Effect of different infusion modes of pirarubicin on recurrence rate and adverse reactions in patients with postoperative chemotherapy for bladder cancer: A Meta-Analysis

doi:10.21203/rs.3.rs-3886814/v1

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Effect of different infusion modes of pirarubicin on recurrence rate and adverse reactions in patients with postoperative chemotherapy for bladder cancer: A Meta-Analysis

https://doi.org/10.21203/rs.3.rs-3886814/v1

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Objective This meta-analysis aims to compare the effect of postoperative pyrazobicin bladder thermal perfusion and plain perfusion in reducing the bladder cancer recurrence rate and the incidence of adverse effects in bladder cancer patients. Methods Computer searches were undertaken on the Cochrane Library, PubMed, the Wanfang database, China Knowledge Network (CNKI) and Wipu databases, all with a search time frame from inception to March 2023. Meta-analysis was performed using the RevMan 5.4.1 software.

Results 18 studies were included, and the results showed that compared to normal perfusion, postoperative pirarubicin bladder thermal perfusion was more effective in reducing the 2-year recurrence rate, the 1-year recurrence rate, and the incidence of urinary pain in bladder cancer patients.

Conclusion Compared to conventional infusion chemotherapy, postoperative pyrazobicin bladder heat infusion reduced the tumour recurrence rate and the incidence of adverse effects in bladder cancer patients more effectively.

Bladder cancer

Pirarubicin

Thermal perfusion

Normal perfusion

Comparison

Meta-analysis

Bladder cancer , a common urinary tract tumour, has risen significantly in recent years in China. According to 2020 Global Cancer Statistics, there were 573,000 new bladder cancer cases and 213,000 related deaths worldwide in 2020 ^[1]. In addition, bladder cancer is characterized by a significant tendency to relapse. Transurethral Bladder Tumour Resection (TUR-BT) is currently the most effective method for diagnosing and treating non-invasive bladder cancer ^[2]. It removes tumour tissues and allows patients’ tumour stage to be determined based on the procedure. However, turt-bt alone does not permanently eradicate the tumor, and the chance of recurrence is often high.^[3]. Postoperative bladder infusion chemotherapy, which has been demonstrated to be effective, has invariably been used by researchers to lower the bladder cancer recurrence rate ^[4]. As an alternative for reducing the bladder cancer recurrence rate, chemotherapy with pyrazosin by hot instillation has also been explored and found to be more effective ^[5]. However, due to a small sample size, it is difficult to compare the effect of pyrazobicin hot infusion with plain infusion in preventing bladder cancer recurrence, a fact that some studies have recognised and discussed. Herein, we will collect relevant data and conduct a secondary analysis of the literature on the prism of evidence-based medicine to investigate which therapeutic approach is superior in post-TUR-BT bladder cancer therapy. Specifically, this meta-analysis will be based on the impact of transurethral bladder tumour electrosurgery (postoperative bladder perfusion chemotherapy vs. bladder hyperperfusion chemotherapy) on the recurrence rate and adverse effects in bladder cancer patients.

1.1 Inclusion criteria

1.1.1 Study type: Randomised and semi-randomised controlled clinical trials comparing postoperative pirarubicin thermal perfusion with conventional perfusion chemotherapy in bladder cancer treatment.

1.1.2 Study population: Patients undergoing postoperative chemotherapy for bladder cancer.

1.1.3 Interventions: Pyrazosin bladder heat infusion chemotherapy and pyrazosin plain infusion chemotherapy for the trial and control groups, respectively.

1.1.4 Outcome indicators: Bladder cancer recurrence, incidence of haematuria, dysuria, cystitis, bladder irritation signs, and incidence of insomnia.

1.2 Exclusion criteria

Studies that used pirenzosin in combination with other drugs for chemotherapy.

