Is switching intravesical chemotherapeutic agent beneficial in short-term recurrent high-risk non-muscle- invasive bladder tumors? A 5-year retrospective study

doi:10.21203/rs.3.rs-3119549/v1

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Is switching intravesical chemotherapeutic agent beneficial in short-term recurrent high-risk non-muscle- invasive bladder tumors? A 5-year retrospective study

https://doi.org/10.21203/rs.3.rs-3119549/v1

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published 31 Jan, 2024

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Objective: To assess whether switching intravesical chemotherapeutic agent is beneficial in short-term recurrent high-risk non-muscle-invasive bladder cancer (NMIBC) after failure of previous intravesical therapy.

Materials and methods: From June 2010 to October 2015, 215 patients with NMIBC, who had tumor recurrence within one year of first-line drugs for Intravesical chemotherapy (IVC), were assigned to two groups. After a second time complete TUR treatment, we immediately changed the intravesical instillation agent for 107 patients (group A), whereas the other 98 patients continued to use their original intravesical instillation agent (group B - control group). All patients received an immediate instillation of epirubicin (EPI), gemcitabine (Gem) or hydroxycamptothecin (HCPT) after TURBT and followed by regularly induction plus maintenance instillations. Recurrence rate and progression rate were assessed by Chi-square test, while recurrence-free survival and progression-free survival were calculated using the Kaplan–Meier method.

Results: In this study, the recurrence rate was 49.5% (53/107) in group A and 50.0% (49/98) in group B, while progression rate was 18.7% (21/107) in group A and 23.5% (23/98) in group B. Neither recurrence nor progression rates showed any significant differences between the two groups. Median progression interval between two groups were 24 months and 17 months, respectively (p=0.044). Average progression time between two groups were 28.7months and 19.3 months, respectively (p=0.035). In the Kaplan–Meier plot, no difference was found with respect to recurrence-free survival and progression-free survival. Moreover, univariate analysis suggested that only tumor grade could be an independent risk factor related to recurrence (HR = 0.632; 95% CI 0.425-0.942; p = 0.024), while the presence of carcinoma in situ may be an independent risk factor related to progression (HR=0.159; 95% CI 0.037-0.683; p=0.013).

Conclusions: Switching IVC agent can significantly prolong time of progression in patients with short-term recurrent high-risk NMIBC who are unavailability or unsuitability for BCG instillation. Furthermore, the finding may provide a new basis for drug selection in combination IVC.

Instillation therapy

Intravesical chemotherapy༛Drug switching༛Non-muscle-invasive bladder cancer༛Time to progression

Bladder cancer is among the top ten most common cancer types in the world, with approximately 550,000 new cases annually[1]. An estimated 85,594 new cases of bladder cancer occurred in China in 2020 with over 75%being non-muscle-invasive bladder cancer (NMIBC) the majority are histologically low grade[2, 3]. Transurethral resection (TUR) surgery and adjuvant treatment with Intravesical chemotherapy (IVC) or immune therapy remain the main treatment modality for NMIBC [4–7]. However, successful management still remains a challenge, as approximately 33% of patients have recurrence within 12 months after post-resection IVC [8].

Multiple studies have shown that primary or acquired drug resistance for bladder cancer cells often leads to chemotherapy failure and tumor recurrence [9, 10]. Use of drugs that have different mechanisms of action may overcome tumor chemotherapy resistance and are unlikely to have cross-resistance, either alone or in combination [11–13]. Until the Chinese Food and Drug Administration (FDA) approved BCG for the treatment of bladder cancer, our practice had been the use of switching intravesical chemotherapeutic agents for short-term recurrent non-muscle-invasive bladder tumors. We theorize that switching intravesical chemotherapeutic agents following the failure of short-term intravesical chemotherapy will provide a significant fraction of patient relief of recurrence and progression. In this study, the aim of our research is to determine the efficacy of switching IVC drugs in patients with short-term recurrent high-risk NMIBC.

