Intra-arterial chemotherapy plus BCG, a promising combination adjuvant treatment for high-risk NMIBC

doi:10.21203/rs.3.rs-1943507/v1

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Research Article

Intra-arterial chemotherapy plus BCG, a promising combination adjuvant treatment for high-risk NMIBC

https://doi.org/10.21203/rs.3.rs-1943507/v1

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Purpose

To develop a novel combination therapy for high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT), namely, intra-arterial chemotherapy (IAC) plus BCG immunotherapy, and to compare the feasibility and safety of the two therapies.

Materials and methods

A retrospective study was conducted on the data of 119 patients who were diagnosed with high-risk NMIBC and underwent TURBT in the past five years. Those who did not complete the treatment were excluded, and the remaining 98 patients were divided into two groups: both groups received intravesical BCG immunotherapy, while the BCG+IAC group received 4 courses of extra intra-arterial chemotherapy. Clinical and follow-up data were processed using statistical software.

Result

The recurrence rate was 22.2% in the BCG+IAC group and 35.8% in the BCG group, whereas the progression rates were 8.9% and 24.5%, respectively. In the Kaplan-Meier plot, a statistically significant difference was observed with respect to recurrence-free survival (p=0.025), as well as the progression-free survival of the two groups was similar (p=0.019). 22.2% of the patients with adverse effects of IAC and 79.6% of patients suffered from adverse reactions to BCG immunotherapy, and most of the adverse effects were mild and tolerable. Univariate and multivariate analysis indicated that multifocal and treatment were independent risk factors for recurrence, while the history of recurrence and treatment were independent risk factors for progression.

Conclusion

IAC could be a promising auxiliary treatment for BCG immunotherapy in decreasing the recurrence and progression rate of high-risk NMIBC with little additional toxicity.

Date of registration:10^th, April 23, 2022. TRN: ChiCTR2200058555, retrospectively registered

Intra-arterial chemotherapy

BCG

high-risk non-muscle-invasive bladder cancer

combination therapy

retrospective study

Bladder cancer is the 9th most commonly diagnosed cancer worldwide, with an estimated 470000 new cases and 200000 deaths in 2020[1–3]. It is reported that 1 in 100 men and 1 in 400 women will be diagnosed with bladder cancer sometime in life, and currently, more than 1.65 million people worldwide suffer from bladder cancer [4]. Non-muscle invasive bladder cancer (NMIBC), which includes diseases confined to the mucosa (carcinoma in situ (CIS), Ta) and submucosa (T1), accounts for approximately 75% of these cases[5, 6]. The European Organization for Research and Treatment of Cancer (EORTC) risk tables are widely used for NMIBC risk classification to estimate the probabilities of recurrence and progression. According to these tables, the European Association of Urology (EAU) guidelines recommend categorizing patients into low-risk, intermediate-risk, and high-risk tumors groups[7]. Transurethral resection of bladder tumor (TURBT) following intravesical instillation is the standard treatment for high-risk NMIBC[7]. It is well established that intravesical BCG immunotherapy is superior to chemotherapy in reducing recurrence and progression, particularly in intermediate-high risk NMIBC[1]. According to a review, BCG immunotherapy induces initial complete response rates of 55–65% for high-risk papillary tumors and 70–75% for CIS. However, there are still 25–45% of patients will not benefit from BCG therapy, and up to 40% of patients will eventually relapse[8]. Intra-arterial chemotherapy (IAC) has been proven to be an effective way to control micro-metastasis by elevating local drug concentrations[9–12], and has already been used in treating bladder cancer since the 1970s[13]. Our previous studies have already revealed that IAC combined with intravesical chemotherapy (IVC) could reduce the recurrence and progression rate of high-risk NMIBC compared to IVC alone[14–16]. Furthermore, IAC + IVC was as effective as BCG with similar recurrence rate[17]. This suggests that IAC could be an additional treatment that may decrease the recurrence rate of BCG immunotherapy. The purpose of this study was to evaluate the efficacy and safety of IAC + BCG combination therapy for high-risk NMIBC. The outcomes could open up new possibilities for the treatment of NMIBC.

