Abstract
Background/Aim: Toxicity-related discontinuation remains problematic in cisplatin-based cervical cancer treatment. This study aimed to evaluate the association between renal function assessed using individualized estimated glomerular filtration rate (eGFR) and the completion rate of cisplatin-based concurrent chemoradiotherapy (CCRT) in patients with cervical cancer.
Patients and Methods: This retrospective study included patients with cervical cancer who received CCRT with cisplatin (40 mg/m2/week, six cycles) at our institution between April 2015 and March 2024. Exclusion criteria included a Cockcroft–Gault-estimated creatinine clearance rate (CGCCr) <60 ml/min, prior chemotherapy or radiotherapy, initial cisplatin dose reduction, and Eastern Cooperative Oncology Group Performance Status ≥2. The primary endpoint was the cisplatin treatment completion rate. Renal function was assessed using individualized eGFR, and a comparative analysis was performed between the completion and non-completion groups.
Results: A total of 80 patients were included, of whom 68 (85%) completed the planned cisplatin regimen. Although all patients had CGCCr ≥60 ml/min, individualized eGFR assessment revealed that 19% of patients had eGFR <60 ml/min. The proportion of patients with an eGFR <60 ml/min was significantly higher in the non-completion group (58% vs. 12%, p=0.001). Logistic regression analysis showed that patients with individualized eGFR <60 ml/min had a significantly higher risk of cisplatin treatment non-completion (adjusted odds ratio=8.69; 95% confidence interval=2.14-35.3, p=0.0025).
Conclusion: Patients with an individualized eGFR <60 ml/min showed significantly higher cisplatin non-completion rates even when their CGCCr was ≥60 ml/min. These findings suggest that individualized eGFR assessment, in addition to CGCCr, should be considered for optimizing cisplatin dosing in cervical cancer CCRT.
Introduction
In Japan, uterine cancer was ranked fifth in terms of cancer incidence among women in 2020, with approximately 10,000 new cases of uterine cancer reported annually (1). In the treatment of locally advanced cervical cancer, concurrent chemoradiotherapy (CCRT) combining cisplatin and radiation therapy has been shown to significantly reduce local recurrence and distant metastasis, thereby improving overall survival. As such, this regimen is recommended in the current Japanese clinical guidelines (2-5).
However, cisplatin is associated with a range of adverse effects, including nausea, vomiting, myelosuppression, and nephrotoxicity. These toxicities can lead to treatment delays or discontinuation, potentially resulting in incomplete treatment schedules (6, 7). Given that cisplatin is predominantly excreted renally, the 2022 Guidelines for the Management of Kidney Injury in Cancer Chemotherapy recommends dosage adjustments based on renal function (8). Specifically, dosage modifications according to creatinine clearance (CCr) are advised: 75% of the standard dose for patients with CCr of 46-60 ml/min, 50% for CCr of 31-45 ml/min, and contraindication for CCr ≤30 ml/min (8, 9).
These CCr values are typically estimated using the Cockcroft–Gault (CG) equation (CGCCr), which is based on serum creatinine (SCr) measurements obtained using the Jaffe method, which is commonly used in Western countries (10). However, the CGCCr has several limitations. First, owing to differences in SCr measurement methodologies between Western countries and Japan (11), the CG equation may overestimate renal function in Japanese patients (12, 13). This overestimation is closely associated with an increased risk of chemotherapy-related adverse events, emphasizing the need for a more accurate assessment of renal function (14).
Second, the CG equation was originally developed using data from Caucasian patients in Canada; however, its validity in Asian populations, including Japanese patients, remains unclear (15). In response to these limitations, a Japanese equation for estimating glomerular filtration rate (eGFR) was developed. This standardized eGFR has demonstrated greater accuracy than CGCCr in evaluating renal function in Japanese patients (12).
In particular, among patients with cancer, individualized eGFR values calculated by removing body surface area (BSA) normalization from the standardized eGFR (expressed in ml/min) have been shown to estimate renal function more accurately than CGCCr (13). Nevertheless, to date, no studies have investigated the relationship between renal function assessed using individualized eGFR and the completion rate of cisplatin therapy. Therefore, this study aimed to evaluate the association between renal function assessed by individualized eGFR and the completion rate of cisplatin-based CCRT in patients with cervical cancer.