2.1 Patients

This study retrospectively reviewed a consecutive series of patients who had been previously diagnosed with NMIBC, suffered a relapse within one year after initial TUR and IVC between June 2010 to October 2015. After tumor recurrence and re-treatment with TURBT, we immediately changed the intravesical instillation agent for group A patients, whereas group B patients continued to use their initial drug. All patients received an immediate instillation of EPI, Gem or HCPT after transurethral resection of the bladder tumor (TURBT) and followed by regularly induction plus maintenance instillations. Inclusion criteria: ① Patients who underwent complete TURBT in our hospital, and postoperative pathology confirmed high-risk NMIBC; ② All patients had the first recurrence within 1 year after TURBT and IVC;③Received regular bladder cancer drug treatment as required after the operation, and the perfusion drug is either HCPT, Gem or EPI; ④Unavailability or unsuitability for BCG instillation, refused or were not candidates for cystectomy; Exclusion criteria: ① Tumor residual after TURBT; ②Cases with a previous or simultaneous diagnosis of upper-tract urothelial carcinoma (UTUC); ③Patients were treated with other antitumor treatments except HCPT, GEM or EPI; ④ Presence of malignant tumors or serious diseases; ⑤Case data are incomplete during follow-up.

2.2 Intravesical chemotherapeutic treatment protocol

All patients received an immediate instillation within 24 h after initial complete TURBT. Induction IVC was performed subsequently once a week until 8 weeks. And next, maintenance therapy consisted of 10 monthly treatments until the tumor recurred. After the patient received TURBT again, patients in group A had their intravesical chemotherapy drugs changed, but patients in group B did not. Patients in both groups continued to be treated according to the above perfusion protocol. HCPT (40mg/40ml NS), Gem (1000mg/50ml NS), and Epirubicin (50mg/40ml NS) was left inside the bladder for 120, 60, and 60 minutes each time, respectively. The patient was instructed to empty the bladder and no heavy drinking, fluids or diuretics for 2 hours before instillation. The patient was advised to roll and switch positions during the installation to maximize the affected bladder wall contact.

2.3 Follow‑up and outcomes

Pathological analysis was performed after the initial complete TURBT to confirm stage and grade, and cystoscopy was performed every 3 months. Bladder biopsy was performed to confirm the diagnosis when suspicious tumor was found during the cystoscopy. After the TURBT again, the second pathological analysis was performed again to confirm the stage and grade. Cystoscopy was then performed every 3 months for a period of 2 years, then every 6 months for the next 3 years. The patient’s hospital visit records (including outpatient and inpatient care) and follow-up were used to understand and record the postoperative tumor recurrence. Recurrence was defined as any intravesical tumor recurrence or metastasis. Compared to the second pathological analysis, the recurrence of a tumor at a higher stage or grade and/or worsening of disease was defined as tumor progression, as described in refs [14]. The diagnosis of high-risk bladder tumors is based on either one of the two pathology reports. High-risk tumors were defined as including any of the following: ①T1 tumor, ②high-grade tumor, ③CIS, and ④multiple, recurrent, and large (> 3 cm) TaG1G2/LG tumors (all features must be present)[5, 15].

2.4 Statistical analysis

All data in this study were analyzed using statistical analysis software SPSS23.0 where all tests were two sided, and p value below 0.05 was considered statistically significant. The recurrence rate, progression rate, overall survival, time to second recurrence and progression were assessed. Second recurrence and progression curves were calculated using Kaplan–Meier method. The patients’ characteristics between group A and group B were compared through independent sample Student t test for continuous parameters and Chi-square test for categorical parameters.

3.1 Patients

A total of 334 patients were reviewed in the beginning and according to our criteria, 119 patients were excluded. The rest 215 patients included 107 patients in Group A and 98 patients in Group B. The number of patients and details of instillation drugs used are shown in Fig. 1. Detailed patient characteristics are listed in Tables 1 and 2, all statistical significances were not found in other parameters.

