Serum Platinum Levels Research Articles

Building a model to predict the risk of multiple severe neurotoxicities in cancer survivors after cisplatin treatment.

e24066 Background: Cisplatin treatment is used for many cancers, including testicular, ovarian, and head and neck malignancies. Cancer survivors with multiple cisplatin-related toxicities can have poor health-related quality of life (HRQOL). Identification of clinical and genetic factors that predict the risk of these neurotoxicities is critical. Methods: Testicular cancer survivors (TCS) enrolled in the Platinum Study completed surveys, underwent physical examination, extensive audiometric testing, and phlebotomy for genotyping and serum platinum analysis. Cases included TCS with two or more severe toxicities (hearing loss [HL], tinnitus, and peripheral sensory neuropathy [PSN]), defined as follows: hearing threshold > 40dB based on geometric mean of 4-12kHz, responding yes to “Do you have ringing or buzzing in the ears?” and/or EORTC-CIPN20 scores in the severe range for items related to sensory neuropathy. Controls were restricted to TCS without any toxicities. TCS with a single toxicity were excluded from analyses. Penalized logistic regression lasso method was used to create the model to predict the binary outcome. Creatinine clearance and residual serum platinum levels were calculated. Polygenic risk scores (PRS) for traits commonly associated with pharmacokinetics and HL, tinnitus, and PSN were calculated for TCS in the training (n = 284) and validation (n = 157) data sets using PRS publicly available in The Polygenic Score Catalog using PRSice 2.3.3. Models were trained and tested in R 4.1.2. Results: A model to assess the risk of developing multiple severe neurotoxicities that could be used without blood work and additional analysis was developed. Clinical predictors incorporated into the model were age at testicular cancer diagnosis, age at phlebotomy, weight and height. PRS incorporated were age-related sensorineural hearing loss (PGS000762), body fat percentage (PGS002133), creatinine in urine (PGS001944), and peripheral nervous system disease (PGS002039). The accuracy of this model was 77.71%, which was significantly greater than the no information rate (NIR) of 65.61% (p = .00067). The positive and negative predictive values (PPV and NPV) were 72.09% and 79.82%, respectively. The AUC-ROC was 0.804. Adding residual platinum levels and creatinine clearance increased the accuracy of the model to 78.34%, which was significantly greater than the NIR (p = .00035). The PPV was 75.00% and the NPV was 79.49%. The area under the receiver operating characteristic curve (AUC-ROC) was 0.832. Conclusions: TCS are often faced with multiple severe neurotoxicities such as HL, tinnitus, and PSN, which impact HRQOL for many decades. If confirmed, a penalized regression model using clinical and genetic characteristics can predict the risk of developing these phenotypes to guide clinicians in treatment and post-treatment management plans.

Semen and serum platinum levels in cisplatin-treated survivors of germ cell cancer.

BackgroundTesticular cancer survivors often have impaired gonadal function possibly related to chemotherapy. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility.MethodsAdult cisplatin‐treated testicular cancer survivors were enrolled. High‐Performance Liquid Chromatography‐tandem mass spectrometry was used to measure semen and serum platinum levels. Semen quality and DNA Fragmentation Index (DFI) were assessed.ResultsFrom 11/2017 to 12/2019, 38 patients (median age 32 years; range: 19–52) were enrolled. Median cumulative cisplatin dose was 301 mg/m2 (range: 274–404). Platinum levels were higher in semen than in blood (p = 0.03). Semen platinum levels were not significantly associated with time from last cisplatin dosing (r = −0.34; p = 0.09) nor cumulative dose (r = −0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p < 0.001) but not with semen platinum level (r = −0.15, p = 0.46). DFI was not significantly associated with time from last cisplatin dosing (r = 0.55, p = 0.08) or semen platinum level (r = −0.32, p = 0.33). In four patients with serial semen samples, platinum level decreased and sperm concentration and motility increased over time.ConclusionsPlatinum is detected in semen of testicular cancer survivors at higher levels than matched blood samples. These preliminary findings may have important implications for the reproductive health of survivors of advanced testicular cancer, further study is needed to assess the relationship between platinum persistence in semen and recovery of fertility postchemotherapy.

