Risk factors for failing to complete gemcitabine–cisplatin neoadjuvant chemotherapy in muscle invasive bladder cancer patients

Abstract

Purpose

We evaluated the risk factors associated with failure to complete gemcitabine–cisplatin (GP) neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC).

Materials and Methods

In total, 231 patients with MIBC treated with NAC before undergoing radical cystectomy between 2013 and 2022 participated in this study. Logistic regression analysis was performed to assess the relationship between the likelihood of incomplete NAC and clinical and demographic variables, including age, sex, hypertension (HTN), diabetes mellitus (DM), prechemotherapy glomerular filtration rate, clinical T stage, clinical N stage, and body mass index (BMI).

Results

Of 231 patients, 209 (90.5%) and 22 (9.5%) completed and discontinued the NAC course, respectively. The mean age was 66.13±9.15, 65.63±9.07, and 70.86±8.66 years for the total sample, continuation, and discontinuation groups, respectively (p=0.010). No significant inter-group differences in sex, HTN, height, weight, BMI, pre-chemotherapy glomerular filtration rate, clinical T stage, or clinical N stage were observed. According to the results of the multivariable analysis, age (odds ratio [OR] 1.076, 95% confidence interval [CI] 1.013–1.143, p=0.018) and the presence of DM (OR 2.541, 95% CI 1.028–6.281, p=0.043) were significantly associated with NAC discontinuation.

Conclusions

Thus, older age and presence of DM are potential risk factors for GP NAC discontinuation in patients with MIBC. Further studies are required to validate our findings and develop strategies to minimize the rate of GP NAC discontinuation in this population.

INTRODUCTION

Bladder cancer is the 10th most prevalent cancer worldwide at 549,000 new cases and 200,000 deaths annually, as well as the 13th most common cause of cancer-related deaths [1]. Approximately 30% of all patients with bladder cancer are diagnosed with muscle-invasive bladder cancer (MIBC) [2]. The Clinical Practice Guidelines in Oncology for Bladder Cancer of the National Comprehensive Cancer Network [3] and the Guidelines on Muscle-Invasive Bladder Cancer of the European Association of Urology [4] strongly recommend the administration of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) for patients with MIBC. NAC plays a crucial role in the management of MIBC by improving the 5-year overall survival (OS) by <8% compared to RC [5]. NAC is used to treat any micro-metastases of the disease that are present at the time of diagnosis, as the disease burden is at its lowest at this point in the clinical course [6].

However, completion of a NAC course is arduous [7]. Approximately 20% of patients with MIBC do not complete the planned number of NAC cycles due to serious side effects, which may be fatal and hinder subsequent treatment [8]. Gemcitabine plus cisplatin (GP) chemotherapy can induce nausea, vomiting, alopecia, nephrotoxicity, hepatotoxicity, neutropenia, thrombocytopenia, and anemia [5,9]. To date, the relationship between NAC discontinuation and patient hypertension (HTN), diabetes mellitus (DM), clinical T stage, clinical N stage, or pre-NAC glomerular filtration rate (GFR) is unknown. The only variable that had been studied regarding failure to complete the NAC course is body mass index (BMI) [10].

Identifying the risk factors associated with NAC discontinuation is essential for the optimization of treatment strategies and improvement of patient outcomes. This study aimed to investigate risk factors for GP NAC discontinuation in patients with MIBC.

MATERIALS AND METHODS

1. Study population

This study was approved by the Institutional Review Board (IRB) of Asan Medical Center (approval number: 2023-0590). It was conducted in accordance with the tenets of the 1964 Declaration of Helsinki and its subsequent amendments. The requirement for informed consent of the patient was waived by the IRB. However, all patients whose data were retrospectively analyzed were informed regarding usage of their anonymized clinical information and offered the opportunity to object to its use or publication.

We retrospectively reviewed 231 patients with MIBC who received a GP NAC regimen before undergoing RC using standard techniques between 2013 and 2022. These patients were selected because GP NAC is the most frequently used treatment regimen at our institution. Patients treated with other NAC regimens were excluded (Fig. 1).

Fig. 1. Flowchart depicting selection of patients who completed gemcitabine–cisplatin neoadjuvant chemotherapy (GP NAC). RC, radical cystectomy; AMC, Asan Medical Center.

Demographic data from patients, including age, sex, height, weight, and BMI, and clinical characteristics, including HTN, DM, clinical T stage, clinical N stage, pre-NAC GFR, and post-NAC side effects, were evaluated.

Side effects were analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [11]. For each patient, genitourinary pathologists determined the tumor grade according to the 2004 World Health Organization grading system. The pathological stage was determined according to the tumor, node, and metastasis staging system (8th edition) [12,13].