1.3 Search strategy

An electronic search was performed on PubMed, China Knowledge Base (CNKI), the China Biomedical Literature Database (CBM), and WanFang databases to collect literature on clinical trials of bladder thermal perfusion chemotherapy and bladder perfusion chemotherapy for bladder cancer. The search time frame was set from the inception of the databases to March 2023. The Chinese (key) search terms included bladder cancer, bladder tumour, bladder malignancy, thermal perfusion chemotherapy, thermal perfusion therapy, and perfusion therapy. On the other hand, the English (key) search terms included Urinary Bladder Neoplasms, Bladder Cancer, Bladder Cancers, Bladder Tumor, Bladder Neoplasm, Thermo-chemotherapy, Chemohyperthermia, Hyperthermia, and C-HT. The language of the articles was restricted to Chinese and English. The search terms were adjusted as necessary per each database’s corresponding characteristics using a combination of subject terms and keywords, and multiple pre-searches were performed prior to the formal search. Furthermore, relevant journals were searched manually, and references and similar literature for the retrieved material were tracked to ensure the completeness of the included studies.

1.4 Evaluation of the quality of the literature

Two independent investigators evaluated the quality of the literature based on the risk of bias assessment tool recommended by the Cochrane Collaboration ^[6]. The aspects considered were sequence generation, random allocation method, allocation concealment, subject blinding measures, investigators and outcome evaluators, completeness of outcome data regarding whether results were reported selectively, and other sources of bias. All assessments were expressed in three categories: low bias, high bias, and unclear risk.

1.5 Data extraction

Two independent trained researchers performed data extraction from the literature, with a third researcher assisting in resolving any ambiguities encountered in the literature. Two researchers used a data extraction form to collect and examine data obtained from the included literature. Extracts included: (i) Basic information (authors, year of publication, and baseline status); (ii) Study design (study population, interventions, and evaluation indicators); and (iii) Other information reflecting the quality of the literature.

1.6 Data analysis

Data on patients in the hot and normal perfusion groups were extracted and entered into the RevMan 5.4.1 software for heterogeneity analysis and combined statistics. A fixed-effects model was used to statistically analyse the data if homogeneity existed between multiple studies (P > 0.1 and I^２< 50%). On the other hand, if heterogeneity existed between multiple studies (P < 0.1 or I^２> 50%), it was first analysed and processed, and a random-effects model was applied for the analysis if it was still not eliminated. Given that the data used in this study were continuous variables, the Odds Ratio (OR) was used as an indicator for teaching effectiveness analysis, and its 95% CI (Confidence Interval) was calculated for all statistical analyses.

2.1 Basic information on the included literature

The initial search yielded 16,390 articles, of which 12,415 articles were excluded after the preliminary check. After the initial screening, we further read the topics and abstracts of the articles obtained and excluded studies that did not meet the inclusion criteria. Subsequently, we conducted a detailed review of the full text of the studies included, which yielded 18 articles that fully met the inclusion criteria, of which 15 were in Chinese and 3 were in English ^[7-24](Pic.1).

2.2 The literature quality evaluation results

Cochrance 5.4.1 was used in the methodological quality assessment to evaluate the risk of bias for inclusion in the Randomized Control Trials (RCTs), and the results showed that of the 18 RCTs, two were of high quality and were assessed as grade A, whereas 16 were of moderate quality and were assessed as grade B (Fig.1).

2.3 Comparison of results between pyrazosin bladder thermal perfusion and conventional perfusion chemotherapy in bladder cancer patients

2.3.1 Two-year postoperative recurrence rates

Thirteen studies demonstrated two-year recurrence rates in bladder cancer patients in the postoperative hot-infusion piroplasin and normal infusion treatment groups. The studies included 630 and 631 patients in the trial group and control groups, respectively. No statistical differences were found between the test and control groups at baseline in any of the studies. Additionally, no statistical heterogeneity was observed between the studies (p = 0.47. I² = 0); hence, the statistics were combined using a fixed effects model. Compared to the control group, the pyrazobicin heat infusion treatment group showed lower odds of bladder cancer recurrence post-surgery, with a statistically significant difference. Furthermore, there was an overall risk ratio of 0.29 (95% CI: 0.20-0.44) for the test group compared to the control group, indicating a 71.0% lower odds of recurrence for bladder cancer patients post-surgery (Fig. 2).