Integration of a polygenic risk score of kidney function with cumulative cisplatin dose and time variables for the prediction of serum platinum levels.

12063 Background: Platinum levels are measurable in the serum for decades after cisplatin therapy and higher levels may be related to chemotherapy-induced toxicities. Since cisplatin is cleared exclusively by the kidney, we hypothesized that a genetic predictor of kidney function, an estimated glomerular filtration rate polygenic risk score (eGFR PRS), would significantly associate with serum platinum levels and could improve prediction models. Methods: Within a large well-characterized, multicenter clinical cohort of cisplatin-treated testicular cancer survivors (TCS), we conducted analyses on all patients with genetic data and serum platinum levels. Genotyping was performed on the HumanOmniExpressExome chip and standard QC measures were included. Serum platinum concentrations were quantified by inductively coupled plasma mass spectrometry. For all TCS, time since therapy (TIME) and cumulative cisplatin dose were collected. The eGFR PRS was developed from the Chronic Kidney Disease Genetics (CKDGen) consortium meta-analysis summary statistics using PRS-CS. Using principal component analysis, we restricted the analysis to TCS of genetically determined European ancestry, then calculated the genome-wide PRS for all participants. We performed Cox regression analyses to evaluate prediction models of serum platinum that included cumulative dose and TIME, as well as a model including eGFR PRS. Data are presented as median(interquartile range). Results: 901 patients were included in our analysis with a median diagnosis age of 31 (26 - 38) years, cumulative cisplatin dose of 400 (300-400) mg/m2, and time since first cisplatin dose of 4.6 (2.3-9.5) years. The median serum platinum level for all TCS was 305 (121-981) ng/L. When stratified into quartiles by eGFR PRS, TCS in the lowest quartile had a median serum platinum level of 316 (139-1014) ng/L while TCS in the highest had a median of 268 (106-731) ng/L. Comparison of two Cox regression models for serum platinum prediction, one including only cumulative dose and TIME as predictors and a second including dose, TIME, eGFR PRS, and an eGFR PRS*TIME interaction term, we determined the model including eGFR PRS had a lower AIC (14350 vs 16180) suggesting a more parsimonious model. Further, eGFR PRS was a significant independent predictor of serum platinum levels (p = 0.02) and the impact of eGFR PRS varies over time (eGFR PRS*TIME, p = 0.05). Conclusions: The genetic predictor of kidney function circumvents the use of renal function measures that may have been impaired by initial cisplatin administration. It is a significant independent predictor of serum platinum levels and consistent with expectation: TCS with higher genetically predicted kidney function had lower serum platinum levels. Our results suggest kidney function inferred by genetics may improve the prediction of serum platinum levels.

Clinical and Genome-Wide Analysis of Multiple Severe Cisplatin-Induced Neurotoxicities in Adult-Onset Cancer Survivors.

Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities. The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case-control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed. Age at clinical examination (P = 6.4 × 10-16) and cumulative cisplatin dose (P = 5.4 × 10-4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10-9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10-14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10-5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10-5) and FAM20C (P = 5.5 × 10-5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines. Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels. Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10-3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10-3). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P = 4.6 × 10-8, a SNP intronic to MYH14). This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.

Abstract 3904: Pharmacokinetic modeling of serum platinum reveals extent of long-term exposure and associated comorbidities after cisplatin treatment