2. Statistical analysis

Univariable and multivariable logistic regression analyses were used to evaluate the odds ratio (OR) and 95% confidence interval (CI) for clinical and demographic variables and the probability of NAC discontinuation and adverse effects. The patients were classified into two groups according to their clinical stage: one group with Ta–T2b and another with T3a–T4b. They were also divided into two groups according to the clinical N stage: one with N0 and another with ≥N1. Age, pre-NAC GFR, and BMI were evaluated as continuous variables. Serious side effects were considered to have occurred if (1) patient records indicated side effects above CTCAE grade 3; (2) a change in chemotherapy regimen from GP to gemcitabine plus carboplatin was recorded; or (3) the patient was treated with a reduced dose. Categorical variables were expressed as absolute values (%). All statistical analyses were performed using IBM SPSS Statistics software version 25 (IBM Corp.).

RESULTS

This study included 231 patients with MIBC who received GP NAC prior to undergoing RC. Of 231 patients, 209 (90.5%) and 22 (9.5%) completed and discontinued the NAC course, respectively, before undergoing RC. The baseline demographic and clinical characteristics of the patients are presented in Table 1. The mean age was 66.13±9.15, 65.63±9.07, and 70.86±8.66 years in the entire population, among those who continued NAC, and among those who discontinued NAC, respectively (p=0.010). Most of the patients (82.7%) were male. HTN and DM were present in 44.2% and 28.6% of all patients, respectively. The mean BMI was 24.48±3.26 kg/m², and the mean pre-NAC GFR was 75.16±15.76 mL/min/1.73 m². Within the sample, 46.8% and 23.4% were in the clinical stages ≥T3 and ≥N1, respectively.

Table 1. Baseline clinical and demographic characteristics of patients.

		Total	Group 1 (NAC completion)	Group 2 (NAC discontinuation)	p-value
Number of patients		231	209 (90.5)	22 (9.5)
Age (y)		66.13±9.15	65.63±9.07	70.86±8.66	0.010
Sex					0.911
	Male	191 (82.7)	173 (82.8)	18 (81.8)
	Female	40 (17.3)	36 (17.2)	4 (18.2)
HTN		102 (44.2)	90 (43.1)	12 (54.5)	0.304
DM		66 (28.6)	55 (26.3)	11 (50.0)	0.047
Height (cm)		164.65±7.88	164.86±7.95	162.70±7.01	0.222
Weight (kg)		66.95±11.84	67.37±11.94	62.92±10.19	0.094
BMI (kg/m2)		24.48±3.26	24.54±3.26	23.89±3.27	0.375
Pre-NAC GFR (mL/min/1.73 m2)		75.16±15.76	75.79±15.63	69.09±16.11	0.058
Clinical stage ≥T3		108 (46.8)	97 (46.4)	11 (50.0)	0.750
Clinical stage ≥N1		54 (23.4)	50 (23.9)	4 (18.2)	0.547

Values are presented as number (%) or mean±standard deviation.

HTN, hypertension; DM, diabetes mellitus; BMI, body mass index; NAC, neoadjuvant chemotherapy; GFR, glomerular filtration rate.

The univariable and multivariable logistic regression analyses of the study variables and NAC discontinuation are shown in Table 2. Age and DM were significantly associated with discontinuation. No significant differences in sex, HTN, height, weight, BMI, clinical T or N stages, were observed between the continuation and discontinuation groups. According to the univariable analysis, age (OR 1.079, 95% CI 1.007–1.144, p=0.012) and presence of DM (OR 2.800, 95% CI 1.149–6.823, p=0.023) were significantly correlated with NAC discontinuation. According to the multivariable analysis, age (OR 1.076, 95% CI 1.013–1.143, p=0.018) and presence of DM (OR 2.541, 95% CI 1.028–6.281, p=0.043) were also independent predictors of NAC discontinuation.

Table 2. Logistic regression analysis of neoadjuvant chemotherapy discontinuation before undergoing radical cystectomy.

	Univariable			Multivariable
	OR	95% CI	p-value	OR	95% CI	p-value
Age	1.079	1.007−1.144	0.012	1.076	1.013−1.143	0.018
Sex	0.936	0.299−2.932	0.910
HTN	1.587	0.656−3.836	0.305
DM	2.800	1.149−6.823	0.023	2.541	1.028−6.281	0.043
Pre-NAC GFR (continuous)	0.973	0.946−1.001	0.061
Clinical T stage (T3–4 vs. T1–2)	0.866	0.360−2.086	0.748
Clinical N stage (N0 vs. N1–2)	0.707	0.228−2.186	0.547
BMI (continuous)	0.939	0.818−1.078	0.373

HTN, hypertension; DM, diabetes mellitus; NAC, neoadjuvant chemotherapy; GFR, glomerular filtration rate; BMI, body mass index; OR, odds ratio; CI, confidence interval.