Patients

In this study, we retrospectively enrolled patients who were pathologically diagnosed with high-risk NMIBC after TURBT for nearly 5 years at our hospital. According to EAU stratification[7], high-risk NMIBC consists of any of the following standards: 1) T1 tumor; 2) G3 (HG) tumor; 3) carcinoma in situ (CIS); and 4) multiple, recurrent, and large (> 3 cm) TaG1G2/LG tumors (all features must be present). The exclusion criteria were: 1) patient age over 85, 2) pathologically confirmed as MIBC or distant metastasis beyond the pelvis, 3) previously underwent instillation of BCG, chemotherapeutic drugs or picibanil, 4) history of taking oral anticoagulant, 5) ineligible for IAC, uncontrollable urinary tract infections. We recommended all of the participants to undergo BCG + IAC therapy before the treatment began. The mechanism of IAC treatment and BCG treatment, a potentially greater benefit of the combination therapy, the wide range of possibilities of adverse effects of the two treatments as well as the extra cost of IAC were plainly illustrated to the patients. Patients were given the right of options and no induced suggestions were offered by our urologists. Finally, those who chose to undergo BCG + IAC therapy were included in combination group while others were included in BCG group. In total, 119 patients were enrolled, and the two groups underwent identical BCG treatment schedule, while the combination group underwent extra four courses of IAC treatment. For various reasons, 21 patients were excluded, and the findings of the study were mainly based on the remaining 98 patients. All subjects conformed to the treatment schedule, and those who had previously received intravesical chemotherapy, similar treatment or did not complete the BCG or IAC treatment for any reason were excluded.

This study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University and conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Intravesical bacillus Calmette- Guérin (BCG) immunotherapy treatment protocol

All patients received intravesical BCG immunotherapy after TURBT. The instillation schedule rests with the manufacturer’s recommendations, in which induction courses included 6 cycles of weekly instillation, while the maintenance schedule included intensive instillation at three intervals: 3, 6, and 12 months in the first year, and every 6 months thereafter for 2 additional years. Reconstituted BCG (120 mg diluted in 50 ml of 0.9% saline) was maintained inside the bladder for 2 h.

BCG combined with Intra-arterial chemotherapy (IAC) treatment protocol

Patients in the IAC + BCG group received 4 courses of extra intra-arterial chemotherapy with an interval of 1 month when the first IAC was implemented within 1 month after TURBT. Each time an IAC treatment was performed, an angiographic catheter was selectively placed into the patients’ internal iliac arteries using Seldinger’s percutaneous technique, and cisplatin (60 mg/m²) and epirubicin (50 mg/m²) were then administered to local blood vessels through the catheter. The instillation plan was determined based on previous similar studies. Routine blood examinations and blood biomedical detection were performed before and after every IAC treatment. To avoid adverse gastrointestinal reactions, all participants were subsequently prescribed proton pump inhibitors.

Follow-up and outcomes

After surgery, all patients were recommended to undergo cystoscopy every 3 months for a 2-year period and then every 6 months for a 3-year period. When a suspicious mass was discovered, bladder biopsy was performed to identify the nature of the mass and its stage and grade. Specialists conducted follow-up through telephone inquiries and inspection of the information system of our hospital and recorded the outcomes. Recurrence was defined as intravesical tumor recurrence or metastasis. Progression was defined as tumor progression to T1-4stage or metastasis. Adverse effects of IAC and BCG instillation were scored and recorded according to the Common Terminology Criteria for Adverse Effects (CTCAE v4.0) grading system.

