description and to increase the scope of the study.

Ethical Consideration:

Permission was approved from the Institutional Ethical Committee to conduct this study. The aim and objective of the study were clearly explained to the patients. A patient consent form was obtained from patients who are willing to co-operate the study.

Sampling Technique, Sample Size, and participants:

Simple random sampling technique was employed as a sampling technique in the study. In this study the required sample size(n) is 67, the population size(N) is 80, the fraction of responses(r) is 50, the confidence level (c) is 95% and the margin of error (E) accepted is 5%.

Participants:

Patients with age group > 18 years, patients receiving only weekly cisplatin therapy were included in the study. Patients who are critically ill, who are not willing to participate in the study, patients who are receiving combinational chemotherapy were excluded from the study.

Data collection and analysis:

Patient’s baseline Serum Creatinine and Blood Urea Nitrogen values were noted down from the laboratory data. The patient was followed for three successive chemotherapy schedules. The follow-up values of Serum Creatinine and Blood Urea Nitrogen was noted from the laboratory data. Finally, all the four observed values of serum Creatinine and blood urea nitrogen (baseline, chemotherapy 1, chemotherapy 2, and chemotherapy 3) were tabulated and analyzed statistically for associations. Initially before starting first chemo cycle patients hearing quality was assessed by plotting the audiometry graph and it was taken as the baseline value. Patients with an age greater than 60 years were excluded for assessing hearing loss. Similarly, after the first and second chemotherapy cycles, the hearing quality was assessed and the values were noted.

Qualitative data like gender, employment, marital status, type of cancer was collected from the case sheets of the patient and ototoxicity grades were collected from the audiometric report. Quantitative data like age was collected from the case sheet and nephrotoxicity was collected from the laboratory reports of the patients. Qualitative data was represented as a bar chart or pie chart. Frequency and percentage were calculated for the qualitative data. Quantitative data was represented as histogram or line chart. Mean, Standard deviation and confidence interval was calculated for the quantitative data.

Association between cisplatin and nephrotoxicity was calculated using the Friedman Test. Association between cisplatin and ototoxicity was calculated using Fishers Exact test. Correlation between baseline renal function assessing parameters and other successive chemotherapies was done using Spearman’s Rho test. The level of significance was considered at p-value <0.05.

RESULTS AND DISCUSSION:

Table 1: Age wise distribution of patients suffering from Nephrotoxicity (n=81)

S. No.	Age in years	Frequency	Percentage
1	20 – 30	06	7%
2	31 – 40	15	18%
3	41 – 50	23	30%
4	51 – 60	20	24%
5	61 – 70	17	21%

Fig. 1: Gender wise distribution of patients suffering from Nephrotoxicity

Table 2: Distribution of various cancers in males and female patients (n=81)

Clinical Diagnosis of Cancer	No. of Male Patients	No. of Female Patients	%
Cervical Carcinoma	0	27	33.33%
Carcinoma of Head and Neck	28	18	56.79%
Carcinoma of Lung	1	0	1.23%
Carcinoma of Urinary Bladder	1	0	1.23%
Anal Canal Carcinoma	2	2	4.93%
Carcinoma of Penis	2	0	2.46%

Table 4: Association of Cisplatin therapy and Nephrotoxicity

S. No.	Parameter	Chi- square value	p- value
1	Serum Creatinine	8.24	0.013
2	Blood Urea Nitrogen	6.59	0.037

Table 5: Correlation of Serum Creatinine and BUN in different times of chemotherapy

Time of chemotherapy	r_s value	t- value	p-value
Serum Creatinine
Baseline and CT1	0.399	3.87	0.000
Baseline and CT2	0.501	5.16	0.000
Baseline and CT3	0.598	6.64	<0.000
Blood Urea Nitrogen (BUN)
Baseline and CT1	0.207	1.26	0.041
Baseline and CT2	0.088	0.73	0.233
Baseline and CT3	0.186	1.58	0.059

As shown in Table 1, the mean age group of patients was 50.50±12.04 years. The most commonly affected age group in our study was 41 – 60 years (54%). Figure 1 showed that females were more commonly affected (58%). As shown in table 2, Carcinoma of head and neck was more prevalent in our study (56.79%).