Table 3 shows the results of the logistic regression analyses of the relationship between patient variables and the serious side effects of NAC pre-RC. There were (1) 46 patients who showed Grade 3 or 4 adverse effects, (2) nine whose chemotherapy regimen changed from GP to gemcitabine plus carboplatin, and (3) 45 who were treated with reduced doses of GP. BMI was the only variable that showed a significant association with the serious side effects of NAC; patients with lower BMI were more likely to experience serious side effects than those with higher BMI (OR 0.915, 95% CI 0.841–0.996, p=0.040).

Table 3. Logistic regression analysis of the serious side effects of neoadjuvant chemotherapy administered before undergoing radical cystectomy.

	OR	95% CI	p-value
Age	1.027	0.997−1.058	0.082
Sex	0.619	0.312−1.227	0.169
HTN	0.925	0.544−1.572	0.774
DM	1.471	0.826−2.620	0.190
Pre-NAC GFR (continuous)	1.002	0.986−1.019	0.782
Clinical T stage (T3–4 vs. T1–2)	1.287	0.758−2.185	0.350
Clinical N stage (N0 vs. N1–2)	0.680	0.359−1.289	0.237
BMI (continuous)	0.915	0.841−0.996	0.040

HTN, hypertension; DM, diabetes mellitus; NAC, neoadjuvant chemotherapy; GFR, glomerular filtration rate; BMI, body mass index; OR, odds ratio; CI, confidence interval.

Adverse events resulting from GP NAC were assessed in our study population. The results are presented in Table 4. Along with hematologic adverse events, non-hematologic adverse events, such as nausea, fatigue, constipation, and anorexia, were commonly observed. The most common hematologic adverse event was neutropenia (27.7%), followed by anemia (16.5%) and thrombocytopenia (2.6%). Among patients with neutropenia, 41 (17.7%) had grade 3 or 4 neutropenia. The most common non-hematologic adverse events reported were nausea (23.4%), fatigue (20.8%), constipation (19.5%), and anorexia (16.0%). Other less frequent adverse events included hiccups (9.1%), skin rash (8.7%), dizziness (7.4%), vomiting (4.8%), epigastric sores (5.2%), diarrhea (3.5%), alanine aminotransferase elevation (3.5%), headache (3.5%), insomnia (2.6%), dyspepsia (2.6%), peripheral neuropathy (2.6%), cough (2.2%), alopecia (2.2%), general aching or weakness (1.7%), weight loss (1.7%), sputum (0.9%), epistaxis (0.9%), and toothache (0.4%).

Table 4. Frequency of adverse events in patients who received gemcitabine−cisplatin neoadjuvant chemotherapy before undergoing radical cystectomy.

Adverse events		Patients	Grade 3 or 4 adverse events
Non-hematologic		173 (74.9)	4 (1.7)
	Nausea	54 (23.4)	3 (1.3)
	Fatigue	48 (20.8)	1 (0.4)
	Constipation	45 (19.5)	1 (0.4)
	Anorexia	37 (16.0)	-
	Hiccup	21 (9.1)	-
	Skin rash	20 (8.7)	-
	Dizziness	17 (7.4)	-
	Vomiting	11 (4.8)	1 (0.4)
	Epigastric sore	12 (5.2)	-
	Diarrhea	8 (3.5)	-
	ALT elevation	8 (3.5)	-
	Headache	8 (3.5)	-
	Insomnia	6 (2.6)	-
	Dyspepsia	6 (2.6)	-
	Peripheral neuropathy	6 (2.6)	-
	Cough	5 (2.2)	-
	Alopecia	5 (2.2)	-
	General aches or weakness	4 (1.7)	-
	Weight loss	4 (1.7)	-
	Sputum	2 (0.9)	-
	Epistaxis	2 (0.9)	-
	Toothache	1 (0.4)	-
Hematologic		64 (27.7)	41 (17.7)
	Neutropenia	64 (27.7)	41 (17.7)
	Anemia	38 (16.5)	-
	Thrombocytopenia	6 (2.6)	2 (0.9)

Values are presented as number (%).

ALT, alanine aminotransferase.