Patients and Methods
Study population. This retrospective study included patients with cervical cancer who received CCRT with cisplatin (40 mg/m2/week, six cycles) at our institution between April 2015 and March 2024. Whole-pelvis external beam radiotherapy (EBRT) was administered in daily fractions of 1.8 or 2.0 Gy, five days per week, for a total dose of 50 or 50.4 Gy. Intracavitary brachytherapy (ICBT) was delivered in four fractions of 6 Gy each, for a total dose of 24 Gy. Patients received intravenous hydration of 500 ml prior to cisplatin administration and 1,500 ml following the administration, in addition to oral fluid intake. Antiemetic therapy consisted of palonosetron, aprepitant, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy), and prophylactic administration of granulocyte-colony stimulating factor (G-CSF) was not performed.
Patients were excluded if they met any of the following criteria: those with CGCCr of less than 60 ml/min, those with a prior history of chemotherapy or radiotherapy, those who received a reduced dose of cisplatin from the initial treatment cycle, those with an Eastern Cooperative Oncology Group Performance Status of two or higher.
Patients whose treatment was interrupted or delayed due to scheduling issues or personal preferences, those who discontinued treatment due to suspected allergic reactions or drug eruptions caused by cisplatin, and those for whom treatment discontinuation could not be definitively attributed to cisplatin-related adverse effects were also excluded.
Data collection. Data regarding the following variables were collected: (1) patient factors (age, smoking history, alcohol use, cancer stage, body weight, BSA, and body mass index), (2) laboratory data (serum creatinine, albumin, white blood cell, neutrophil, hemoglobin, and platelet counts), (3) Cisplatin-related data (total dose administered, treatment discontinuation or delay, and reasons for deviations). Laboratory values were obtained using the collection date closest to the initiation of cisplatin treatment. The primary endpoint of this study was the cisplatin treatment completion rate.
Patients were categorized into two groups: the cisplatin completion group, defined as patients who completed the scheduled cisplatin regimen as planned (six cycles within six weeks), and the cisplatin non-completion group, defined as patients who discontinued or delayed cisplatin treatment owing to adverse effects and failed to complete the scheduled regimen (any hold or <six cycles). A comparative analysis was performed between the two groups.
Renal function assessment. SCr levels were measured using an enzymatic method. Renal function before cisplatin initiation was assessed using the following formulas:
Cockcroft–Gault formula (15): CGCCr (ml/min)=([140 − age (years)] × weight [kg])/(72 × SCr [mg/dl]) × 0.85 (for females)
Japanese equation for eGFR (12): Standardized eGFR (ml/min/1.73 m2)=194 × SCr (mg/dl)−1.094 × age (years)−0.287 × 0.739 (for females)
Individualized eGFR (non-BSA adjusted): Individualized eGFR (ml/min)=standardized eGFR (ml/min/1.73 m2) × BSA/1.73
Du Bois formula for BSA (16): BSA (m2)=0.007184 × weight (kg)0.425 × height (cm)0.725
Statistical analysis. Continuous variables were compared using the Mann–Whitney U-test. Categorical variables related to renal function classification (individualized eGFR ≥60 ml/min vs. <60 ml/min) were analyzed using Fisher’s exact test. The association between renal function (individualized eGFR) and cisplatin treatment completion was evaluated using a logistic regression analysis. All statistical analyses were conducted using EZR software version 1.68 (17).
Ethical considerations. This study was approved by the Ethics Committee for Human Research of Niigata University (approval number: 2024-0161). Patient consent was obtained using an opt-out method.
Results
Patient characteristics. Eighty patients were included in this study (Figure 1). The baseline patient characteristics are summarized in Table I. The number of patients in the cisplatin non-completion group was 12 (15%), while 68 (85%) completed the cisplatin treatment schedule. No statistically significant differences were observed in baseline characteristics between the two groups. The median age (interquartile range) was 65 years (53-70 years) in the non-completion group and 55 years (46-65 years) in the completion group, with a trend toward older age in the non-completion group (p=0.07).
