Correlations Between Metformin and Prognosis and Adverse Reactions in Patients Undergoing Radical Cystectomy Followed by Adjuvant GC Chemotherapy for Bladder Cancer

doi:10.21203/rs.3.rs-5022906/v1

Download PDF

Research Article

Correlations Between Metformin and Prognosis and Adverse Reactions in Patients Undergoing Radical Cystectomy Followed by Adjuvant GC Chemotherapy for Bladder Cancer

https://doi.org/10.21203/rs.3.rs-5022906/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Objective

The objective of this research was to examine the influence of metformin on both prognosis and adverse reactions in patients who have undergone radical cystectomy (RC) and subsequently received adjuvant gemcitabine and cisplatin (GC) chemotherapy for muscle-invasive bladder cancer (MIBC).

Methods

A retrospective evaluation was performed on data from 243 patients who had undergone RC followed by adjuvant GC chemotherapy at the Affiliated Hospital of Xuzhou Medical University, Xuzhou First People’s Hospital, and Xuzhou Third People’s Hospital during the period from April 2014 to April 2024. The subjects were categorized into three categories based on metformin usage: non-diabetic (No DM), type 2 diabetic with metformin use (DM, Metformin), and type 2 diabetic without metformin use (DM, no Metformin). Clinical and pathological characteristics were compiled and subjected to analysis. Progression-free survival (PFS) was assessed utilizing the Kaplan-Meier technique, while Cox proportional hazards models were employed for multivariable analysis.

Results

Among the 243 patients, diabetes was present in 68 individuals, of whom 51 were administered metformin. When compared to the non-diabetic cohort, diabetic patients who received metformin exhibited significantly elevated PFS rates at 1, 2, and 3 years (p = 0.024). Both univariate and multivariate analyses indicated that the utilization of metformin correlated with a reduced risk of disease progression (hazard ratio = 0.66, 95% confidence interval 0.45–0.96, p = 0.031). Moreover, those administered metformin experienced a significantly lower frequency of grade 3 or higher adverse reactions during chemotherapy in contrast to those who did not receive metformin (p = 0.011).

Conclusion

The administration of metformin is strongly correlated with enhanced prognosis and a reduction in adverse reactions in patients who have undergone RC, followed by adjuvant GC chemotherapy for MIBC. This research offers robust clinical evidence supporting the application of metformin as an adjuvant therapy in MIBC and establishes a basis for future investigations into the mechanisms by which metformin exerts its effects in cancer treatment.

GC adjuvant chemotherapy

MIBC

metformin

Bladder cancer (BLCA), recognized as one of the most prevalent malignancies of the urinary system, has been marked by a persistent global increase in incidence ^[1][2]. Of these cases, 20–25% are identified as muscle-invasive bladder cancer (MIBC) ^[3], a condition that significantly compromises patients’ quality of life and life expectancy due to its aggressive nature and potential for metastasis. Radical cystectomy (RC) is established as the standard therapeutic approach for MIBC ^[4], aiming to remove the primary tumor comprehensively. Nevertheless, the recurrence rate following surgery remains substantial, with approximately 30% of patients encountering recurrence within a median of 12 months post-cystectomy ^[1][3–9]. To mitigate the likelihood of postoperative recurrence and metastasis, adjuvant chemotherapy has emerged as a pivotal therapeutic strategy. A meta-analysis of 1183 patients revealed that, in comparison to surgery alone, adjuvant cisplatin-based chemotherapy reduced mortality risk by 18% and enhanced recurrence-free survival (RFS) by 29% ^[10]. The gemcitabine and cisplatin (GC) chemotherapy regimen is recognized for its effectiveness and relatively manageable adverse effects. Consequently, the National Comprehensive Cancer Network guidelines advocate for GC adjuvant chemotherapy in individuals with pathological stage ≥ T3 and/or lymph node-positive disease at the time of cystectomy, provided they are suitable for cisplatin-based therapy and have not undergone neoadjuvant cisplatin-based chemotherapy ^[11].

Nevertheless, the toxic side effects associated with chemotherapy drugs are significant and cannot be disregarded. Frequently observed gastrointestinal adverse reactions, including nausea and vomiting, as well as bone marrow suppression-related complications such as leukopenia and thrombocytopenia, during GC adjuvant chemotherapy, not only diminish patients’ quality of life ^[12–16], but may also lead to decreased treatment adherence, ultimately influencing treatment efficacy. Consequently, the identification of adjuvant therapies that can effectively mitigate chemotherapy-induced adverse reactions while enhancing therapeutic outcomes has emerged as a focal point of research in the field of BLCA treatment.

Metformin, a commonly prescribed oral hypoglycemic agent ^[17], has increasingly attracted interest in recent years for its potential anticancer properties. The anticancer activity of metformin has been demonstrated in both in vitro and in vivo studies ^[18]. A growing body of basic research and clinical evidence indicates that metformin may directly inhibit tumor cell proliferation, migration, and invasion through multiple mechanisms, with a particular emphasis on the inhibition of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway ^[19]. Additionally, metformin is thought to exert indirect effects on the host by reducing blood glucose levels and exerting anti-inflammatory actions ^[20][21], which have been linked to improved outcomes in various malignancies, encompassing breast, prostate, and colon cancers ^[22]. Moreover, existing literature suggests that metformin use may mitigate adverse reactions to cisplatin-based chemotherapy and prevent the development of chemotherapy resistance in cancer cells ^[23]. Despite numerous in vitro studies indicating that the combination of metformin and cisplatin-based chemotherapy drugs can enhance patient outcomes in cancer treatment, the effect of metformin on the cytotoxicity induced by cisplatin and gemcitabine remains uncertain. These findings also imply that metformin could play a significant role in the postoperative adjuvant chemotherapy of BLCA, particularly when cisplatin is combined with gemcitabine.

