Epirubicin and Non-Muscle Invasive Bladder Cancer Treatment: A Systematic Review

1. Introduction

Bladder cancer (BC) is the second most frequent urological malignancy affecting 573.000 patients yearly worldwide [1] More than 75% of patients diagnosed with bladder cancer have a cancer confined to the mucosa or the lamina propria [2].

The standard treatment for NMIBC is Transurethral Resection of the Bladder Tumors (TURBT) followed by additional adjuvant treatment, which comprises single-shot intravesical chemotherapy dose induction +/- maintenance chemotherapy for up to three years [3,4,5]. For low-risk tumors, single instillations of drugs, such as single postoperative Mitomycin C (MMC), Epirubicin (EPI), or Gemcitabine (GEM) have been found to be effective in reducing disease recurrences [6,7].

For intermediate, high-risk and very high-risk bladder tumors, the most effective adjuvant therapy is with Bacillus Calmette-Guérin (BCG) [8]. BCG therapy is typically given as a series of 6 weekly instillations followed by a maintenance regimen up to 3 years.

In case of BCG ineligible of unresponsive patients, or in case of BCG shortage there are available some chemotherapeutical agents such as EPI, MMC or GEM for intravesical instillations [9], at least 6 times weekly, but a fix regimen it has been not establish yet. A full year regimen is nowadays considered as a minimum for best efficacy of the drugs (6 weekly instillations followed by instillation at 6 weeks intervals for a year) [10]. However, a shared decision-making regarding adjuvant therapy with the patient relies also on various factors, including age [11], stage, grade, and risk stratification of bladder cancer, as well as individual patient characteristics such as sarcopenia [12].

As a treatment for bladder cancer EPI still has a wide spectrum of use in many countries and geographical areas due to its therapeutic efficacy for NMBIC and lack of alternative approved treatments, on the other hand in other countries such as the US is not approved for intravesical treatment [13]. According to European Association of Urology (EAU) guidelines, EPI is an option in patient unfit for BCG or in case of BCG shortage [2]. In the US alone it is estimated that more than 8000 patients are not receiving BCG due to global shortage [14]. So, as an alternative adjuvant therapy after TURBT for bladder tumors, EPI has shown in time effectiveness in reducing recurrences. EPI works by interfering with the DNA of cancer cells, preventing their replication and growth [15].

Considering these facts, we aimed to look at all the relevant literature regarding the efficacy and toxicity of EPI. In this regard we searched for relevant literature regarding recurrence free survival (RFS) and progression free survival (PFS) rates after EPI treatment compared with those after BCG, MMC and GEM. A second focus was to analyze the impact of adding hyperthermia when using EPI in comparison to hyperthermia with MMC.

2. Materials and Methods

A systematic search of MEDLINE, Webofscience, clinicaltrials.gov and Googlescholar databases was performed on December 31, 2023, using any combination of the terms: Epirubicin (EXP) AND Bladder Cancer (EXP) OR Epirubicin (EXP) AND non-muscle invasive bladder cancer (EXP). All original articles that fulfilled the inclusion criteria were included. We performed additional cross checking of reference lists, and “hand searched” for any additional references.

Studies were considered eligible if they included patients with NMIBC, had a prospective or retrospective design, included at least 10 patients, and assessed the oncological impact of EPI treatment compared with those after BCG, MMC and GEM or EPI standard treatment alone or using chemohyperthermia. Language of publication was not an exclusion criterion. Primary outcomes were comparison of recurrence and progression rates between EPI and MMC or GEM or BCG. The secondary outcome was to evaluate the safety profile of EPI and the impact of using device assisted intravesical administration of EPI. For each selected study, the following items were recorded: first author’s name, year of publication, country, study design, number of patients, patients’ characteristics, variables included in multivariable analysis, recurrence rate, progression rate, follow-up, and adverse events (AEs), when reported. Two investigators (SC and MF) independently conducted literature search and extracted data from included full-text articles; disagreements were resolved by consensus with a third investigator (MDV).

3. Results

3.1. Adverse Events after Intravesical instillations with Epirubicin

A number of 11 studies reported adverse events after adjuvant intravesical instillations with EPI, using a regimen of at least 6 weekly instillations. They included 1165 patients in total, of which 207 were females. The instillation regimen was not uniform as it is no clear recommendation and varied from 6 installations until 17 instillations [16,17,18]. The most frequently reported adverse events were cystitis (34%) , followed by dysuria, pollakiuria, hematuria, bladder irritation/spasms, fever, nausea and vomiting, and generalized skin rash (2.3%) [19], see Table 1.

3.2. Epirubicin versus BCG

Nine studies compared EPI to BCG in terms of recurrence and progressions rates. They included 1422 patients, of which 316 were females. Prognostic factors included age, gender, number, tumor stage pTa-pT1 and grade G1-G3 (12-19). The recurrence rate was lower for patients treated with BCG instillations [20,21,22,23,24] and regarding progression the difference was limited or no difference was noticed [20,21], see Table 2.