Flowchart of patient selection. CGCCr: Cockcroft–Gault-estimated creatinine clearance rate.
Patient characteristics.
Renal function assessment by individualized eGFR. The results of the renal function assessment using individualized eGFR are shown in Table II. Although all patients had a CGCCr of ≥60 ml/min, individualized eGFR assessment revealed that 19% of the patients (15 out of 80) had an eGFR <60 ml/min. Specifically, 12% (eight of 68) of patients in the cisplatin completion group had individualized eGFR <60 ml/min, compared to 58% (seven of 12) in the non-completion group, with a statistically significant difference (p=0.001, Table II).
Renal function assessment by individualized eGFR.
Logistic regression analysis of cisplatin non-completion. Logistic regression analysis was performed to assess the factors associated with cisplatin non-completion after adjusting for age. Patients with individualized eGFR <60 ml/min had a significantly higher risk of cisplatin treatment non-completion compared to those with individualized eGFR ≥60 ml/min [adjusted odds ratio=8.69; 95% confidence interval (CI)=2.14-35.3; p=0.0025, Table III].
Logistic regression analysis of cisplatin non-completion.
Clinical characteristics of patients with cisplatin non-completion. Patient details are provided in Table IV. The most common reason for discontinuation was neutropenia, which was observed in six cases (50%), followed by thrombocytopenia in two cases (17%), renal dysfunction in two cases (17%), hepatotoxicity in one case (8%), and febrile neutropenia in one case (8%). Overall, hematologic toxicity accounted for the majority of treatment discontinuations, occurring in nine cases (75%).
Clinical characteristics of patients with cisplatin non-completion (n=12).
Logistic regression analysis of grade ≥3 neutropenia. A logistic regression analysis was conducted to evaluate the association between renal function and the incidence of grade ≥3 neutropenia, with adjustment for age. Patients with an individualized eGFR <60 ml/min demonstrated a significantly higher risk of developing grade ≥3 neutropenia compared to those with an individualized eGFR ≥60 ml/min (adjusted odds ratio=9.44; 95% CI=1.45-61.6; p=0.019; Table V).
Logistic regression analysis of grade ≥3 neutropenia.
Discussion
In Japan, the use of the CGCCr equation may overestimate renal function due to differences in SCr measurement methods and racial variations (11-13). Given the potential for severe adverse effects associated with cisplatin, accurate renal function assessment is particularly important. Although individualized eGFR has been shown to provide a more precise estimation of renal function than the CGCCr in Japanese patients (13), no previous studies have investigated the association between individualized eGFR and cisplatin-related toxicity. To the best of our knowledge, this is the first study to focus on the overestimation of renal function by CGCCr and to evaluate the relationship between renal function assessed by individualized eGFR and cisplatin-related toxicity among patients with CGCCr ≥60 ml/min.
In the present study, 15% (12 of 80) of patients did not complete cisplatin treatment. Kotha et al. (18) previously reported a cisplatin-based CCRT non-completion rate of 15.7% in patients with cervical cancer, which is comparable to our findings. Although all patients enrolled in our study had CGCCr values ≥60 ml/min, individualized eGFR assessment revealed that 19% (15 of 80) of patients had a renal function <60 ml/min. Notably, the proportion of patients with an eGFR <60 ml/min was significantly higher in the non-completion group (58%, seven of 12) than in the completion group (12%, eight of 68; p=0.001, Table II).
Previous reports have highlighted the risk of renal function overestimation by CGCCr in Japanese populations, stemming from differences in SCr measurement methods between Japan and Western countries (11-13). In our study, renal impairment that was undetected by the CGCCr assessment was identified through individualized eGFR, suggesting that this discrepancy may have affected the completion rates of cisplatin treatment in real-world clinical settings. Moreover, among patients with individualized eGFR <60 ml/min, the cisplatin non-completion rate was significantly higher at 42% (seven of 15), with an adjusted odds ratio of 8.69 (95% CI=2.14-35.3; p=0.0025, Table III). These findings are consistent with those of prior studies utilizing CGCCr adjusted by +0.2, supporting the notion that the overestimation of renal function by CGCCr could lead to cisplatin overdosing and subsequent treatment interruption or delay (14).