Objectives and Significance of the Study

In light of the aforementioned background, this research endeavors to investigate the impact of metformin on the prognosis and chemotherapy-induced adverse reactions in patients with BLCA who have undergone RC and subsequently received gemcitabine in combination with cisplatin chemotherapy. By conducting a retrospective analysis of patient data from Xuzhou Medical University Hospital, Xuzhou First People’s Hospital, and Xuzhou Third People’s Hospital, where patients underwent adjuvant GC chemotherapy following BLCA surgery, this study aims to elucidate the potential role of metformin in the postoperative adjuvant treatment of BLCA. Additionally, it seeks to provide a robust scientific foundation for clinical decision-making in the development of more rational and effective treatment strategies. The results of this investigation are expected to provide fresh perspectives on enhancing the quality of life and treatment outcomes for patients with BLCA.

2.1 Patient cohort

A retrospective evaluation was performed on a cohort of 243 individuals who underwent RC followed by adjuvant GC chemotherapy at the Affiliated Hospital of Xuzhou Medical University, Xuzhou First People’s Hospital, and Xuzhou Third People’s Hospital during the period from April 2014 to April 2024. The inclusion criteria were: (1) individuals diagnosed with muscle-invasive urothelial carcinoma of the bladder who had undergone RC and/or pelvic lymph node dissection; (2) those who had consistently received a minimum of four cycles of adjuvant GC chemotherapy postoperatively; (3) individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The exclusion criteria included: (1) individuals with histology other than urothelial carcinoma; (2) individuals with concurrent malignancies; (3) those who had undergone neoadjuvant chemotherapy or radiotherapy; (4) individuals with preoperative imaging that revealed metastatic urothelial carcinoma on chest, abdomen, and pelvic computed tomography (CT) or positron emission tomography-CT. Clinical parameters were reviewed through electronic medical records and prescription databases. The assessment of medication usage, including metformin and other oral hypoglycemic agents or insulin, was conducted prior to surgery. Patients were classified into three groups: non-diabetic (No DM), referring to those without a prior diagnosis of type 2 diabetes or metformin use until the day of surgery; diabetic with metformin use (DM, Metformin), indicating those with a confirmed diagnosis of type 2 diabetes and long-term metformin use up to the day of surgery; and diabetic without metformin use (DM, no Metformin), representing those with a confirmed diagnosis of type 2 diabetes but no history of metformin use.

2.2 Treatment Regimen

All patients included in the study had undergone total cystectomy followed by adjuvant chemotherapy with gemcitabine in combination with cisplatin. The treatment protocol consisted of intravenous administration of gemcitabine at a dose of 1250 mg on days 1 and 8, and intravenous cisplatin at a dosage of 70 mg/m² on day 2, with treatments repeated every 21 days for a minimum of four cycles. All included patients underwent postoperative follow-up, with a review at least every 3–4 months in the first year after surgery, once every six months in the second year, and annually thereafter. The follow-up content included physical examination, routine hematological tests, and upper urinary tract and chest CT scans as needed, until disease progression. Disease progression was defined as tumor recurrence in the surgical area, regional lymph nodes, and distant metastasis.

2.3 Pathological Assessment

The pathological staging of specimens was carried out according to the TNM classification of the International Union Against Cancer for BLCA and the grading system established by the World Health Organization in 2004. All surgical specimens were processed in accordance with standard pathological protocols.

2.4 Clinical and Pathological Characteristics

The clinical and pathological data collected included gender, age, body mass index (BMI), history of hypertension and smoking, ECOG performance status, tumor stage and grade, number and maximum diameter of tumors, lymph node involvement, surgical method, previous transurethral resection of bladder tumor (TURBT), and the specific number of postoperative chemotherapy cycles administered.

2.5 Statistical Analysis

All variables were dichotomized, and the distribution of baseline data was evaluated through normality tests. Descriptive statistics were appropriately applied depending on whether variables followed a normal or non-normal distribution. For the comparison of categorical data, Fisher’s exact test was utilized when expected frequencies fell below 5; otherwise, the chi-squared test was employed. Kaplan-Meier curves were constructed to evaluate progression-free survival (PFS) across the different groups. Univariate and multivariate Cox proportional hazards models were applied to determine factors linked to PFS, with all parameters incorporated into the multivariate analysis to examine the relationship between metformin use and PFS. Multivariate analysis and pairwise comparisons were executed to investigate the link between metformin administration and chemotherapy-related adverse events. In this study, all P-values were two-sided, with statistical significance set at P < 0.05. All statistical analyses were conducted utilizing R software (version 4.2.2) and MSTATA software.

3.1 Clinical and Pathological Characteristics

The baseline characteristics of the patients, along with their association with metformin usage, are depicted in Table 1. Among the 243 enrolled patients, 68 (28%) were diagnosed with diabetes, with metformin being administered to 51 (75%) of these diabetic individuals. No statistically significant differences were identified in pathological staging, lymph node involvement, pathological grading, surgical approach, TURBT prior to RC, or chemotherapy cycles across the groups, except for a variation in BMI distribution (p = 0.039).

