Analysis of Epirubicin in Treating Non-muscle Invasive Bladder Tumors: Retrospective Descriptive Analysis, Monocentric Study

Purpose: BCG and MMC are the most popular drugs for adjuvant intravesical instillations in Non-Muscle-Invasive Bladder Cancer (NMIBC). In recent years, there has been a risk of shortage of these two agents worldwide. For this reason, our study aims to determine the characteristics of NMIBC in our department and the results following their treatment with Epirubicin.

Methods: This inquiry is a retrospective descriptive study of 09 patients regrouped from the Urology Department of Cheikh Khalifa Hospital.

Results: The results obtained revealed a predominance of low-grade urothelial carcinomas with an intermediate risk of recurrence and progression. Intravesical instillations of Epirubicin have shown a recurrence rate of 44.44% and a progression rate of 33.33%, with local side effects observed in 5 patients.

Conclusion: Despite the limited number of patients in our study, treatment with Epirubicin has demonstrated therapeutic efficacity, approaching that of BCG and MMC, with an acceptable toxic profile.

Introduction

Bladder cancer is a frequently diagnosed urological cancer, predominantly in men, with smoking as a major risk factor. Cystoscopy is crucial for detecting and describing lesions. Transurethral resection is the main treatment approach for diagnostic and therapeutic purposes. The most common form is urothelial carcinoma, often non-invasive. Treatment varies based on recurrence and progression risk. Given the shortage of standard treatments like BCG or Mitomycin C, Epirubicin is a promising alternative. The study evaluates the effectiveness of Epirubicin in treating non-muscle invasive bladder tumors (TVNIM), based on nine cases at the Urology Department of Cheikh Khalifa International University Hospital.

Materials and Methods

The study is a retrospective descriptive analysis of Epirubicin in treating non-muscle invasive bladder tumors, conducted over five years (2018–2023) at Cheikh Khalifa Ibn Zaid International Hospital’s Urology Department. It involved reviewing over a hundred patient files, with only nine meeting the inclusion criteria: patients over 18 years with confirmed TVNIM who received Epirubicin intra-vesical instillation. Exclusion criteria included unworkable files, unreachable patients, and those lost to follow-up. Data was collected using a specially designed form (see Appendix), from patient registries, medical records, DxCare, LIMS paraclinical data, and direct patient contact for missing information. The staff responsible provided information on the feasibility of epirubicin instillation.

Results

The study included 9 patients, with an average age of 68.3 years (range 61–76). There were more men than women, with a male-to-female ratio of 2:1.

Fig. 1 shows an overview of the medical and surgical history of the patients. Most patients had a history of smoking (88.89%), with longer and heavier use in men. One patient reported alcohol use, and another had exposure to occupational toxins. Additionally, 33.33% had recurrent urinary infections, and one patient was on oral anticoagulants for heart issues. There were no cases of diabetes, and no one reported a family history of urothelial tumors.

Fig. 1. Chart representing the medical and surgical history of the patients.

All patients experienced macroscopic hematuria, and some also had bladder disorders and pain. Clinical exams showed stabilitiy, with no signs of masses or pain. Pelvic ultrasound showed intra-vesical masses in 88.89% of cases, but there was no involvement of the upper urinary tract. No abnormalities were identified in urine analysis.

Cystoscopy confirmed and detailed the bladder tumors in all patients. Most tumors were in a single location, typically on the bladder wall, and were mostly smaller than 3 cm (although varied in size and number). The histopathology after transurethral resection showed low-grade papillary urothelial carcinomas, with most patients staged as pTa and a few as pT1.

Risk assessment showed varied risks for recurrence and progression among patients. All patients received intravesical epirubicin instillations according to a standard protocol, which included pre-treatment cystoscopy and urine culture to ensure no infections. The protocol followed the recommended dosage and patient preparation procedures.

Local side effects were observed in 55.55% of patients, though no systemic issues were reported. These side effects were manageable and did not result in any serious complications.

Cystoscopy during follow-up showed that 44.44% of patients had recurrence, and 33.33% showed tumor progression. However, imaging scans did not reveal any abnormalities in the upper urinary tract during follow-up. These findings are shown in Fig. 2.

Fig. 2. The distribution of tumor recurrences in our patients.

Discussion

Epirubicin, developed in France and Italy in the early 1980s, is a chemotherapy drug part of the anthracycline family. It is derived from Doxorubicin, differing in the epimerization of the 4′-OH group, resulting in a lower pKa of 8.08 [1] and increased lipophilicity [2]. Epirubicin is used to treat various solid tumors and hematological cancers [1].