Table 1

Patient and Primary tumor characteristics
	Group A n = 107	Group B n = 98	P value
Age medium (range years)	66(32–89)	65(25–86)	0.601
Sex (n %)			0.869
Male	84(78.5)	76(77.6)
Female	23(21.5)	22(22.4)
T category (n %)			0.393
Ta	26(24.3)	29(29.6)
T1	81(75.7)	69(70.4)
Grade (n %)			0.402
Low grade	44(41.1)	46(46.9)
High grade	63(58.9)	52(53.1)
CIS (n %)			0.095
No	104(97.2)	98(100)
YES	3(2.8)	0(0)
Tumor size (n%) ^a			0.358
< 3 cm	77(72.0)	76(77.6)
≥ 3 cm	30(28.0)	22(22.4)
Multifocal (n %)			0.585
No	28(26.2)	29(29.6)
YES	79(73.8)	69(70.4)
^a Maximum size of largest tumor resected

Table 2

Clinical features of recurrent tumors
	Group A	Group B	P value
T category (n %)			0.052
Ta	36(33.6)	46(46.9)
T1	71(66.4)	52(53.1)
Grade (n %) (WHO 2004)			0.258
Low grade	44(41.1)	48(49.0)
High grade	63(58.9)	50(51.0)
CIS (n %)			0.348
No	105(98.1)	94(95.9)
YES	2(1.9)	4(4.1)
Tumor size (n%) ^a			0.552
< 3 cm	102(95.3)	95(96.9)
≥ 3 cm	5(4.7)	3(3.1)
Multifocal (n %)			0.072
No	41(38.3)	26(26.5)
YES	66(61.7)	72(73.5)
^a Maximum size of largest tumor resected

3.2 Efficacy

Recurrence rate between Group A and Group B were 49.5% (53/107) and 50.0% (49/98), respectively (p = 0.947). Progression rate between two groups were 18.7% (21/107) and 23.5% (23/98), respectively (p = 0.620). Overall survival was 96.3% (103/107) and 96.9% (95/98), respectively (p = 0.585). Recurrence interval in Group A and Group B ranged from 4–56 and 3–44 months, with a median recurrence interval of 14 and 13 months, respectively (p = 0.331), and a mean recurrence interval of 18.6 and 15.5 months (p = 0.186). All the above comparisons were not statistically significant. Progression interval in Group A and Group B ranged from 10 to 60 and 4–44 months, with a median progression interval of 24 and 17 months (p = 0.044) and a mean progression interval of 28.7 and 19.3 months (p = 0.035), and the difference was statistically significant. In Group A, four patients died of bladder cancer. In Group B, three patients died of bladder cancer. The above results are summarized in Table 3.

Table 3

Clinical outcome of patients in both groups
	Group A	Group B	P value
Tumor recurrence rate	49.5% (53/107)	50.0% (49/98)	0.947
Median recurrence interval	14.0(months)	13.0(months)	0.331
Average recurrence time	18.6(months)	15.5(months)	0.186
Tumor progression rate	18.7% (21/107)	23.5% (23/98)	0.620
Median progression interval	24.0(months)	17.0(months)	0.044
Average progression time	28.7(months)	19.3(months)	0.035
Overall survival	96.3% (103/107)	96.9% (95/98)	0.790

Kaplan–Meier curves for recurrence-free survival and progression-free survival are shown in Figures. 2 and 3, of which both of the outcomes were not statistically associated with treatment strategies (p = 0.588 and p = 0.788, respectively).

Univariate analysis was performed in the tumor-related factors and the P value was set at 0.05. Tumor grade was found to be the independent risk factor related to recurrence (HR 0.632; 95% CI 0.425–0.942; p = 0.024). CIS was found to be the independent risk factor related to progression (HR 0.159; 95% CI 0.037–0.683; p = 0.013). The results are shown in Tables 4 and 5.

