Thermal Intravesical Chemotherapy Reduce Recurrence Rate for Non-muscle Invasive Bladder Cancer Patients: A Meta-Analysis

Background: Non-muscle invasive bladder cancer accounts for nearly 80% of newly diagnosed bladder cancer cases, which often recur and progress. This meta-analysis was evaluated by the adverse events and recurrence rate of thermal intravesical chemotherapy vs. normal temperature intravesical chemotherapy in the treatment of non-muscle invasive bladder cancer. Methods: A systematic review and cumulative analysis of studies reporting adverse events and recurrence rate of thermal intravesical chemotherapy vs. normal temperature intravesical chemotherapy was performed through a comprehensive search of Pubmed, Embase, Cochranelibrary.com, CNKI, Wanfang Med Online database and VIP database. All analyses were performed using the Revman manager 5. Result: Twelve studies (11 randomized controlled trials and 1 retrospective study) including 888 patients, 445 in the thermal intravesical chemotherapy group, and 443 in the normal temperature intravesical chemotherapy group, met the eligibility criteria. Patients in the thermal intravesical chemotherapy group had a lower risk of disease recurrence than those who had normal temperature intravesical chemotherapy (24 months follow-up group: RR = 0.30, 95% CI: 0.21–0.43, P < 0.00001, I2 = 0%; 36 months follow-up group: RR = 0.27, 95% CI: 0.14–0.54, P = 0.0002, I2 = 0%) while no significant difference in adverse events rate (RR = 0.89, 95% CI = 0.53–1.52; P = 0.67, I2 = 78%). Conclusions: When compared with normal temperature intravesical chemotherapy, thermal intravesical chemotherapy can reduce the recurrence rate without increasing incidence of adverse events in patients with non-muscle invasive bladder cancer.


INTRODUCTION
Bladder cancer is one of the most common tumors in the urology system. In terms of its morbidity, it ranks the fourth among men and eleventh among women in all kinds of tumor, respectively (1). Last year, bladder cancer contributed more than 500,000 new cases and 190,000 deaths in 185 countries (2). Non-muscle invasive bladder cancer (NMIBC) makes up nearly 80% of newly diagnosed bladder carcinoma cases, of which Tis accounts for 10%, T1 for 30%, and Ta for 60% (3). Although the prognosis of patients with NMIBC have made great progress over the past decades, the recurrence and progression rate is still high. More than 60% of NMIBC patients will recur and more than 20% will progress into higher stages (4). Therefore, the economic burden created by intensive treatment and surveillance of NMIBC is very heavy for both individuals and governments.
Transurethral resection of bladder tumor (TURBT) is the most important diagnostic method and also the main treatment of NMIBC, but it could not prevent the recurrence and progression (5). Thus, adjuvant intravesical therapy came into being. It consists of bladder infusion chemotherapy and immunotherapy (6). One of the most effective intravesical therapy is bacillus Calmette-Guerin (BCG), which requires special care for its bio toxicity (7). And many other drugs, including mitomycin C (MMC), pirarubicin (THP), gemcitabine (GEM), hydroxycamptothecine (HCPT), etc. have been applied to intravesical chemotherapy (8). Despite all these efforts, the recurrence rate remains at 30% (9). In a word, preventing recurrence of NMIBC after TURBT still remains a challenge (10).
In recent years, thermal therapy has received increasing attention as a treatment for malignant tumors (11). High temperatures may enhance drug function by encouraging tumor cells to absorb more chemotherapeutic agents, redistributing their intracellular concentrations, altering metabolic patterns FIGURE 1 | Flow diagram of study selection in the meta-analysis. and/or inhibiting repair of DNA damage (12). Since NMIBC is prone to recurrence, thermal intravesical chemotherapy has been developed to improve the effectiveness of the treatment (13). It seems that thermal intravesical chemotherapy is good for patients with NMIBC (14). This meta-analysis is aimed to discuss whether thermal intravesical chemotherapy is associated with better efficacy with less or at least the same adverse events than normal temperature intravesical chemotherapy.

Eligibility Criteria
Studies were suitable for inclusion if they meet the following criteria: (1) participants: NMIBC patients receiving TURBT; (2) intervention: thermal intravesical chemotherapy; (3) control: normal temperature intravesical chemotherapy; (4) containing both of the following outcomes: recurrence rate and adverse event; (5) study design: randomized controlled trials (RCTs) or retrospective studies. The adverse event is as follow: cystitis, bladder irritation, hematuria, urinary pain, lower urinary tract symptoms, urinary tract infection, anorexia, anxiety, insomnia, rash, lower abdomen skin redness, fatigue, myelosuppression, influenza-like symptoms, and abnormal blood biochemical indexes. Exclusion criteria are as follows: (1) thermal intravesical chemotherapy was discontinued during the treatment schedule; (2) data cannot be obtained even after contacting the author; (3) duplicated publications. When multiple studies were delivered by the same researcher based on similar patients, only the most comprehensive or largest one was included.