The precise mechanism of Epirubicin’s action is not fully understood. It operates as an intracellular cytotoxic agent, primarily affecting the S and G2 phases of the cell cycle, with potential alteration of the M and G1 phases at high concentrations. Epirubicin’s main action is the inhibition of DNA replication through intercalation between DNA base pairs, stabilizing the Topoisomerase II-DNA complex, thus inhibiting cleavage. Other mechanisms include direct inhibition of DNA Helicases, indirect inhibition of DNA and RNA polymerases, and the formation of free radicals. 50% DNA inhibition is achieved at 17 μmol/L Epirubicin, and 50% inhibition of basal membrane degradation, crucial in metastatic proliferation, occurs at 37 μmol/L [3].

Intravesical Instillation Protocol

The intravesical instillation protocol for Epirubicin involves a cumulative dose limit of 900 mg/m2 body surface area [4]. Patients undergo a fluid restriction 12 hours before the procedure, and a urine strip test is conducted to ensure sterility. The treatment dosage varies: 50 mg for 8 weeks for papillary bladder carcinoma, up to 80 mg for carcinoma in situ, and 30 mg for Epirubicin-induced cystitis. Epirubicin is diluted to a 50 ml volume. Post-resection prophylaxis includes a 50 mg dose weekly for 4 weeks, followed by monthly instillations for 11 months [4]. The instillation is administered for 1–2 hours, with the patient repositioning to ensure full bladder coverage. Post-instillation, 58%–84% of the dose is eliminated [5].

The scientific literature indicates an acceptable rate of side effects following Epirubicin use. Tabayouong et al. [6] found that in 2,298 patients treated with Epirubicin, hematuria occurred in 2.9% to 29% of cases, urinary disorders in 4.6% to 8%, and chemical cystitis in 0.4 to 7%. Our study aligns with this, showing hematuria in 33.33% of patients and urinary disorders in one case (11.11%). No chemical cystitis was recorded. Shang et al. [7] and Mitsomori et al. [8] observed higher rates of chemical cystitis. Contrasting results from Yang et al. [9] indicate higher hematuria and chemical cystitis rates. This variation suggests other factors influencing complications. Comparatively, Mitomycin C (MMC) used in intravesical chemotherapy shows similar toxicity to Epirubicin, with studies by Bosschieter et al. [10], Zaza et al. [11], and Tabayouong et al. [6] reporting similar rates of hematuria and chemical cystitis. Intravesical BCG instillations, although effective, have higher local complication rates, as indicated by studies from Zaza et al. [11], Shang et al. [7], and Yang et al. [9]. In conclusion, Epirubicin and MMC have similar toxicity profiles, unlike BCG which has a higher rate of local complications.

The study discusses the variability in therapeutic protocols for intravesical Epirubicin instillations and their outcomes, with recurrence rates ranging from 26.2% to 55.64% across different studies [8], [12], [13]. The study’s findings indicate a high recurrence rate. Comparisons with BCG and MMC treatments reveal a lower recurrence rate with BCG [14], [15]. However, progression rates are similar across Epirubicin, BCG, and MMC. This study reports a higher progression rate, possibly due to its limited patient number. Overall, the efficacy of Epirubicin, BCG, and MMC in preventing the progression of non-muscle invasive bladder tumors is considered comparable (see Fig. 3).

Fig. 3. The recurrence and progression rates of different molecules from different studies.

Conclusion

The main goal of this research was to determine the characteristics of non-muscle invasive bladder tumors in their Urology department and their response to Epirubicin instillations. The study concluded that tobacco use and occupational carcinogen exposure are key risk factors, with hematuria being a major clinical sign. Cystoscopy and pathological studies confirmed predominantly stage pTa urothelial cancer. Epirubicin instillations resulted in a 44.44% recurrence rate and tumor progression in 33.33% of patients, with good tolerance and no systemic complications. Despite the efficacy of BCG and MMC, Epirubicin remains an effective alternative. The study’s limitation was its small patient number, partly due to strict inclusion criteria and reduced activity during the COVID-19 pandemic. Further research with more patients and longer follow-up is suggested for more comprehensive results.

Appendix

Operating Sheet

1. Identity

a) Surname: ___

b) Name: ___

c) Gender (M/F): ___

d) Occupation: ___

e) Exposure to aromatic amines (Y/N): ___

f) Origin: ___

2. History

a) Toxic

i) Tabacco (Passive/Active): ___

ii) Cannabis (Y/N): ___

iii) Alcohol (Y/N): ___

b) Medical

i) Infectious (Recurrent urinary infections/Uro-genital diarrhea/Uro-genital TBK): ___

ii) Urological: ___