Table 1

Patient demographics and baseline characteristics
Characteristic	Group				p-value
Characteristic	Overall, N = 243¹	DM, metformin, N = 51¹	DM, no metformin, N = 17¹	No DM, N = 175¹	p-value
Gender					0.502²
Female	43 (17.70%)	11 (21.57%)	4 (23.53%)	28 (16.00%)
Male	200 (82.30%)	40 (78.43%)	13 (76.47%)	147 (84.00%)
Age					0.136²
˂75	215 (88.48%)	41 (80.39%)	16 (94.12%)	158 (90.29%)
≧ 75	28 (11.52%)	10 (19.61%)	1 (5.88%)	17 (9.71%)
BMI					0.039³
˃23.0	161 (66.26%)	29 (56.86%)	8 (47.06%)	124 (70.86%)
≦ 23.0	82 (33.74%)	22 (43.14%)	9 (52.94%)	51 (29.14%)
Hypertension					0.439²
No	213 (87.65%)	43 (84.31%)	14 (82.35%)	156 (89.14%)
Yes	30 (12.35%)	8 (15.69%)	3 (17.65%)	19 (10.86%)
Smoking history					0.355³
No	104 (42.80%)	20 (39.22%)	10 (58.82%)	74 (42.29%)
Yes	139 (57.20%)	31 (60.78%)	7 (41.18%)	101 (57.71%)
ECOG					0.591³
0	162 (66.67%)	31 (60.78%)	12 (70.59%)	119 (68.00%)
1	81 (33.33%)	20 (39.22%)	5 (29.41%)	56 (32.00%)
Number of tumors					0.331²
˂3	223 (91.77%)	45 (88.24%)	15 (88.24%)	163 (93.14%)
≧ 3	20 (8.23%)	6 (11.76%)	2 (11.76%)	12 (6.86%)
Maximum diameter					0.666³
˂3	80 (32.92%)	15 (29.41%)	7 (41.18%)	58 (33.14%)
≧ 3	163 (67.08%)	36 (70.59%)	10 (58.82%)	117 (66.86%)
Pathologic staging(T)					0.750²
2	96 (39.51%)	24 (47.06%)	6 (35.29%)	66 (37.71%)
3	60 (24.69%)	12 (23.53%)	5 (29.41%)	43 (24.57%)
4	87 (35.80%)	15 (29.41%)	6 (35.29%)	66 (37.71%)
Lymphatic invasion(N)					0.503³
0	157 (64.61%)	35 (68.63%)	9 (52.94%)	113 (64.57%)
1	86 (35.39%)	16 (31.37%)	8 (47.06%)	62 (35.43%)
Pathology grade					0.802²
HG	229 (94.24%)	48 (94.12%)	17 (100.00%)	164 (93.71%)
LG	14 (5.76%)	3 (5.88%)	0 (0.00%)	11 (6.29%)
Operation⁴					0.287³
1	144 (59.26%)	28 (54.90%)	13 (76.47%)	103 (58.86%)
2	99 (40.74%)	23 (45.10%)	4 (23.53%)	72 (41.14%)
TURBT before RC					0.265²
No	56 (23.05%)	16 (31.37%)	4 (23.53%)	36 (20.57%)
Yes	187 (76.95%)	35 (68.63%)	13 (76.47%)	139 (79.43%)
Chemotherapy cycle					0.804²
˃4	23 (9.50%)	5 (10.00%)	2 (11.76%)	16 (9.14%)
4	219 (90.50%)	45 (90.00%)	15 (88.24%)	159 (90.86%)
¹n (%)
²Fisher's exact test
³Pearson's Chi-squared test
⁴Operations:1 means Laparoscopic Radical Cystectomy with Orthotopic Ileal Neobladder Reconstruction; 2 means Laparoscopic Radical Cystectomy with Cutaneous Ureterostomy (Single or Bilateral)

3.2 Kaplan-Meier Survival Analysis

Over a median follow-up duration of 17 months, disease progression was observed in 174 individuals (71.6%). The RFS rates at one, two, and three years were 75.6%, 25.0%, and 13.4% for non-diabetic patients; 84.9%, 52.8%, and 23.6% for diabetic patients on metformin; and 70.1%, 14.3%, and 7.17% for diabetic patients not on metformin (Table 2). The three-year RFS rate was significantly higher for patients on metformin compared to those who were not (p = 0.024, Fig. 1).

Table 2

Kaplan-Meier Estimates for Progression- free Survival Rates (95% CI)
Characteristic	N	Event N	1-year	2-year	3-year	p-value1
Overall	243	216	77.0% (71.8%, 82.6%)	29.1% (23.7%, 35.8%)	14.8% (10.7%, 20.5%)
Group	243	216				0.024
No DM			75.6% (69.5%, 82.3%)	25.0% (19.2%, 32.5%)	13.4% (9.05%, 19.9%)
DM, metformin			84.9% (75.2%, 95.9%)	52.8% (39.2%, 71.2%)	23.6% (13.1%, 42.8%)
DM, no metformin			70.1% (51.2%, 96.0%)	14.3% (4.02%, 51.1%)	7.17% (1.09%, 47.0%)
1Log-rank test

3.3 Univariate and Multivariate Analysis

The univariate analysis indicated that, in comparison to non-diabetic patients, those administered metformin (HR: 0.68, 95% CI 0.47–0.97, p = 0.036) exhibited a diminished risk of disease recurrence, whereas diabetic patients not on metformin (hazard ratio [HR]: 1.48, 95% confidence interval [CI] 0.87–2.52, p = 0.150) did not demonstrate a significantly higher risk of disease progression. In the multivariate regression analysis, after adjustments were made for age, gender, BMI, hypertension, smoking history, tumor stage, grade, tumor number and maximum diameter, lymph node involvement, surgical approach, and chemotherapy cycles, patients receiving metformin (HR: 0.66, 95% CI 0.45–0.96, p = 0.031) continued to show a significant association with reduced RFS when compared to non-diabetic patients. For those not treated with metformin, diabetes seemed unrelated to an elevated likelihood of disease progression (p > 0.05)(Table 3).