Abstract Platinum is detectable in the plasma years after completion of cisplatin treatment. Although it has been hypothesized that circulating platinum contributes to the severity and persistence of cisplatin’s adverse effects, results have been inconsistent due to the lack of an effective pharmacokinetic model that takes into account time since therapy and the use of relatively small patient cohorts. Here, we report the largest pharmacokinetic study to date of 1,013 testicular cancer survivors (TCS) assessed 1-35 years after completion of cisplatin-based chemotherapy, and perform a genome-wide association study (GWAS) to assess genetic contributions to our pharmacokinetic phenotype computed from serum platinum levels. Eligible TCS given 300 or 400 (± 15 mg/m2) cisplatin underwent extensive audiometric testing and clinical examination, as well as completed questionnaires at the time of follow-up. We then built an empirical pharmacokinetic model by considering time since treatment and cumulative cisplatin dose received, fitting the data to a power (log-log linear) model as a log-log transformation linearized relationship with time. This power model was used to generate a residual platinum value (RPtV) that likely correlates with the area under concentration-time curve. Using linear regression, we found positive associations between RPtV and several clinically relevant phenotypes including the cumulative burden of morbidity for cisplatin-induced toxicities (β = 0.08, p = 8.42x10-3), peripheral sensory neuropathy (β = 0.14, p = 5.45x10-3), Raynaud’s phenomenon (β = 0.09, p = 0.04), hypercholesterolemia (β = 0.22, p = 0.02), LDL-cholesterol (β = 2.67x10-3, p = 0.01), luteinizing hormone (β = 0.02, p = 0.01), and age at clinical examination (β = 0.02, p = 2.04x10-7). Multinomial regression indicated that these associations are much more prominent in patients designated with high RPtV (&amp;gt; 1 standard deviation above the mean). In addition, we found a strong negative association with creatinine clearance (β = -9.04x10-3, p = 1.03 x10-10). GWAS implicated two SNPs that met genome-wide significance: rs78225733 (p = 6.9 x 10-9) in a gene desert on chromosome 12 and rs45623132 (p = 1.1 x 10-8), which is intronic to meningioma 1 (MN1). Taken together, our novel pharmacokinetic model indicates serum platinum levels are associated with several cisplatin-induced toxicities and comorbidities, and that finding methods by which to reduce circulating platinum once patients have been cured of their disease could be an effective strategy to improve their overall quality of life. Citation Format: Matthew R. Trendowski, Omar El-Charif, Zepeng Mu, Mark J. Ratain, Heather Wheeler, Paul C. Dinh, Darren R. Feldman, Shirin Ardeshir-Rouhani-Fard, Robert J. Hamilton, David J. Vaughn, Chunkit Fung, Taisei Mushiroda, Lawrence H. Einhorn, Lois B. Travis, M. Eileen Dolan. Pharmacokinetic modeling of serum platinum reveals extent of long-term exposure and associated comorbidities after cisplatin treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3904.

Persistence of platinum in semen of cisplatin-treated survivors of advanced testicular cancer.

519 Background: Even in patients (pts) with widely metastatic germ cell tumors cure rates are high with cisplatin based chemotherapy. Survivors of testicular cancer often have impaired gonadal function possibly related to chemotherapy. Most pts develop temporary azoospermia with recovery in about 50% after 2 years and 80% after 5 years. Platinum persists in blood in these pts, however, it is not known whether platinum also persists in semen. Methods: Pts who completed cisplatin &gt; 3 months previously were enrolled. Age, total cisplatin dose and date of completion of treatment were collected. A semen sample was collected from each patient for analysis to assess semen quality. A blood sample was collected to assess FSH/LH/testosterone/creatinine. Serum and semen platinum levels were measured using HPLC-tandem mass spectrometry. Results: Between 11/2017 and 09/2018, 9 pts (median age 32 years; range: 18-52) were enrolled to the study, all were treated with standard Bleomycin, Etoposide, Cisplatin regimen. Blood samples were collected from 7 pts, and semen samples from 4 pts. Median total cisplatin dose given was 658 mg (range: 570-780). Median serum platinum concentration was 0.395 ng/mL (range: 0.10-0.94) at a median of 10 months (range 4.5-13) post completion of treatment. Median semen platinum concentration was 1.06 ng/mL (range: 0.25-1.47) at a median of 10 months (range: 6-14) post completion of treatment. Semen platinum levels were associated with total cisplatin dose administered (Pearson correlation, r = 0.645) and time from completion of treatment (Pearson correlation, r = 0.386). In all 4 pts with matched samples, the semen platinum level was higher than the serum platinum level. Semen analysis showed 2 pts were azoospermic post treatment, 1 of these was also azoospermic prior to treatment; 1 pt had normal semen analysis post treatment and 1 had a low sperm count post treatment. Conclusions: This is the first study demonstrating that platinum persists in semen &gt; 6 months post completion of cisplatin-containing chemotherapy. Platinum levels are higher in semen than in blood following treatment. Our preliminary findings may have important implications for reproductive health of survivors of advanced testicular cancer.