2.3.2 One-year recurrence rates

Thirteen studies demonstrated a one-year recurrence rate in bladder cancer patients in the postoperative hot infusion piroplatin and the normal infusion treatment groups. The studies included 674 and 681 patients in the trial and control groups, respectively. No statistical differences were found between the test and control groups at baseline in any of the studies. Additionally, no statistical heterogeneity was observed between the studies (p = 0.06. I² = 42); hence, the statistics were combined using a fixed effects model. Compared to the control group, the pyrazobicin heat infusion treatment group showed lower bladder cancer odds of recurrence post-surgery, with a statistically significant difference. Furthermore, there was an overall risk ratio of 0.35 95% CI:0.27-0.47) for the test group compared to the control group, indicating a 65.0% lower odds of recurrence for bladder cancer patients post-surgery (Fig. 3).

2.3.3 Incidence of haematuria

Haematuria was the most common adverse effect during treatment. Its overall incidence in the included studies was 9.6% and 30% in the trial and control groups, respectively. Fourteen studies demonstrated a recurrence rate for haematuria in bladder cancer patients in the postoperative hot infusion pirenzosin and the normal infusion treatment groups. The studies included 674 and 681 patients in the trial and control groups, respectively. No statistical differences were found between the test and control groups at baseline in any of the studies. Furthermore, no statistical heterogeneity was observed between studies (P = 0.76, I² = 0); hence, the statistics were combined using a fixed effects model. Compared to the control group, the pyrazobicin heat infusion treatment group showed lower odds of recurrence after bladder cancer treatment, which was not statistically significant. Additionally, there was an overall risk ratio of 0.76 (95% CI: 0.54-1.06) for the trial group compared to the control group, indicating a 65.0% lower odds of recurrence for bladder cancer patients post-surgery (Fig. 4).

2.3.4 Incidence of painful urination

Painful urination during treatment was also a common adverse effect. Three studies with 106 cases each in the trial and control groups analysed the impact of pyrazosin thermal infusion on improving the incidence of bladder irritation signs after bladder cancer treatment. In the included studies, the overall incidence was 4.7% and 16% in the trial and control groups, respectively. Additionally, the three studies analysed the effect of postoperative pyrazobicin heat infusion in reducing the incidence of urinary pain after bladder cancer treatment. No statistical heterogeneity was found between studies (p = 0.73, I^２= 0); hence, the statistics were combined using a fixed effects model. Furthermore, a statistically significant difference was found between pyrazosin bladder thermal perfusion and plain perfusion [OR = 0.25, 95% CI: 0.09-0.7)] (Fig. 5).

2.3.5 Bladder irritation signs

Four studies were conducted to analyse the effect of pyrazopidine heat infusion in improving the incidence of bladder irritation signs after bladder cancer treatment, with 193 and 189 cases in the trial and control groups, respectively. In the included studies, the overall incidence was 26% and 32% in the trial and control groups, respectively. The three studies had statistical heterogeneity (p = 0.06, I^２= 56). Thus, the statistics were combined using a random effects model. No statistically significant difference was found between pyrazosin bladder thermal perfusion and normal perfusion (OR = 0.61, 95% CI: 0.31-1.44) (Fig. 6).

In clinical practice, postoperative bladder perfusion chemotherapy for bladder cancer patients is widely used to prevent tumour recurrence. According to research, mitomycin C and anthracycline chemotherapeutic agents are commonly used in clinical practice due to their effect and the fact that most patients are tolerant to the adverse effects of perfusion drugs ^[25]. Furthermore, studies have investigated the impact of bladder thermal perfusion on preventing bladder cancer recurrence. Based on the existing literature, this meta-analysis compares pyrazosin hot infusion chemotherapy with plain infusion chemotherapy in preventing tumour recurrence and adverse effects in bladder cancer patients.