Table 4

Univariate and multivariate analysis of influencing factors (Cox regression)
Characteristic	Univariable					Multivariable
Characteristic	N	Event N	HR1	95% CI1	p-value	N	Event N	HR1	95% CI1	p-value
Gender
Female	43	41	—	—		43	41	—	—
Male	200	175	0.78	0.55, 1.10	0.159	199	174	0.76	0.53, 1.08	0.125
Age
˂75	215	194	—	—		215	194	—	—
≧ 75	28	22	1.19	0.77, 1.86	0.434	27	21	1.46	0.90, 2.36	0.123
BMI
˃23.0	161	144	—	—		160	143	—	—
≦ 23.0	82	72	1.14	0.86, 1.52	0.361	82	72	0.99	0.73, 1.35	0.969
Hypertension
No	213	190	—	—		212	189	—	—
Yes	30	26	1.06	0.71, 1.60	0.766	30	26	0.81	0.52, 1.25	0.337
Smoking history
No	104	91	—	—		104	91	—	—
Yes	139	125	1.11	0.85, 1.46	0.441	138	124	0.99	0.72, 1.38	0.971
Number of tumors
˂3	223	199	—	—		222	198	—	—
≧ 3	20	17	0.90	0.55, 1.48	0.687	20	17	0.80	0.46, 1.38	0.418
Maximum diameter
˂3	80	77	—	—		80	77	—	—
≧ 3	163	139	1.06	0.80, 1.40	0.707	162	138	0.89	0.65, 1.21	0.440
Pathologic staging(T)
2	96	84	—	—		96	84	—	—
3	60	53	1.35	0.95, 1.92	0.090	59	52	1.17	0.79, 1.72	0.429
4	87	79	1.80	1.31, 2.47	< 0.001	87	79	1.79	1.27, 2.50	< 0.001
Lymphatic invasion(N)
0	157	138	—	—		157	138	—	—
1	86	78	1.10	0.83, 1.45	0.517	85	77	1.07	0.80, 1.44	0.650
Pathology grade
HG	229	203	—	—		228	202	—	—
LG	14	13	0.46	0.25, 0.86	0.015	14	13	0.49	0.25, 0.94	0.032
Operation
1	144	131	—	—		144	131	—	—
2	99	85	0.76	0.58, 1.00	0.051	98	84	0.77	0.57, 1.04	0.085
TURBT before RC
No	56	52	—	—		56	52	—	—
Yes	187	164	0.93	0.68, 1.28	0.660	186	163	0.80	0.56, 1.13	0.201
Chemotherapy cycle
˃4	23	19	—	—		23	19	—	—
4	219	196	0.81	0.50, 1.30	0.380	219	196	0.79	0.48, 1.31	0.361
Group
No DM	175	165	—	—		175	165	—	—
DM, metformin	51	36	0.68	0.47, 0.97	0.036	50	35	0.66	0.45, 0.96	0.031
DM, no metformin	17	15	1.48	0.87, 2.52	0.150	17	15	1.42	0.81, 2.49	0.222
1HR = Hazard Ratio, CI = Confidence Interval

3.4 Impact on Chemotherapy Toxicities

During the assessment of chemotherapy-induced adverse reactions, gastrointestinal symptoms such as nausea and vomiting, alongside hematological toxicities like leukopenia and thrombocytopenia, were the most frequently observed adverse effects across the three patient cohorts. Grade 3 or more severe hematological toxicities were reported in 70 out of 175 non-diabetic patients (40.00%), 11 out of 51 diabetic patients on metformin (21.57%), and 6 out of 17 diabetic patients not on metformin (35.29%) (Table 4). Additionally, patients on metformin exhibited a lower incidence of grade 3 or higher hematological adverse events compared to those not on metformin (21.57% vs. 37.14%). When compared to non-diabetic patients, those receiving metformin demonstrated a reduced incidence of grade 3 or higher adverse reactions (p = 0.0157), whereas the presence of diabetes among non-metformin users did not appear to correlate with an increased incidence of severe adverse reactions (p > 0.05). Even after adjusting for variables such as gender, age, BMI, hypertension, smoking history, tumor characteristics, and chemotherapy cycles, metformin use remained associated with a lower incidence of grade 3 or 4 adverse reactions (p = 0.011)(Table 5).

Table 5

Correlation analysis of the impact on chemotherapy-related adverse reactions (Pairwise Comparison)
	No DM	DM, metformin	DM, no metformin
	(N = 175)	(N = 51)	(N = 17)
Responders	70.00 (40.00%)	11.00 (21.57%)	6.00 (35.29%)
Non-Responders	105.00 (60.00%)	40.00 (78.43%)	11.00 (64.71%)
Unstratified Response Analysis
Risk Difference, RD (%) (95% CI)		-18.43 (-31.85 - -5.01)	-4.71 (-28.55–19.14)
Risk Ratio, RR (95% CI)		0.54 (0.31–0.94)	0.88 (0.45–1.72)
Odds Ratio, OR (95% CI)		0.41 (0.20–0.86)	0.82 (0.29–2.31)
p-value (Chi-squared test)		0.0157	0.7048
p-value (Fisher's exact test)		0.0197	0.7991

The outcomes of this study demonstrate that the use of metformin significantly enhances PFS in patients receiving adjuvant GC chemotherapy following RC for BLCA. This finding highlights the potential significance of metformin in cancer therapy, particularly within the adjuvant context post-BLCA surgery. Although the specific mechanisms of metformin were not directly examined in this study, both the existing literature and our results imply that metformin may exert its anticancer and toxicity-reducing effects through several pathways. Beyond the previously mentioned mechanisms, including inhibition of tumor cell proliferation, promotion of apoptosis, and suppression of invasion and metastasis, metformin might also influence the tumor microenvironment, regulate the expression of inflammatory cytokines, and ultimately enhance its anticancer properties. Additionally, metformin could potentially mitigate the deleterious effects of chemotherapy by modulating energy metabolism and cellular signaling pathways.