Study Search and Selection
Eligible studies focusing on the topic were identified through searching Pubmed, Embase, Cochranelibrary.com, CNKI, Wanfang Med Online database and VIP database. The search    strategy is given in Appendix I. We also browsed reference lists of systematic reviews on this topic to find any other qualified articles. All searches without language limits but limited to studies on humans. Two independent reviewers (LK and ZJ) examined the titles and abstracts according to eligibility criteria mentioned before. Studies underwent full-text examination after removing duplicated, irrelevant, review, case report, letter, editorial and non-comparative design studies. Divergences were resolved by discussion with another reviewer (S-YX).

Quality Assessment and Data Extraction
The quality of all included RCTs was assessed using the "risk of bias" tool recommended by the Cochrane Collaboration. It consists of the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. The Newcastle-ottawa quality scale was used to assess the quality of retrospective studies. Two reviewers (LK and ZJ) independently evaluated the quality of studies in these domains.
Data extraction was also executed by two reviewers (LK and ZJ) independently. The following information was extracted: first author's name, year of publication, study period, study design, sample size, clinical protocols, and number of patients who completed the study, age of participants, median follow-up, treatment schedule, and relevant data on outcomes. Disagreements were discussed and consensus was finally achieved.

Statistical Analysis
Relative risks (RR) with 95%CIs for the adverse events rate were calculated to evaluate the safety of thermal intravesical chemotherapy, as well as for the recurrence rate of different follow-up groups to assess the effectiveness. Chi-squared tests were used to detect heterogeneity between studies included in this meta-analysis. Considering that the statistical power of the heterogeneity test is generally low, a P-value of 0.10 was set as the significance threshold for the heterogeneity. The heterogeneity was considered significant if P ≤ 0.1. We used I-squared (I 2 ) statistic to indicate the proportion of variation between the studies due to heterogeneity. The larger the I 2 value represented, the higher the heterogeneity was. And I 2 > 50% suggested substantial heterogeneity among the studies. Fixed effect model was adopted when no significant heterogeneity was detected (P > 0.1 and I 2 < 50%), otherwise, random effect model would be used. We did subgroup analyses between two treatment regimens according to the clinical protocols of study (hyperthermic intravesical chemotherapy vs. external

Study Selection
Five hundred and twenty-eight studies were identified from the aforementioned databases. One hundred and nine duplicated studies were first removed. Four hundred and nineteen studies were under screening titles and abstracts, among which 14 potentially relevant studies were obtained, and full texts were carefully checked for eligibility examination. Finally, 12 studies with a total of 888 participants were included in the metaanalysis. The process of study selection is shown in Figure 1.

Study Characteristics
The characteristics of the included studies are summarized in Table 1. These studies were published between 2003 and 2019, 11 studies with an RCT design and one, a retrospective study. A total of 888 participants were enrolled, with a median size of 74 (ranging from 40 to 150). All of the studies had enrolled patients with NMIBC. The median duration of follow-up across the studies was 24 months. Treatment schedules varied between these studies.

Quality Assessment
The "risk of bias" tool recommended by the Cochrane Collaboration was adopted to assess the quality of included RCTs (Figure 2). Five studies (16,18,19,22,24) described how random sequence was generated, and all RCTs except Colombo et al. didn't describe the allocation concealment and Blind method.
No incomplete or selective outcome data was reported. Quality assessments of cohort studies were conducted according to the Newcastle-Ottawa Scale (NOS), which was developed to assess bias risk including three domains with eight items ( Table 2).