Platinum deposition in skin as a possible mechanism for peripheral sensory neuropathy (PSN) in patients (pts) with colorectal cancer (CRC) following oxaliplatin-based therapy.

685 Background: Oxaliplatin plus fluorouracil (FOLFOX) is a standard treatment for CRC pts. One of the most common and dose-limiting side effects of oxaliplatin is PSN. The mechanism of this phenomenon is poorly understood. Previous studies suggested that higher serum platinum levels were related to more severe neuropathy in testicular cancer pts. Methods: CRC pts who completed adjuvant FOLFOX at least 6 months prior to enrollment are eligible. Baseline demographic and treatment information were collected. EORTC CIPN20 (with EORTC QLQ-C30) questionnaire was used for self-reported PSN symptom assessment. Peripheral blood samples were collected for total/free platinum concentrations using high-performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS). Skin biopsies were obtained from the lower leg of consented pts. Imaging mass cytometry (IMC) was used to visualize platinum deposition (195Pt) and intra-epidermal nerve fiber (IENF) (PGP9.5-154Sm) in formalin-fixed paraffin embedded (FFPE) skin biopsy samples stained with a metal-conjugated antibody cocktail. Results: Nine patients were enrolled. Median age was 51.8 yr (range: 34.5-69.4 yr); male/ female: 5/4; mean cumulative dose of oxaliplatin was 800.7 ± 188.2 mg/m2; median time from last dose of oxaliplatin to enrollment was 48 months (range: 7.2-65.6 months). The mean sensory score from CIPN20 was 15.4 ± 4.3 (range: 10-25). Platinum was undetectable in plasma samples collected from all 9 patients. In skin samples, IMC showed significant platinum depositions and IENF. Conclusions: Severity of PSN was not related to cumulative dose of oxaliplatin or interval from last dose of oxaliplatin. Although platinum was undetectable in plasma in these patients, platinum was readily detectable in skin biopsies up to 65.6 months post completion of FOLFOX. This is the first demonstration of platinum deposition in skin post oxaliplatin treatment and it provides a possible mechanism for oxaliplatin-induced PSN.

Impact of Long-Term Serum Platinum Concentrations on Neuro- and Ototoxicity in Cisplatin-Treated Survivors of Testicular Cancer

Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated. In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, "not at all"; 1, "a little"; 2, "quite a bit"; or 3, "very much." Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age. At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses. Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

Concurrent Weekly Cisplatin Chemotherapy and Radiotherapy in a Haemodialysis Patient with Locally Advanced Cervix Cancer

Aims Concurrent cisplatin chemo-radiotherapy improves outcome in cervical carcinoma. In haemodialysis patients, cisplatin is potentially hazardous. We report the treatment of a haemodialysis patient with cervix cancer using cisplatin-based chemo-radiation. Mathematical modelling using toxicity data from a range of cisplatin dosages and schedules reported in published studies was undertaken. Materials and methods The patient was treated using weekly cisplatin chemotherapy 25 mg/m 2. The serum platinum levels were measured. Correlations between reported toxicity and platinum levels for a variety of cisplatin schedules in published studies were evaluated. Results Treatment was completed with no interruptions and minimum acute toxicity. The platinum levels rose progressively. The elimination half-life was prolonged at 6.6–7.5 days. The percentage extraction varied between 7.7 and 41.0%. The cumulative cisplatin dose correlated with neurotoxicity ( P = 0.002). Myelotoxicity correlated with the peak cisplatin level in the first 15 days of treatment ( P = 0.01). With an elimination half-life of 7.5 days, 35 mg/m 2 weekly is predicted to have the same risk of myelotoxicity and neurotoxicity as 40 mg/m 2 weekly in a patient with normal renal function. Conclusions Weekly cisplatin chemotherapy 25 mg/m 2 can be delivered safely in a haemodialysis patient. Dialysis is effective in eliminating platinum even if carried out more than 3 h after infusion, but it should commence as soon as possible after cisplatin infusion, as the incidence of myelotoxicity is related to the peak platinum level.