Statistical analysis

All data were organized, analyzed, and tabulated using the statistical package for social science (SPSS) software, version 25.0. All tests were two-sided, and p value below 0.05 was considered statistically significant. Overall survival, recurrence rate, progression rate, and time to first recurrence were calculated. Recurrence and progression curves were processed with Kaplan-Meier analysis. The characteristics of patients in the two groups were compared using independent sample t-tests, rank-sum tests, and Chi-square tests. The Chi-squared test was used for categorical parameters. The t-test was used for continuous parameters conforming to the normal distribution law, while the rank-sum test for non-normal distribution parameters.

A total of 119 patients were initially enrolled in the study, and 21 patients were finally excluded (Fig. 1). The records of the remaining patients, including 45 patients in the BCG + IAC group and 53 patients in the BCG alone group, were analyzed. As for patients’ characteristics, no statistically significant difference was found between the two groups. The recurrence intervals of the two groups ranged from 11 to 56 and 9 to 56 months, respectively, and the median recurrence intervals of the two groups were 23.5 and 24 months, respectively (p = 0.622). The progression intervals of the BCG + IAC and BCG alone groups ranged from 18 to 33 months and 9 to 48 months, with median progression intervals of 25 and 24 months, respectively (p = 1.000). The follow-up times of the two groups ranged from 16 to 69 and 12 to 68 months, and the median follow-up times were 35 and 37 months, respectively. The recurrence rates of the two groups were 22.2% (10/45) and 35.8% (19/53), respectively, and there was no statistically significant difference between the BCG + IAC and BCG alone groups according to the Chi-square test (p = 0.141). The rates of progression were 8.9% (4/45) and 24.3% (13/53), respectively, with no significant difference (p = 0.060). The overall survival of the two groups was similar (95.6% vs. 96.2%, p = 1.000). One of the patients in BCG + IAC group died of cerebral ischemic stroke, and another patient died pulmonary metastasis of bladder cancer. While in the BCG alone group, one patient died of pulmonary metastasis of bladder cancer, and another died from renal failure. All these results were summarized in Table 1.

Table 1

Patient and tumor characteristics & Clinical outcome of high-risk patients in BCG + IAC and BCG groups
	Overall(n = 98)	BCG + IAC(n = 45)	BCG(n = 53)	P value
Characteristic
Age, years				0.400^※
Mean ± SD	63.23 ± 1.139	64.20 ± 1.507	64.42 ± 1.678
Median	64.5	66	64
Range	33–88	36–82	33–88
Gender, n (%)				0.531
Males	83(84.7)	37(82.2)	46(86.8)
Females	15(15.3)	8(17.8)	7(13.2)
Grade, n (%)				0.157
Low grade	20(20.4)	12(26.7)	8(15.1)
High grade	78(79.6)	33(73.3)	45(84.9)
T category (n%)				0.277
Ta	27(27.6)	10(22.2)	17(32.1)
T1	71(72.4)	35(77.8)	36(67.9)
CIS				0.728
No	89(90.8)	40(88.9)	49(92.5)
Yes	9(9.2)	5(11.1)	4(7.5)
Tumor size (n%)^a				0.372
༜3cm	57(58.2)	24(53.3)	33(62.3)
≥3cm	41(41.8)	21(46.7)	20(37.7)
Multifocal (n%)				0.526
No	27(27.6)	11 (24.4)	16(30.2)
Yes	71(72.4)	34(75.6)	37(69.8)
History of recurrence. (n%)				0.666
No	72(73.5)	34(75.6)	38(71.7)
Yes	26(26.5)	11(24.4)	15(28.3)
Clinical outcomes
Tumor recurrence rate		22.2% (10/45)	35.8% (19/53)	0.141
Median recurrence interval		27(months)	24 (months)	0.622
Tumor progression rate		8.9% (4/45)	24.5% (13/53)	0.060
Median progression interval		25 (months)	23(months)	1.000
Median follow-up time		35 (months)	37 (months)	0.949
Overall survival		95.6% (43/45)	96.2% (51/53)	1.000
^aMaximum size of largest tumor resected
^※Analyzed with Mann-Whitney U test

The Kaplan-Meier curves for recurrence-free survival (RFS) and progression-free survival (PFS) are shown in Figs. 2 and 3. The BCG + IAC group had a higher estimated RFS rate (77.8% vs. 64.2%, p = 0.025, Fig. 2), while the PFS of the two groups seemed to be similar (91.1% vs. 75.5%, p = 0.019).