Table 3 represents the laboratory values of serum creatinine and blood urea nitrogen. The mean serum creatinine value at baseline (0.79± 0.17) was slightly higher in 3^rd chemotherapy cycle (0.93±0.56). There was a statistically significant association between cisplatin therapy and nephrotoxicity (Table 4). However, as shown in table 5, there was a strong positive correlation between baseline and different cycles of cisplatin chemotherapy and serum creatinine. The statistical significance was very high (p<0.000) between baseline and 3^rd chemotherapy cycle.

Table 6: Age wise distribution of patients suffering from ototoxicity (n=42)

S. No.	Age in years	Frequency	Percentage
1	30 - 40	08	19%
2	41 – 50	14	33%
3	51 – 60	13	31%
4	61 - 70	07	17%

Fig. 2: Gender wise distribution of patients suffering from ototoxicity

Table 7: Comparison of Ototoxicity between different times of chemotherapy

S. No.	Ototoxicity	p-value
1	Right Ear	0.302
2	Left Ear	0.387
3	Both Ears	0.325

The mean age group of patients was 50.50±11.56 years. The highest incidence of Ototoxicity occurred at the age of 41-50 years with 14 patients (Table 6). A shown in figure 2, females were more commonly affected in our study (761%). As shown in table 7, There was no statistically significant association between weekly cisplatin dose and ototoxicity (right ear, p=0.302; left ear, p=0.387; both ears, p=0.325) in our study. The mean dose of weekly cisplatin in the sample was 55mg/m².

The incidence of nephrotoxicity gradually increased with age. Patients younger than 48 years had a 26% risk for renal toxicity which increased to 35% for patients aged 48-62 years and 41% for patients for more than 62 years. Although increased age was a risk factor for nephrotoxicity, our study also demonstrates that weekly cisplatin treatment is not necessarily contraindicated in elderly patients⁸. Women had a twofold increased risk for renal toxicity compared with men. The reason for this gender difference is not known. In a previous study, it was found that unbound cisplatin clearance was 15% higher in men than in women but age had no significant influence on this clearance⁸.

The mean dose of weekly cisplatin in our study was 55.74 mg. Hisato et al⁹ found that 32% of individuals who received cisplatin at the dose the at least 60mg/sq. developed acute nephrotoxicity despite the adoption of conventional measures of hydration and osmotic dieresis). Hoek et al ¹⁰ reported a reduction of nephrotoxicity by adjusting cisplatin schedule which reports less renal failure for patients receiving a weekly schedule.

Kose et al¹¹ had mentioned similar renal toxicity between the two different cisplatin regimens, even total cisplatin doses in three weekly group were higher than weekly group (210 mg/m2 vs. 162 mg/m2, p<0.0001). Espelia et al ¹² reported that up to 53.7% of patients treated with three weekly cisplatin suffered acute renal failure compared 35% weekly patients despite no statistical significance (p=0.07). In a study by Mukund et al²⁴, creatinine was increased significantly than BUN after cisplatin treatment and also the frequency and severity of cisplatin nephrotoxicity may be reduced by slow intravenous electrolyte infusions and maintaining the hydration, before, during and immediately after the administration of cisplatin.

Smaller individual doses of cisplatin may lead to less chemotherapy-induced morbidity when a prophylactic procedure of its administration is respected. Good tolerance of this alternative cisplatin dosing schedules has also been reported in multiple large randomized trials in locally advanced HNC ^{13, 14}as well as in cervical cancer^15,16, because it resulted in a higher rate of completion of chemoradiation and less serious (grade 3/4) renal and hematologic toxicity. Additionally, more frequent cisplatin administration could provide radiosensitizing chemotherapy as a larger proportion of the administered RT dose. Therefore, concomitant weekly cisplatin with RT is a safe and effective treatment regimen.