One of the essential mechanisms by which metformin exerts its anticancer effects is through the activation of the AMPK pathway, subsequently leading to the suppression of the mTOR signaling pathway. This cascade results in the inhibition of tumor cell proliferation, the induction of apoptosis, and the reduction of tumor growth, thereby manifesting its anticancer efficacy ^[24][25]. Additionally, metformin has the capacity to alter the tumor microenvironment by suppressing the activity of tumor-associated fibroblasts and inhibiting tumor angiogenesis, which may mitigate tumor aggressiveness and metastatic potential ^[26]. Its anti-inflammatory and immunomodulatory properties, demonstrated by the reduction of pro-inflammatory cytokine secretion and the enhancement of CD⁸⁺ T cell activity, further contribute to the suppression of tumor growth ^[27]. Moreover, the antioxidant capabilities of metformin might enhance patient tolerance to chemotherapy by diminishing oxidative stress and decreasing DNA damage, thereby potentially improving prognosis ^[28].

Metformin has been observed to potentially enhance survival outcomes across various cancer types. For example, in the case of prostate cancer, the use of metformin has been correlated with a notable improvement in overall survival (OS), reflected by a pooled HR of 0.79 (95% CI 0.63–0.98) when compared to non-users ^[29]. In gastric cancer, particularly among diabetic patients who have undergone gastrectomy, metformin has been demonstrated to significantly extend cancer-specific survival (CSS), with the most substantial benefits seen in stage III gastric cancer patients ^[30]. Regarding BLCA, several studies have investigated the clinical effects of metformin. For instance, one study highlighted a significant link between metformin usage and enhanced OS in patients with non-muscle-invasive bladder cancer (NMIBC), where the most favorable outcomes were identified in diabetic patients utilizing metformin ^[31]. Rieken et al. conducted two studies revealing that, in comparison to non-diabetic patients, those using metformin displayed a reduced risk of disease recurrence in NMIBC (HR: 0.50, 95% CI: 0.27–0.94, p = 0.03) and a decreased risk of disease progression (HR: 0.61, 95% CI 0.37–0.98, p = 0.04), cancer-specific mortality (HR: 0.56, 95% CI 0.33–0.97, p = 0.04), and all-cause mortality (HR: 0.54, 95% CI 0.33–0.88, p = 0.01) in MIBC patients following RC ^[32][33]. Furthermore, another study identified a significant link between metformin intake and improved RFS, PFS, and CSS in BLCA patients ^[34].

Recent investigations have concentrated on the potential synergistic interactions between metformin and various chemotherapeutic agents, notably cisplatin and gemcitabine, in the context of BLCA treatment. Metformin has been found to enhance the cytotoxic effects of these chemotherapy drugs, thereby further inhibiting the proliferation of tumor cells. For example, the combination of metformin with gemcitabine has been shown to produce significant synergistic antitumor effects, thereby increasing the sensitivity of BLCA cells to chemotherapy while simultaneously reducing drug resistance ^[35]. Additionally, metformin is posited to mitigate adverse reactions related to chemotherapy, particularly those induced by cisplatin and gemcitabine. Research indicates that metformin may decrease toxicity to normal tissues by modulating intracellular energy metabolism and enhancing antioxidant stress responses. This protective effect is not limited to the mitigation of common hematological toxicities but may also play a crucial role in alleviating chemotherapy-associated gastrointestinal symptoms and systemic discomfort ^[36].

However, certain studies have observed that prolonged metformin usage in BLCA patients may correlate with reduced OS, disease-specific survival, and RFS, indicating possible variations in metformin’s effects across distinct patient populations ^[37]. Although the efficacy of metformin may not be pronounced in specific cancer types, such as renal and head and neck cancers, where no statistically significant link with enhanced survival outcomes has been detected ^[38], it still possesses the potential to extend PFS and CSS in particular cancer types, offering valuable insights for its role in cancer treatment.

Notably, this study assessed the influence of metformin on chemotherapy-related adverse reactions, demonstrating that patients administered metformin exhibited significantly lower incidences of grade 3 or higher hematological adverse reactions as well as overall adverse reactions when compared to non-users (21.57% vs. 37.14% and 21.57% vs. 40.00%, respectively). This discovery not only highlights metformin’s potential in mitigating chemotherapy toxicity but also systematically unveils this effect for the first time in BLCA patients undergoing postoperative chemotherapy, suggesting new avenues for future clinical treatment strategies. Through the utilization of a large patient cohort and robust statistical analysis, this study not only affirms the potential benefits of metformin in adjuvant BLCA therapy but also sheds light on its clinical relevance and protective effects. Compared to prior research, the results of this study demonstrate greater clinical significance and wider applicability ^[39–41].