3.3. Epirubicin versus Mitomycin C

Two studies [25,26] had investigated the effect of EPI compared to that of MMC and they showed that there is no significant differences between the two drugs (EPI vs. MMC) regarding progression and recurrence, see Table 3.

3.4. Epirubicin versus Gemcitabine

Two studies [27,28] had investigated the effect of EPI compared to that of GEM. They included 459 patients, of which 135 were female. Zhang et.al [28] has shown a statistical significance of low recurrence and progression in patients with high risk NMBIC, treated with GEM with a (HR of 0.165, 95% CI 0.069–0.397, p= 0.000) for recurrence and (HR = 0.160, 95% CI 0.032–0.799, p= 0.026) for progression. On the other hand, Wang et.al [27] found no statistical significance regarding recurrence and progression, see Table 4.

3.5. Chemohyperthermia with Epirubicin

Chiancone et al. [29] looked at the oncological results of EPI as adjuvant treatment using hyperthermic intravesical chemotherapy (HIVEC) administration. They included 26 patients, of which 18 males and 8 females. Recurrence occurred in two patients (7.69%) from the high-grade group and in one (3.85%) from low grade group, and two patients (7.69%) had progression. They concluded that EPI with HIVEC is a valid option of treatment for high grade NMBIC with BCG intolerance, and there was no difference in oncological outcomes compared to MMC. Similar results were reported also by Arends et al. [30] when using the Synergo device to administrated EPI or MMC into the bladder, see Table 5.

4. Discussion

We found out by analyzing the current available data that the most common adverse event after adjuvant intravesical instillation with EPI are cystitis, dysuria, pollakiuria and hematuria [31]. Similar after MMC were reported as follows: cystitis (34%), skin rash, pruritis and local irritation [25]. After Gemcitabine were reported the most nausea/vomiting (44.2%) and constipation/diarrhea (23.4%) [32]. It seems that the overall toxicity of EPI is in the same range as other therapeutic options for intravesical chemotherapy.

However, it is well known that the treatment with BCG is more efficient in terms of preventing progression as we showed in the summary table of the included studies (Table 2). Data that was already confirmed by the meta-analysis of You et al.[33].

In terms of adjuvant chemotherapy, it was not observed a clinically significant difference between EPI, MMC or GEM. The RFS and the PFS rates are slightly similar. However, a recent meta-analysis showed that among 22 studies that adopted induction followed by maintenance intravesical therapy, with reference to the lower-dose BCG, EPI was associated with a significantly higher risk of recurrence (Odds ratio [OR]: 2.82, 95% CI: 1.54-5.15), but not other intravesical chemotherapies, with no significant differences in risk of progression among the intravesical therapies [34]. Further prospective studies are needed to answer this key question, which drug has the best tolerability, safety, and impact on oncological outcomes. Some trials are already recruiting patients to test in vitro the drug with the most antitumor efficacy [35]. Until then, clinicians should use all the therapies available based on shared decision making with the patient and based on guidelines recommendations.

In the case of using chemohyperthermia it seems that might be a certain benefit, however not quantifiable yet. In case of MMC, a recent Randomized Clinical Trial (RCT) showed that RFS at 24 months was 61% (95% CI 51-69%) in the chemohyperthermia arm and 60% (95% CI 50-68%) in the control arm (HR 0.92, 95% CI 0.62-1.37; log-rank p = 0.8) [36]. These results should be interpreted taking into account that it was used for chemohyperthermia instillations only the Combat bladder recirculating system (Combat Medical, St. Albans, UK) and there are many other systems available for hyperthermia intravesical instillations [37], and their use may lead to other results. Further, from the all available data it was observed no difference in case of RFS estimates between patients treated with EPI and patients treated with MMC [38]. Regarding comparison with standard of care, this is BCG treatment. A recent meta-analysis showed no statistical significant difference between chemohyperthermia and BCG, as adjuvant treatment [39]. However, there is a paucity of data regarding this question and a solid conclusion cannot be drawn.

Limitation of this current review lays on the retrospective nature of the included studies, lack of sufficient data published to confirm a difference between drugs used for adjuvant intravesical instillation, heterogeneity of reported data, number of patients included and no prospective head-to-head comparison.

5. Conclusions

Epirubicin has meaningful efficacy in addressing NMIBC; however, its efficacy and indications are limited to selected patients, mainly with an intermediate risk according to EAU guidelines stratification and to those unfit or unresponsive to BCG therapy. Retrospective studies highlight that BCG stands out as more effective than Epirubicin in terms of preventing recurrence. Epirubicin exhibits similar oncological performances to Gemcitabine and Mitomycin C currently used for adjuvant therapy in NMIBC. Novel delivery mechanisms such as hyperthermia are promising newcomers.