Table 4

Univariate analysis according to recurrence
Factor	HR (95% CI)	P value
Sex
Female vs male	1.388(0.894–2.155)	0.144
Age (years)
< 65 vs ≥ 65	0.835(0.564–1.235)	0.367
Multifocal
No vs yes	1.141(0.763-1,707)	0.521
Tumor size (cm)
< 3 vs ≥ 3	0.845(0.311–2.299)	0.845
T category
Ta vs T1	0.865(0.580–1.291)	0.478
Grade
Low vs high	0.632(0.425–0.942)	0.024^*
CIS
No vs yes	0.393(0.123–1.252)	0.393
Treatment
Switchers vs Non-switchers	1.112(0.755–1.638)	0.592
CI confdence interval, HR hazard ratio; *Signifcant diference

Table 5

Univariate analysis according to progression
Factor	HR (95% CI)	P value
Sex
Female vs male	0.974(0.481–1.972)	0.942
Age (years)
< 65 vs ≥ 65	1.249(0.682–2.291)	0.471
Multifocal
No vs yes	0.925(0.490–1.744)	0.809
Tumor size (cm)
< 3 vs ≥ 3	21.366(0.024 to > 10^3)	0.377
T category
Ta vs T1	1.180(0.650–2.144)	0.586
Grade
Low vs high	0.853(0.470–1.549)	0.602
CIS
No vs yes	0.159(0.037–0.683)	0.013^*
Treatment
Switchers vs Non-switchers	0.922(0.510–1.667)	0.789
CI confdence interval, HR hazard ratio; *Signifcant diference

Since the US FDA approval of bacillus Calmette-Guérin (BCG), Various guidelines recommend the use of BCG vaccine as the standard adjunctive therapy for intermediate- and high-risk NMIBC and an option for intermediate-risk NMIBC especially after MMC failure [5, 6, 16]. BCG therapy is more effective in reducing the risk of tumor progression and recurrence, by approximately 27% and 32%, respectively[17, 18]. However, there are several problems with intravesical BCG immunotherapy in China. First, the recent global shortage of BCG has precluded the use of BCG in in most hospitals in China[19, 20]. Second, BCG efficacy remains suboptimal (up to 40%failure rate at 2 years) [21, 22]. Third, BCG vaccine therapy causes more toxicity and post-treatment side effects than IVC[16]. Furthermore, it is not covered by basic medical insurance in China and are often too expensive for patients to afford (over $10 000 at 1 year)[20]. The China FDA approved BCG in 2015, and until then IVC had been the first-line treatment option to prevent recurrence of non-muscle-invasive bladder cancer after surgery [15]. Therefore, the BCG vaccine was not included in the scope of this study.

A proportion of patients will suffer from recurrence of NMIBC in short term, even after receiving induction and maintenance IVC after TURBT. If the BCG is unavailability or unsuitability, for this apparent treatment resistance, the Canadian Urological Association recommends single agent chemotherapy (e.g., mitomycin-C, Gem) or sequential combination of IVC (e.g., Gem /docetaxel) is recommended with induction followed by monthly maintenance for up to one year [13, 23]. McElree et al report retrospective outcomes from a single center that treated 75 patients with sequential intravesical valrubicin and docetaxel as salvage therapy for recurrent non-muscle invasive bladder cancer (NMIBC) following the failure of intravesical BCG and/or Gem-docetaxel. The recurrence-free survival rate in low- and high-grade disease was 73% and 38%, respectively. Among patients with high-grade disease, overall, cancer-specific, and cystectomy-free survivals were 87%, 96%, and 84% at 2 years, respectively [24]. Due to cumulative, synergistic or different antitumor mechanisms of action, combination chemotherapy given could reduce drug resistance and further diminish the recurrence rate, but one could also expect higher local toxicity [13, 25]. Chen et al used a triple-drug regimen of MMC, doxorubicin, and cisplatin (MDP) in patients with newly diagnosed papillary NMIBC [26]. Compared with maintenance doxorubicin, the MDP group had a significantly lower recurrence rate but double discontinuation rate due to adverse events.

Single-agent IVC has been a mainstay salvage treatment and foundational to future trials of combination therapy [27]. In a retrospective study, 72 patients with recurrent NMIBC after failure of previous intravesical therapy (MMC, EPB and CPT), received Gem or original IVC [28]. The study results showed that Gem is more effective than original chemotherapy in 2-year tumor-free survival rates (70.8% vs 45.8%). However, the authors did not state whether switching IVC drug after the failure of IVC is beneficial in NMIBC.