Although the potential benefits of metformin in BLCA patients have been highlighted, several limitations must be recognized. Firstly, the retrospective nature of this study introduces the possibility of selection bias, particularly with regard to patient inclusion criteria and metformin usage. Given that all participants were sourced from a single medical center or comparable healthcare environments, the external validity of these findings may be constrained, making it challenging to generalize them to diverse patient populations or different healthcare settings. Furthermore, the relatively short duration of follow-up, while suggesting metformin’s potential advantages at the three-year mark, may not offer a comprehensive assessment of long-term outcomes. Despite efforts to control for confounding factors through multivariable analysis, there remains the possibility that unmeasured or unknown variables could have impacted the results. Future research should incorporate prospective randomized controlled trials to validate these findings and explore metformin’s mechanisms in BLCA treatment more thoroughly, thereby providing a stronger scientific foundation for clinical practice.

In conclusion, the findings of this study offer essential clinical evidence supporting the use of metformin in adjuvant BLCA therapy. Given that metformin is a widely prescribed antidiabetic medication, its safety and tolerability are well-documented. Therefore, the integration of metformin into adjuvant therapy for BLCA presents significant benefits. Future research should investigate optimal dosing, timing of administration, and combination strategies with other therapies to enhance its anticancer efficacy and safety profile. Considering the heterogeneity of BLCA, subsequent studies should also evaluate metformin’s effectiveness across various BLCA subtypes and stages to inform personalized treatment approaches. Ultimately, a more comprehensive understanding of metformin’s role in improving prognosis and reducing adverse reactions will refine treatment protocols, leading to better patient outcomes and potentially influencing treatment strategies for other malignancies.

This study involved a retrospective analysis of 243 individuals who underwent RC for BLCA and received GC chemotherapy, highlighting the beneficial effects of metformin in enhancing patient outcomes and minimizing adverse reactions to chemotherapy. The findings suggest that diabetic patients who were administered metformin exhibited a significant improvement in RFS compared to those diabetic patients who did not receive metformin or non-diabetic patients, and they also experienced a lower incidence of grade 3 or higher adverse reactions. This observation not only underscores the potential of metformin as an anticancer agent but also establishes a scientific foundation for its integration into adjuvant treatment protocols for BLCA post-surgery in clinical practice.

In conclusion, metformin presents dual advantages in both enhancing prognosis and mitigating chemotherapy-related toxicity in the adjuvant treatment of BLCA, thereby warranting further promotion and utilization in clinical settings. Future studies should concentrate on elucidating the specific mechanisms of metformin, determining the optimal dosage, and developing strategies for its combined use with other therapies, with the aim of maximizing its clinical efficacy.

All abbreviations are indicated in the text. Such as: gemcitabine and cisplatin (GC), muscle-invasive bladder cancer (MIBC), radical cystectomy (RC), Progression-free survival (PFS), and so on.

Ethics approval and consent participate

This retrospective study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of The Affiliated Hospital of Xuzhou Medical University. Since the study involved the review of existing medical records and did not require direct patient contact or intervention, the need for informed consent from individual patients was waived by the ethics committee. However, all patient data were anonymized to ensure patient confidentiality and privacy.

Consent for publication

The authors confirm that all authors have reviewed and approved the final version of the manuscript for publication. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. There are no conflicts of interest to disclose that could potentially influence the publication of this manuscript.

Availability of date and materials

The datasets generated and/or analyzed during the current study are not publicly available due to privacy concerns and ethical restrictions related to patient confidentiality. However, the corresponding author can be contacted ([email protected] or [email protected] ) for reasonable requests related to the study design, data collection and analysis methods, provided they comply with the ethical guidelines and regulations governing the use of human subject data.

Competing Interests

The authors declare that they have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper. All authors have disclosed any potential conflicts of interest and confirmed that no financial or non-financial competing interests exist that could influence the interpretation of data or the writing of this manuscript. The results presented in this study are based solely on scientific research and analysis.

Funding

National Nature Science Foundation of China Youth Project (Project approval number: 81502193)

Authors’ contributions

Lei Zhang and Jingyi Cao are the co-first authors who mainly wrote the manuscript text. Chong Han conducted the investigation and data compilation. Jingwen Zhang performed the formal analysis of this paper. Yiwen Lui was mainly responsible for data validation. Hailong Li, as the corresponding author, participated in the review and editing of the manuscript, project management, fund acquisition, and provided supervision and guidance.

Acknowledgements

During the process of completing this paper, I feel deeply honored to have worked with such an excellent team. First and foremost, I would like to express my special gratitude to Professor Jingyi Cao, who not only devoted a great amount of effort into writing the manuscript but also laid a solid foundation for the formation of this paper with her professional knowledge and unique insights. Chong Han's diligent work in investigation and data compilation enabled our research to be built upon a solid data foundation, and his rigorous attitude is truly admirable. Jingwen Zhang's formal analysis of this paper undoubtedly added an important dimension to its perfection, and his meticulous work is worthy of learning from by all of us. Yiwen Liu's contributions in data validation are also not to be underestimated, as his efforts ensured the accuracy and reliability of the data presented in this paper. Lastly, I would like to express my deepest gratitude to the corresponding author, Hailong Li, who not only provided valuable suggestions during the review and editing of the manuscript but also played an irreplaceable role in project management, fund acquisition, and supervisory guidance. Without the joint efforts of everyone, the completion of this paper would not have been possible. Here, I extend my sincerest thanks to each member of our team!

Declaration of Competing Interest

This was a retrospective data analysis; All authors disclosed no relevant relationships.