DISCUSSION

According to several studies and clinical trials, cisplatinbased NAC is a groundbreaking treatment that improves the OS of patients with MIBC. A randomized controlled trial by the Southwest Oncology Group (SWOG) and the European Organization for Research and Treatment of Cancer (EORTC), SWOG 8710/EORTC 30994, was considered a landmark investigation [14,15]. The trial showed a significantly higher 5-year OS rate of 57% among patients who received NAC compared to 43% in the surgery-alone group. Since then, several other studies and meta-analyses have supported the benefits of neoadjuvant cisplatin-based chemotherapy for patients with MIBC; including the 2011 International Collaboration of Trialists [16] and Nordic Cystectomy Trial 2 [17], which have consistently shown improved survival outcomes with neoadjuvant cisplatin-based chemotherapy. Therefore, cisplatin-based NAC is commonly recommended to patients with MIBC with good performance status.

However, cisplatin interacts with DNA by forming covalent adducts between purine DNA bases and this platinum compound. Moreover, it is cytotoxic, affecting multiple organs in the body [18]. Consequently, cisplatin is associated with various toxic effects, including nephrotoxicity, ototoxicity, hepatotoxicity [19], neurotoxicity, vascular toxicity (which can cause cardiovascular or cerebrovascular pathologies), thrombotic microangiopathy, and the Raynaud phenomenon [20]. Most patients with low GFR appear to require discontinuation or modification of cisplatin-based NAC [21,22]. Thus, 10%–40% of patients with MIBC have been reported to discontinue NAC [8,21]. Herein, the discontinuation rate was approximately 10% (Table 1).

This study aimed to identify the risk factors associated with the discontinuation of GP NAC in patients with MIBC. We found that older age and the presence of DM are risk factors for NAC discontinuation. Here, renal function was an insignificant factor. Age remained a significant risk factor for NAC discontinuation according to the multivariable analysis (OR 1.076, 95% CI 1.013–1.143, p=0.018), indicating its independent impact. This suggests that older patients may be less able to tolerate treatment or more prone to treatment-related complications, leading to discontinuation. This finding may be attributed to an age-related decline in renal function which, although not significant in our study, would increase the half-life of toxic metabolites in chemotherapeutic regimens. Dash et al. [23] reported that >40% of patients aged >70 years are ineligible for cisplatin-based chemotherapy due to impaired renal function. Moreover, there may be a psychological element to age as a discontinuation risk. Many older adults experience a reduced sense of control over their health and fewer emotional ups and downs, adjusting their expectations and attitudes regarding their current health status and ability to recover from adverse health events as they age [24].

Another important finding was the association between DM and NAC discontinuation. The presence of DM was significantly associated with NAC discontinuation in univariable and multivariable analyses. Moreover, it is known to affect tolerance to treatment and response in various cancers [25]. The presence of DM may lead to complications or comorbidities that hinder the completion of NAC. In fact, a study on pancreatic cancer, has shown that patients with poor glycemic control are less likely to complete the NAC course [26]. However, the exact mechanisms responsible for this association are unclear. The postulated mechanisms include the effects of hyperinsulinemia, hyperglycemia, and impaired insulin-like growth factor receptor signaling pathways. This finding highlights the need to carefully consider and treat DM when planning strategies involving cisplatinbased NAC administration to patients with MIBC.

The present study also evaluated the occurrence of serious side effects during NAC (Table 3). Patients with lower BMIs were significantly more likely to suffer serious side effects, indicating that they may be more vulnerable to the toxicity of the GP regimen. Otherwise, the higher the BMI, the better the tolerance to side effects. We can only speculate about the exact mechanism behind the reduced toxicity in the obese as it is unknown. However, some factors may alter the pharmacokinetic profiles of antineoplastic agents in obese patients [27].

Additionally, the adverse events that occurred in this study (Table 4) are almost identical to those described in two recently published papers on using NAC for MIBC treatment [28,29]. In our study, neutropenia was more common than anemia due to the difference in NAC regimen and the patient’s ethnicity from those in the aforementioned papers.

The greatest strength of our study is that, to the best of our knowledge, it is the first to analyze various risk factors for NAC discontinuation. Additionally, it is one of the largest studies in this field.

Our study’s limitations are: First, this study was a retrospective study in which performance status was not considered; therefore, it is vulnerable to potential biases and limitations inherent to the study design. Second, the study population was limited to Asian patients who received the GP NAC regimen only. Furthermore, although this is a single-center study with a relatively large sample size, further larger, prospective, multicenter studies are needed to understand the risk factors for NAC discontinuation, which is important to tailor treatment to patients.

CONCLUSIONS

This study identified older age and the presence of DM as potential risk factors for GP NAC regimen discontinuation in patients with MIBC. Therefore, these variables must be considered when administering cisplatin-based NAC to patients with MIBC. More studies are needed to validate these findings and develop strategies to minimize NAC discontinuation in this population. Prospective studies with larger sample sizes and diverse NAC regimens are needed to explore risk factors further and optimize treatment approaches for patients with MIBC who received NAC.