Herein, eighteen studies (three in English and 15 in Chinese) comprising 1523 patients were included. The patients were categorised into the pirarubicin thermal perfusion treatment group and the pirarubicin normal perfusion control group, with 760 and 763 patients, respectively. This study compared the effect of chemotherapy for bladder cancer in the pirarubicin hot infusion treatment group and the pirarubicin normal infusion control group. The trial group had a significantly lower two-year recurrence rate for bladder cancer compared to the control group, with an overall risk ratio of 0.29 (95% CI: 0.20–0.44), indicating a 71% lower risk of recurrence for patients two years after bladder cancer treatment (Fig. 2). On the other hand, the overall risk ratio for the one-year recurrence rate was 0.35 (95% CI: 0.27–0.47), indicating a 65% lower risk of recurrence at one year after bladder cancer treatment compared to the control group (Fig. 3). These findings imply that pyrazosin bladder heat infusion was effective in reducing the bladder cancer recurrence rate in patients with less risk bias in the data, making the results more credible. This could be explained by the fact that heat therapy acts directly on cells, impacting proteins and cytokines during cell replication and apoptosis, whereas normal tissue cells are less significantly affected due to heat resistance ^[26]. Therefore, controlling the temperature of chemotherapeutic drugs may enhance their effect by promoting the apoptosis of cancer cells while exerting reversible damage to normal tissue cells.

Although several studies have shown that both pyrazobicin hot and normal perfusions can lead to adverse reactions, including hematuria and bladder irritation, the difference in the incidence of these adverse effects between pyrazobicin hot and normal perfusions following bladder cancer surgery was not statistically significant (Figs. 4 and 6). Bladder irritation is caused by the thermal effect of injury (such as mild burns to the bladder mucosa), aseptic inflammatory reactions ^[27], congestion and mucosal oedema, irritation of the bladder, and urinary urgency symptoms, frequency and pain, which are also normal after heat therapy. On the other hand, the causes of haematuria are related to heat exposure, increased bladder mucosa permeability, exudation, tumour tissue necrosis, and trauma formation.

We found a statistically significant difference in the incidence of urinary pain (Fig. 5). Although the overall reduction in bladder irritation signs was not significant for bladder cancer, it significantly reduced the incidence of painful urination, implying that pyribizine heat infusion may, to some extent, prevent increased bladder wall damage as well as reduce the incidence of painful urination in patients.

In conclusion, our meta-analysis confirms that compared to plain perfusion chemotherapy, pyrazobicin bladder thermoperfusion chemotherapy exerts a better effect in patients with postoperative bladder cancer. Furthermore, postoperative pyrazobicin hot instillation in bladder cancer patients reduced the incidence of painful haematuria to some extent, but there was no significant reduction in the incidence of bladder irritation symptoms and haematuria. Finally, it is noteworthy that the results of this study need to be further validated given the low quality of the literature included.

Author Contribution

C. Li. and X. Li. Were mainly responsible for the writing of the manuscript, L. Niu and Y. Bao were mainly responsible for the preparation and data analysis of the manuscript, and all the authors reviewed the manuscript.

Funding and Competing interests

1.This work was supported by Inner Mongolia Medical University face-to-face projec(Project Title is “Symptom cluster characteristics and predictors of bladder cancer patients during chemotherapy based on patient- reported outcomes”.Project number: YKD2022MS053) and Medical and health science and technology plan project of Inner Mongolia Autonomous Region Health Commission(Project Title is “Construction and empirical study on self-management Behavior Model of patients with penile cancer after surgery based on health belief model”.Project number: 202201232).

The authors have no conflict of interest. All data is publicly available.

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Effect of different infusion modes of pirarubicin on recurrence rate and adverse reactions in patients with postoperative chemotherapy for bladder cancer: A Meta-Analysis

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