Cheng L, Lopez-Beltran A, Bostwick DG. Bladder pathology. Wiley-Blackwell; 2012. 10.1002/9781118275436.
Siegel RL, Giaquinto AN, Jemal A, Cancer statistics. 2024. CA Cancer J Clin 2024;74:12–49. 10.3322/caac.21820
Lobo N, Afferi L, Moschini M, et al. Epidemiology, screening, and prevention of bladder cancer. Eur Urol Oncol. 2022;5:628–39. 10.1016/j.euo.2022.10.003.
Sonpavde GP, Mouw KW, Mossanen M. Therapy for muscle-invasive urothelial carcinoma: Controversies and dilemmas. J Clin Oncol. 2022;40:1275–80. 10.1200/JCO.21.02928.
Mohanty SK, Lobo A, Mishra SK, Cheng L. Precision medicine in bladder cancer: present challenges and future directions. J Pers Med. 2023;13:756. 10.3390/jpm13050756.
Konieczkowski DJ, Efstathiou JA, Mouw KW. Contemporary and.
emerging approaches to bladder-. preserving trimodality therapy for muscle-invasive bladder cancer. Hematol Oncol Clin NorthAm. 2021;35:567–84. 10.1016/j.hoc.2021.02.006.
Tripathi A, MacDougall K, Sonpavde GP. Therapeutic landscape beyond immunotherapy in advanced urothelial carcinoma: moving past the checkpoint. Drugs. 2022;82:1649–62. 10.1007/s40265-022-01802-3.
Kamat AM, Hahn NM, Efstathiou JA, et al. Bladder cancer Lancet. 2016;388:2796–810. 10.1016/S0140-6736(16)30512-8.
Advanced Bladder Cancer (ABC) Meta-analysis Collaborators Group. Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and meta-analysis of individual participant data from randomised controlled trials. Eur Urol. 2022;81:50–61. 10.1016/j.eururo.2021.09.028.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81–98.
Ismaili N, Amzerin M, Flechon A. Chemotherapy in advanced bladder cancer: current status and future. J Hematol Oncol. 2011;4:35. 10.1186/1756-8722-4-35. Published 2011 Sep 9.
Shelley M, Cleves A, Wilt TJ, Mason M. Gemcitabine for unresectable, locally advanced or metastatic bladder cancer. Cochrane Database Syst Rev. 2011;4CD008976. 10.1002/14651858.CD008976.pub2. Published 2011 Apr 13.
Jiang L, Zhang Z, Dong P, et al. Efficacy of radical cystectomy plus adjuvant intraarterial chemotherapy with gemcitabine and cisplatin on locally advanced bladder cancer. Chin Med J (Engl). 2014;127(7):1249–54.
Ryan CW, Vogelzang NJ. Gemcitabine in the treatment of bladder cancer. Expert Opin Pharmacother. 2000;1(3):547–53. 10.1517/14656566.1.3.547.
Cognetti F, Ruggeri EM, Felici A, et al. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol. 2012;23(3):695–700. 10.1093/annonc/mdr354.
NICE. National Institute of Health and Care Excellence: Type II Diabetes CG87. 2009.
Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012;48:R31–43.
Dowling RJ, Zakikhani M, Fantus IG, et al. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67:10804–12.
Fidan E, Onder Ersoz H, Yilmaz M, et al. The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus. Acta Diabetol. 2011;48:297–302.
Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011;9:33.
Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol. 2016;27(12):2184–95. 10.1093/annonc/mdw410.
Zhang HH, Guo XL. Combinational strategies of metformin and chemotherapy in cancers, Cancer Chemother. Pharmacol. 78 (1) (2016) 13–26, https://doi.org/10.1007/s00280-016-3037-3, e-pub ahead of print 2016/04/28.
Zhang T, Guo P, Zhang Y, Xiong H, Yu X, Xu S, Wang X, He D, Jin X. The Antidiabetic Drug Metformin Inhibits the Proliferation of Bladder Cancer Cells in Vitro and in Vivo. Int J Mol Sci. 2013;14:24603–18.
Chomaničová N, Gazova A, Adamičková A, Valášková S, Kyselovič J. The Role of AMPK/mTOR Signaling Pathway in Anticancer Activity of Metformin. Physiol Res. 2021;70:663–73.
Shen Z-f, Xue D, Wang K, Zhang F, Shi J, Jia B, Yang D, Zhang Q-j, Zhang S, Jiang H, Luo D, Li X, Zhong Q, Zhang J, Peng Z, Han Y, Sima C, He X, Hao L. Metformin Exerts an Antitumor Effect by Inhibiting Bladder Cancer Cell Migration and Growth, and Promoting Apoptosis Through the PI3K/AKT/mTOR Pathway. BMC Urol. 2021, 21, Article 24.
Wang F, Liu W, Xu X, Yang Y, Yi Q, Guo F, Li J, Zhou J, Kou Q. Autophagy Induction Enhances Tetrandrine-Induced Apoptosis via the AMPK/mTOR Pathway in Human Bladder Cancer Cells. Oncol Rep. 2017;38:1143–51.
Zhou X, Chen YX, Wang F, Wu H, Zhang Y, Liu J, Cai Y, Huang S, He N, Hu Z, Jin X. Artesunate Induces Autophagy Dependent Apoptosis Through Upregulating ROS and Activating AMPK-mTOR-ULK1 Axis in Human Bladder Cancer Cells. Chem Biol Interact. 2020;330:109273.
Xiao Y, Zheng L, Mei Z, Xu C, Liu C, Chu X, Hao B. The impact of metformin use on survival in prostate cancer: a systematic review and meta-analysis. Oncotarget. 2017;8:59.
Chung W-S, Le P-H, Kuo C-J, Chen T-H, Kuo C-F, Chiou M-J, Chou W-C, Yeh T-S, Hsu J-T. Impact of Metformin Use on Survival in Patients with Gastric Cancer and Diabetes Mellitus Following Gastrectomy. Cancers 2020, 12 (8), 2013.
Wang Z, Ong W, Tong S, Sng J, Lata R, Mahendran R, Kesavan E, Chiong E. Beyond Diabetes Mellitus: Role of Metformin in Non-Muscle Invasive Bladder Cancer. Singap Med J. 2020;63(4):209–15.
Rieken M, Xylinas E, Kluth L, et al. Effect of diabetes mellitus and metformin use on oncologic outcomes of patients treated with radical cystectomy for urothelial carcinoma. Urol Oncol. 2014;32(1). 10.1016/j.urolonc.2013.07.006.
Rieken M, Xylinas E, Kluth L, et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int. 2013;112(8):1105–12. 10.1111/bju.12448.
Hu J, Chen J, Cui Y, Zhu Y, Ren W, Zhou X, Liu L, Chen H, Zu X. Association of Metformin Intake with Bladder Cancer Risk and Oncologic Outcomes in Type 2 Diabetes Mellitus Patients. Medicine 2018, 97 (30), e11596.
Ren X, Tian Y, Wang Z, Wang J, Li X, Yin Y, Chen R, Zhan Y, Zeng X. Tislelizumab in Combination with Gemcitabine Plus Cisplatin Chemotherapy as First-Line Adjuvant Treatment for Locally Advanced or Metastatic Bladder Cancer: A Retrospective Study. BMC Urol. 2022;22:108.
Yang Q, Nie Y, Cai M-B, Li Z, Zhu H, Tan Y-R. Gemcitabine Combined with Cisplatin Has a Better Effect in the Treatment of Recurrent/Metastatic Advanced Nasopharyngeal Carcinoma. Drug Des Devel Ther. 2022;16:1145–54.
Wissing M, O’Flaherty A, Dragomir A, Tanguay S, Kassouf W, Aprikian A. Chronic Prednisone, Metformin, and Nonsteroidal Anti-Inflammatory Drug Use and Clinical Outcome in a Cohort of Bladder Cancer Patients Undergoing Radical Cystectomy in Québec, Canada. BMC Urol. 2023, 23 (1), Article 35.
Nayan M, Punjani N, Juurlink DN, Finelli A, Austin PC, Kulkarni GS, Uleryk E, Hamilton RJ. Metformin Use and Kidney Cancer Survival Outcomes: A Systematic Review and Meta-Analysis. Am J Clin Oncol. 2019;42(3):275–84.
Molenaar RJ, van Hattum JW, Brummelhuis I, Oddens J, Savci-Heijink CD, Boevé E, van der Meer S, Witjes JF, Pollak M, Pollak M, de Reijke TM, Wilmink J. Study Protocol of a Phase II Clinical Trial of Oral Metformin for the Intravesical Treatment of Non-Muscle Invasive Bladder Cancer. BMC Cancer. 2019;19(1):1137.
Hamedi B, Khalili A, Roozmeh S, Namazi G, Saraf Z. Combination of Metformin and Chemotherapy Decreases the Recurrence Rates of Epithelial Ovarian Cancers: A Randomized Clinical Trial. Iran J Cancer Manage. 2018;7(2):11621.
Pimentel I, Lohmann AE, Ennis M, Dowling RJO, Cescon DW, Elser C, Potvin K, Haq R, Hamm C, Chang MC, Stambolic V, Goodwin PJ. A Phase II Randomized Clinical Trial of the Effect of Metformin Versus Placebo on Progression-Free Survival in Women with Metastatic Breast Cancer Receiving Standard Chemotherapy. Breast. 2019;48:17–23.