Univariate analysis was performed for tumor-related factors, and the p-value was set at 0.05. Multifocal and treatment were found to be the independent risk factors for recurrence (p = 0.009 and 0.027, respectively). History of recurrence and treatment were found to be independent risk factors for progression (p = 0.011 and 0.024, respectively). Multivariate analysis also confirmed these findings. The results are presented in Table 2.

Table 2

Univariate and multivaritae analysis according to recurrence and progression
	Tumor recurrence					Tumor progression
		Univariate analysis		Multivariate analysis			Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value		HR (95% CI)	P value	HR (95% CI)	P value
Sex
Female vs male	0.429 (0.126–1.461)	0.176	-		-	0.964(0.217–4.279)	0.962	-	-
Age (years)
༜65 vs ≥ 65	1.115 (0.503–2.470)	0.789	-		-	0.753(0.285–1.991)	0.568	-	-
History of recurrence
No vs yes	1.563 (0.671–3.644)	0.301	-		-	3.215(1.218–8.485)	0.018^※	3.499(1.328–9.222)	0.011^※
Tumor size (cm)
༜3 vs ≥ 3	6.966(1.621–29.933)	0.009^※	6.761(1.606–28.464)		0.009^※	1.019(0.387–2.682)	0.969	-	-
T category
Ta vs T1	0.973 (0.430–2.201)	0.947	-		-	0.480(0.184–1.248)	0.132	-	-
Grade
Low vs high	0.886 (0.388–2.023	0.774	-		-	4.365(0.578–32.944)	0.153	-	-
CIS
No vs yes	2.621(0.808–8.503)	0.109	-		-	0.492(0.065–3.713)	0.491	-	-
Treatment
BCG + IAC vs. BCG	0.424(0.193–0.932)	0.033^※	0.418(0.193–0.906)		0.027^※	0.280 (0.090–0.870)	0.028^※	0.269(0.086–0.842)	0.024^※
CI confidence interval, HR hazard ratio
^※Significant difference

Adverse reactions of IAC and BCG were reviewed according to CTCAE v4.0 and summarized in Table 3. In the BCG + IAC group, 22.2% (10/45) of patients experienced adverse complications of intra-arterial chemotherapy, of which five experienced nausea and vomiting, five experienced fever, two experienced hypo-leukemia, three experienced low neutrophil count, one experienced hepatic dysfunction, and five experienced renal dysfunction. All these complications were mild, and no patient withdrew before completing the 4-course intra-arterial chemotherapy. The majority of patients in both groups experienced adverse reactions to BCG immunotherapy, of which 74 experienced cystitis (35 in IAC + BCG group and 39 in BCG group, p = 0.631), 30 experienced hematuria (14 in IAC + BCG group and 16 in BCG group, p = 0.921) and three patients experienced incontinence (1 in IAC + BCG group and 2 in BCG group, p = 1.000). Regarding systemic complications, 11 patients in IAC + BCG group and 12 patients in BCG group had fever (p = 0.834). Eleven patients in IAC + BCG group and eight patients in BCG group experienced flu-like symptoms (p = 0.243). Owing to severe adverse reactions, eight patients in the BCG + IAC group and four in the BCG alone group discontinued the treatment. The adverse reactions to BCG in the two groups were compared, and no significant difference was found between the BCG + IAC and BCG alone groups.