Diet is a risk factor in cisplatin ototoxicity

This study demonstrates that cisplatin ototoxicity depends on dietary factors and correlates with decreased levels of cochlear glutathione and serum albumin. After 12 days of injections, cisplatin (1 mg/kg body weight, s.c.) caused a small hearing loss in guinea pigs fed a regular, full-protein diet (9 ± 6 dB at 8 kHz and 10 ± 9 dB at 18 kHz) but a significantly higher hearing loss in animals on a low-protein diet (23 ± 17 dB at 8 kHz and 32 ± 23 dB at 18 kHz). Animals on the low-protein diet gained significantly less weight than those on the regular diet, and cisplatin treatment lowered the weight gain in both groups. The low-protein diet also significantly reduced cochlear glutathione levels from 180 ± 50 to 90 ± 21 nmol/mg protein and serum albumin from 2.32 ± 0.04 to 1.75 ± 0.06 g/dl. Cisplatin treatment tended to decrease glutathione and serum albumin in animals on a full-protein diet but not on the low-protein diet. Renal function was assessed by measuring blood urea nitrogen (BUN) and serum creatinine. While BUN and creatinine values indicated some cisplatin-induced nephrotoxicity, there was no correlation with the severity of ototoxicity. Furthermore, serum platinum levels did not differ between animals on either diet, ruling out a potential influence of altered pharmacokinetics on ototoxicity. These results suggest that the metabolic state of the animal is a risk factor for cisplatin ototoxicity.

Effects of cis-diamminedichloroplatinum II released from D,L-polylactic acid implanted adjacent to cortical allografts in dogs.

This study was performed to determine the pharmacokinetics and local and systemic effects of cis-diamminedichloroplatinum II (cisplatin) released from an open-cell polylactic acid polymer when the drug delivery device was placed adjacent to a cortical allograft. Bilateral intercalary femoral allografts were implanted in six normal beagles. The polymer containing cisplatin was implanted adjacent to the allograft in one femur, and the polymer without cisplatin was implanted adjacent to the allograft in the contralateral femur. Systemic toxicity was evaluated clinically by hematologic and serum biochemistry tests and urinalysis. Healing of the allograft was monitored radiographically. The femora were evaluated biomechanically, histologically, and histomorphometrically 7.5 months after surgery. Total serum platinum levels were measured by atomic absorption spectrophotometry, and pharmacokinetic parameters were calculated. Healing was impaired slightly by the presence of the polymer with cisplatin, and systemic and local toxicity was mild and transient. After implantation of the polymer with cisplatin, the mean peak total serum platinum concentration was low (1.71 +/- 0.19 micrograms/ml). However, the area under the curve for total serum platinum concentration versus time for the first 21 days was large (27,050 +/- 3,201 micrograms.min/ml). When cisplatin was given as an intravenous bolus at a dose of 70 mg/m2 to six other beagles, the mean peak total platinum concentration was 8.80 +/- 2.1 micrograms/ml and the area under the curve was 940.3 +/- 256.7 micrograms.min/ml. These results indicate that a sustained release of cisplatin can be delivered safely from an open-cell polylactic acid polymer. This device may be useful in the treatment of solid tumors.

Protective Effect of Elastase on cis-Platinum-Induced Renal Toxicity

The protective effects of elastase (Ela) and fosfomycin against renal toxicity of cis-diamminedichloroplatinum (II) (CDDP) were evaluated in an experimental study using rats. When Ela was used concomitantly with CDDP, the elevation of urinary N-acetyl-beta-D-glucosaminidase levels in the early phase and the sharp fall in these levels in the latter phase were prevented. It was also found that the blood urea nitrogen levels and serum creatinine levels were significantly lowered. Histologically, atrophic and necrotic changes in the tubular epithelium were prevented. The total serum platinum levels showed no change with the addition of Ela; however, the platinum levels in the renal tissues were significantly reduced. These results suggested that Ela is effective against platinum deposits in the renal tissues, particularly in the tubular epithelium, thus protecting the kidneys. On the other hand, fosfomycin demonstrated no such positive results suggestive of a protective effect on the renal function parameters or during histological observation.