Table 6

Logistic regression for chemotherapy-related adverse reactions analysis
Characteristic	OR1	95% CI1	p-value
Treatment (unadjusted)
No DM	—	—
DM, metformin	0.41	0.19, 0.83	0.018
DM, no metformin	0.82	0.27, 2.25	0.71
Treatment (adjusted)*
No DM	—	—
DM, metformin	0.34	0.14, 0.75	0.011
DM, no metformin	0.84	0.26, 2.53	0.77
1OR = Odds Ratio, CI = Confidence Interval

No competing interests reported.

Download PDF

Reviews received at journal
17 Oct, 2024
Reviewers agreed at journal
15 Oct, 2024
Reviewers invited by journal
08 Oct, 2024
Editor invited by journal
10 Sep, 2024
Editor assigned by journal
04 Sep, 2024
Submission checks completed at journal
04 Sep, 2024
First submitted to journal
03 Sep, 2024

You are reading this latest preprint version

Correlations Between Metformin and Prognosis and Adverse Reactions in Patients Undergoing Radical Cystectomy Followed by Adjuvant GC Chemotherapy for Bladder Cancer

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

1. Background

2. Methods

2.1 Patient cohort

2.2 Treatment Regimen

2.3 Pathological Assessment

2.4 Clinical and Pathological Characteristics

2.5 Statistical Analysis

3. Results

3.1 Clinical and Pathological Characteristics

3.2 Kaplan-Meier Survival Analysis

3.3 Univariate and Multivariate Analysis

3.4 Impact on Chemotherapy Toxicities

Discussion

Conclusions

Abbreviations

Declarations

References

Table 6

Additional Declarations

Status:

Version 1