Failure to complete CCRT has been associated with a poor prognosis, including higher rates of local recurrence and reduced overall survival (18). Therefore, accurate pretreatment assessment of renal function may help prevent cisplatin discontinuation or delay (19). Hematologic toxicities accounted for the majority of cisplatin non-completion cases in our study, with neutropenia (six cases), thrombocytopenia (two cases), and febrile neutropenia (one case) comprising 75% (nine of 12) of the reasons for discontinuation. Furthermore, in a post hoc analysis, patients with individualized eGFR <60 ml/min demonstrated a significantly higher incidence of grade ≥3 neutropenia compared to those with eGFR ≥60 ml/min. Logistic regression analysis adjusted for age confirmed that reduced renal function was independently associated with an increased risk of severe neutropenia (adjusted OR=9.44; 95% CI=1.45-61.6; p=0.019). These findings suggest that decreased filtration may result in higher systemic exposure to cisplatin, leading not only to renal concerns but also to enhanced hematologic toxicity, particularly bone marrow suppression. This supports the hypothesis that renal clearance plays a critical role in modulating cisplatin-related myelotoxicity, even in patients with seemingly acceptable CGCCr values. Previous studies have also highlighted the importance of pre-treatment renal function assessment in optimizing chemotherapy safety. Yada et al. reported on the use of definitive chemoradiotherapy with FOLFOX in patients with esophageal cancer who were intolerant to cisplatin, reinforcing the need for identifying patients at risk for cisplatin-related complications before initiating treatment (20). Additionally, Saito et al. demonstrated that prediabetic status may exacerbate renal function decline during cisplatin therapy under a short hydration protocol, even when standard nephroprotective measures are taken (21). This finding supports our rationale for using individualized eGFR as a more sensitive metric of renal vulnerability that may not be reflected in CGCCr alone. Additionally, there was a trend toward older age in the non-completion group (p=0.07). Advanced age is a known risk factor for febrile neutropenia (22-24). Other reported risk factors include a history of chemotherapy or radiotherapy, poor performance status, and prior episodes of febrile neutropenia; however, these conditions were excluded from our study population to minimize their potential confounding effects (25).
Study limitations. Firstly, it was a retrospective, observational study, making it difficult to draw definitive conclusions regarding causality, and we could not completely eliminate the potential influence of confounding factors. Prospective cohort or interventional studies are required to enable more rigorous causal inferences and minimize bias. Secondly, this study was based on data from a single institution, and the patient characteristics and treatment strategies may have been specific to that institution. This limits the external validity and generalizability of the findings to other institutions and healthcare settings. Therefore, future multicenter studies including diverse patient populations are necessary to enhance the universality of these findings. Lastly, this study did not aim to evaluate treatment efficacy or safety outcomes but was limited to presenting observational findings. The accumulation of empirical evidence regarding treatment effectiveness requires prospective interventional studies with appropriate control groups. Accordingly, future investigations should include prospective, multicenter, and collaborative studies.
Conclusion
Among patients undergoing cisplatin-based chemoradiotherapy for cervical cancer, those with individualized eGFR <60 ml/min had a significantly higher non-completion cisplatin therapy rate, even when their CGCCr was ≥60 ml/min. Our findings suggest that individualized eGFR assessment, in addition to CGCCr, should be considered for appropriate dose adjustment of cisplatin during CCRT for cervical cancer.
Acknowledgements
The Authors would like to thank Editage (www.editage.jp) for English language editing.
Footnotes
Authors’ Contributions
Naoto Hoshino, Kensuke Yoshida, and Munetoshi Sugiura designed this study and provided critical revisions. Naoto Hoshino, Kensuke Yoshida, and Munetoshi Sugiura were involved in analyzing and writing this manuscript. Naoto Hoshino analyzed the dataset. Yoshitomi Kanemitsu and Akira Toyama reviewed and edited the manuscript. All Authors approved the final version of the manuscript.
Conflicts of Interest
The Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding
No funding was received for conducting this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received August 31, 2025.
- Revision received October 9, 2025.
- Accepted October 13, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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