DISCUSSION
The idea that thermal therapy can treat the tumor can be traced back to 1910 from Coley (27). And Rigatti et al. first applied thermal therapy to treat superficial bladder tumors in 1991 (28). Then Colombo et al. used a microwave device to make local bladder heating for intravesical chemotherapy, with a good overall response rate of 90.8% in 44 superficial bladder cancer patients (29). As the encouraging results were achieved, more and more urologists join to investigate thermal intravesical chemotherapy. Van der Heijden et al. reported 90 patients received combined treatment of MMC and local microwave hyperthermia. Finally, the risk of recurrence was 24.6% after a 2 year follow-up and no one suffered from stage FIGURE 5 | Comparison on recurrence rate between thermal intravesical chemotherapy and normal temperature intravesical chemotherapy after subgroup analysis stratified by different approach used in thermal therapy.  patients. The meta-analysis aimed to figure out whether thermal intravesical chemotherapy is more effective and safer than normal temperature intravesical chemotherapy.
In the present study, the results of 12 eligible studies, include 11 RCTs and 1 retrospective study, were analyzed. Although the adverse events rate was not reduced, it highlighted that thermal intravesical chemotherapy was more advantageous than normal temperature intravesical chemotherapy in reducing risk of tumor recurrence among patients with NMIBC. Subgroup analyses of different chemotherapy approaches and drugs also indicated a significant reduction in recurrence rate without increasing adverse event rate.
The meta-analysis shows that the thermal intravesical chemotherapy can be tolerated relatively by patients. Most treatment adverse events were localized and transient as reporting. Of all the intake studies, only Zhao et al. (15,25) and Colombo et al. (16) reported 12 and 8 patients' discontinuation, respectively. Reasons for withdrawal were various but mostly drug allergy, while Geijsen et al. (10) reported the oldest patients withdrew from complaints of improper hyperthermia treatment positioning. Our meta-analysis shows a lower withdrawal rate of 1.4%, which is close to 3.8% of Lammers's research (14).
There are two approaches to execute thermal intravesical chemotherapy. The first kind is called hyperthermic intravesical chemotherapy. In this way, chemotherapeutic agents dissolve in the solution and put it into a hyperthermic perfusion treatment machine connect with pipeline systems for infusion. The advantage of this method is obvious that we can control the temperature constantly. But still we cannot detect the temperature in the bladder wall since it became thinner during perfusion (27). Moreover, in consideration of single-use pipes, it may be too expensive to afford, especially for NMIBC patients who should generally receive more than six rounds intravesical chemotherapy. The second choice, as we called external thermal field thermotherapy, creates the local bladder heating by microwave. This method is more convenient and cheaper without pipeline systems (15). The weakness of ETFT is the intravesical temperature which could not be supervised with high-precision.
As for chemotherapeutic agents, there are four kinds of drugs used in thermal intravesical chemotherapy in our metaanalysis, including mitomycin C, pirarubicin, gemcitabine, hydroxycamptothecine. Only Zhao et al. compared the efficacy between thermal intravesical chemotherapy and normal temperature BCG perfusion (15), and the result turned out to be no difference in recurrence rate after the 2 years follow-up. BCG has been proved to be the most effective treatment for intermediate-and high-risk NMIBC since its first report in 1976 and became the standard management. Despite its efficacy, BCG perfusion therapy could cause a variety of adverse events, leading to the termination of the treatment in the end (7). More badly, BCG is scarce and expensive in China (15). So we have an urgent need to develop alternative therapy. MMC and THP are the main drugs applied in studies. MMC is an anti-metabolite drug identified from the products of a species of Streptomyces caespitosus (32). It destroys the structure and function of DNA, inhibits the replication of DNA, and kills tumor cells both in the proliferating and resting phase. The advantage of MMC is that normal mucosa of bladder is resistant to it. So patients who received MMC intravesical chemotherapy have fewer adverse events (33). THP can be absorbed into tumor cells quickly as it is one of the most effective agents for reducing recurrence of NMIBC (34). Although it shows no difference in the present meta-analysis, the study of the efficacy of the different thermal intravesical chemotherapeutics should be explored further.
As we all know, before thermal intravesical chemotherapy arises, intraperitoneal perfusion chemotherapy has already been widely used in the treatment of advanced ovarian and gastric cancer or peritoneal metastases. Zhu et al. reported patients after D2 dissection received intraperitoneal chemotherapy with whole abdominal hyperthermia, which reduced the recurrence and metastasis of peritoneal (35). Hotouras et al. systematically reviewed the literature of heated intraperitoneal chemotherapy (HIPEC) for recurrent ovarian cancer patients, and found that HIPEC is associated with benefits (36). Foreseeable, larger prospective studies will be carried out in all these fields.
In China, according to epidemiological investigation report published in 2018, bladder cancer has the highest morbidity among all kinds of urogenital neoplasms. The morbidity of male and female are 8.65 and 2.62 per 100,000 (37). The situation demands immediate action, especially treatment for NMIBC. In this meta-analysis, we found that thermal intravesical chemotherapy can reduce the recurrence rate of NMIBC. It indicates that thermal intravesical chemotherapy might be the next hot topic in academia.

LIMITATIONS
There are some limitations remaining, in spite of the eligibility criteria, that we had set to select published literature. First of all, treatment schedules and chemotherapeutic agents used in thermal intravesical chemotherapy are heterogeneous indeed. Second, risk levels among patients varied, which make it impossible to evaluate the difference in efficacy between thermal intravesical chemotherapy and normal temperature intravesical chemotherapy for patients at specific risk levels. These may bias the conclusions of this study. Beyond these limitations, this meta-analysis was strictly performed with setting reasonable eligibility criteria and reviewing all available publications' data, thus comparing efficacy between thermal intravesical chemotherapy and normal temperature intravesical chemotherapy.

CONCLUSIONS
In summary, compared with intravesical chemotherapy, thermal intravesical chemotherapy was associated with a lower recurrence rate without increasing adverse event rate among patients with NMIBC. Different approaches and drugs show the same effects of the efficacy. More high quality RCTs are still required to confirm those conclusions.