In our study, we obtained 11.90% of the pathological audiogram. This could be due to either high doses or due to older patient cohorts. In our sample (n=42), 33.33% of patients experienced transient symptoms, mostly tinnitus; only 54.76%of respective audiograms was completely normal. Pre-existing hearing loss, age and individual sensitivity to the drug can also play a major role. Of the 42 patients studied, 14 patients have modest hearing impairment before chemotherapy.

In one study ⁸ ototoxicity was observed in 168 patients (42%); 110 patients (28%) had CTC grade-II (reversible tinnitus), 55 patients (14%) with grade-III and 3 patients (1%) had grade-IV Ototoxicity. Hearing loss after cisplatin therapy was dose-dependent, frequency dependent, schedule dependent. Rademaker et al¹⁷ found that hearing loss after cisplatin therapy occurred mainly at cisplatin dosage more than 60mg/sq.m and at high frequencies (4-8 KHz). Of the 60 patients in his study, 9 patients had modest hearing impairment before chemotherapy (grade I). Hearing loss was more severe in older patients than in younger patients. No significant difference in hearing impairment was observed between right and left ear. However, the decrease in hearing threshold measured by audiometry and the subjective hearing loss reported by the patients does not always correlate with the observed CTC grades of ototoxicity. Some patients had minimal or mild shifts in hearing thresholds. Therefore the relationship between the decrease in decibels and the ototoxicity CTC grades needs to be elucidated further.

The mean incidence of ototoxicity was 33% when patients received a single dose of 50mg/sq Cisplatin¹⁸. Andrew et al¹⁹ reported that 15 of the 31 subjects had significant hearing loss following cisplatin chemotherapy. In contrast, in one study ototoxicity of cisplatin was measured by serial tone audiography in 23 patients. Only 8 patients (35%) showed significant audiographic changes. Although none of them developed clinical hearing loss²⁰. Bokemeyer et al ²¹ reported audiometric threshold deviations compatible with persisting ototoxicity in all patients with the application of high single doses of cisplatin (35-50 mg m-2) when cumulative doses > 550 mg m-2 and in all patients with cisplatin > 600 mg m-2, regardless of the single dose given. Of the 16 patients with > 600 mg m-2, cisplatin only five (31%) remained asymptomatic.

Docetaxel+ Gemcitabine (DG) had a better toxicity profile and could be used in the first line setting of advanced NSCLC, especially for patients who cannot tolerate cisplatin ²². Cisplatin when replaced with carboplatin and when monitored for hearing loss, carboplatin showed better efficacy in hearing when compared with cisplatin ²³.

CONCLUSION:

There was a statistically significant association between cisplatin therapy and nephrotoxicity. The ototoxicity of cisplatin can be better known when done in large populations. Cisplatin can be replaced with Carboplatin to minimize or prevent hearing loss.

CONFLICTS OF INTEREST:

The author declares no conflicts of interest

ACKNOWLEDGMENTS:

We are grateful to Dr. C.S.K. Prakash and Dr. P. Prasanth for their support and guidance throughout the research study.

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Received on 22.10.2018 Modified on 16.11.2018

Research J. Pharm. and Tech. 2019; 12(4):1922-1926.

DOI: 10.5958/0974-360X.2019.00322.6

S. No.	Time of Chemotherapy	Serum Creatinine mg/dL	Blood Urea Nitrogen mg/dL
1	Baseline	0.79± 0.17 [0.75, 0.83]	26±5.99 [24.61, 24.39]
2	CT 1	0.88± 0.70 [0.72, 1.05]	25.05±6.79 [23.47, 26.63]
3	CT 2	0.83± 0.24 [0.77, 0.88]	28.02±7.10 [26.37, 29.68]
4	CT 3	0.93±0.56 [0.80, 1.06]	29.56±14.19 [26.26, 32.86]