HCPT, GEM, and EPI, which have different anti-tumor mechanisms, are widely used as first-line drugs for IVC to prevent tumor recurrence after TURBT for NMIBC [16]. To our knowledge, our study is the first single-centered retrospective observation study to compare the efficacy of switching or retaining original chemotherapy drug in this selected subset of patients with NMIBC, failing first-line drugs for adjuvant IVC, for whom unavailability or unsuitability for BCG instillation. In the current study, the recurrence rate of group A was 49.5%, which was similar to the study of van Rhijn et al [29]. Group A showed insignificant advantages in terms of the recurrence rate, the median recurrence interval, and the average recurrence time compared with group B. Although not statistically significant, numerically, group A was preferred to group B. Progression rate in the two groups were 18.7% VS 23.5%, although the association was not statistically significant (p༜0.05), they varied widely, similar to the result of 19.8% reported by Cambier et al[30]. To our surprise, the median recurrence interval and mean time to recurrence in both groups at 5-year follow-up time were statistically associated with treatment strategies (p = 0.044 and p = 0.035, respectively), indicating that the treatment of drug switching used in short-term recurrent NMIBC was able to significantly prolong the interval of progression. It is well known that age, T stage, grade, carcinoma in situ (CIS), multifocal tumor, tumor size and recurrent tumor are all risk factors for recurrence and progression of NMIBC [20]. In the situation of more high-grade, T1 tumors and large tumor, recurrence and progression rates in group A were still were lower than group B, although not statistically significant, possibly indicating that the treatment of drug switching used in short-term recurrent NMIBC was able to reduce the recurrence and progression.

Univariate analyses of baseline patient characteristics were performed to identify predictors of response to switching chemotherapy drugs after the failure of IVC is beneficial in NMIBC. However, in this study, only tumor grade was found to be the independent risk factor related to recurrence (HR = 0.632; 95% CI 0.425–0.942; p = 0.024). While the presence of carcinoma in situ may be an independent risk factor related to progression (HR = 0.159; 95% CI 0.037–0.683; p = 0.013).

In summary, when compared with retaining original IVC agent, switching IVC agent can significantly prolong time of tumor progression, increase objective response rate, and do not appear to improve overall survival. Furthermore, the finding may provide a new basis for drug selection in combination IVC. The study is retrospective so that may have inevitable bias within the procedure of collecting data. Moreover, the sample size is small, which limits the strength of the conclusion that we can draw from them, especially for recurrence rate. The clinical efficacy still needs further multi-centered, large-scale prospective studies to further verify of the advantages switching intravesical chemotherapeutic agent in patients with short-term recurrent NMIBC.

Ethics approval and consent to participate

The study was approved and consented by the Second Hospital of Tianjin Medical University ethics committee (protocol code KY2022024-01). This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This retrospective study was performed after approval from the institutional review board. Institutional review board of the Second Hospital of Tianjin Medical University waived the need for informed consent for this retrospective study.

Consent for publication

Not applicable.

Availability of data and materials

The data and materials presented in this study are available on request from the corresponding author.

Competing interests

The authors declare that they have no competing interests.

Funding

This research was supported by Tianjin Key Medical Discipline (Specialty) Construction Project: TJYXZDXK ‑023A.

Authors' contributions

Conception, study design, writing—review and editing, S.C., Y.Q., and R.L.; collection of patient follow-up data, G.S., X.C. and T.S.; data collation and verification, data analysis, S.W. and H.H. All authors have read and agreed to the published version of the manuscript.

Acknowledgements

We thank all the patients and authors for participating in this study.

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Is switching intravesical chemotherapeutic agent beneficial in short-term recurrent high-risk non-muscle- invasive bladder tumors? A 5-year retrospective study

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Abstract

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1. Introduction

2. Materials and Methods

2.1 Patients

2.2 Intravesical chemotherapeutic treatment protocol

2.3 Follow‑up and outcomes

2.4 Statistical analysis

3. Results

3.1 Patients

3.2 Efficacy

4. Discussion

5. Conclusions

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References

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