Table 3

Adverse reaction of intra-arterial chemotherapy and BCG immunotherapy
	Grade I-II	Grade III-IV	Incidence %
IAC
Nausea/vomiting	5	-	11.1
Fever	5	-	8.9
Hypo-leukemia	2	-	4.4
Neutropenia	3	-	6.7
Increase alanine aminotransferase	1	-	2.3
Increase creatinine	5	-	11.1
BCG
Local
Cystitis	70	4	75.5
Hematuria	25	5	30.6
Incontinence	-	3	3.1
Systemic
Fever	23	-	23.5
Flu-like. symptoms ^a	19	-	19.4
According to CTCAE v4.0, Common Terminology Criteria for Adverse Events, version 4.0
^aMalaise/fatigue/myalgia

According to the EAU guidelines for NMIBC, BCG instillation is the standard treatment strategy for high-risk NMIBC[7]. As many as 25–45% of patients do not benefit from intravesical BCG therapy[8]. Two earlier studies revealed that within a median follow-up time of approximately 2 years, the recurrence and progression rates were relatively high in NMIBC, even though BCG instillation was utilized[18, 19]. Radical cystectomy (RC) is another recommended strategy for high-risk NMIBC, which carries a high risk of perioperative morbidity and mortality, especially in an old and infirm population[5]. It has been suggested that RC can impair patients’ gut function and metabolism, leading to malnutrition, sarcopenia and frailty[20]. All these factors impact the outcomes of patients with bladder cancer. Moreover, owing to urinary diversion, radical cystectomy greatly affects the quality of life of patients. As a result, many patients prefer to reject surgery because of the concern of decline in living standards. To decrease the recurrence rate and delay the progression of NMIBC, so that eventual RC surgery could be avoided, combination therapies and checkpoint inhibitors (CPI) are current research focuses. Pembrolizumab, a CPI, has recently received FDA approval in the treatment of BCG-resistant NMIBC[21], but not for all high-risk NMIBC patients. There are also several ongoing phase I and II trials on CPI for NMIBC (NCT04738630, NCT03317158, NCT05120622, NCT04640623)[22], but no outcome was published so far. The key respect and innovative point of combination therapies is to improve survival rate and prognosis of high-risk NMIBC patients with relatively less costs through ameliorating the standard local treatment of NMIBC rather than systemic treatment.

Among BCG combination therapies, intra-arterial chemotherapy (IAC) is rarely mentioned, which was first used in muscle-invasive bladder cancer and has proven to preserve the bladder or prolong life[9–12]. Our previous studies reported that IAC + IVC was superior to IVC alone in preventing tumor recurrence and progression in NMIBC[14–16]. Another study revealed that, compared to BCG immunotherapy, IVC + IAC has almost equal effects in treating NMIBC[17]. The mechanism of action of BCG is currently considered to be the inflammatory response induced by BCG [23]. Cisplatin and anthracyclines are commonly used in IAC, the former kills tumor cells via oxidative stress-mediated cytotoxicity, cell apoptosis [24], while the latter achieve anti-tumor activity by preventing DNA replication in cancer cells. Certainly, these agents could supplement the anti-tumor effect of BCG owing to distinct mechanisms. Therefore, it is worth exploring whether IAC could bring a gain effect on the therapeutic effect of BCG immunotherapy and ascertaining potentially additional side effects.

In this study, we compared the parameters representing efficacy and toxicity of the two different treatment protocols. The recurrence rate in the BCG alone group was close to a previous study reported by Tom J.H et al. (35.8% vs. 35.2%)[25]. However, it was slightly lower than the rate of 26.4% reported by our previous study[17]. We attribute this to the fact that the follow-up time of both groups in current study were much longer than our previous study (35 and 37 months, respectively. vs. 28 and 25 months). It is rational that tumor recurrence raised with follow-up time extended. The Kaplan-Meier survival analysis showed that the difference in recurrence rate between the two groups was remarkable (p < 0.05). Multivariate analysis for recurrence and progression also revealed that BCG + IAC therapy has better performance in preventing recurrence and progression than BCG alone therapy (p = 0.027 and 0.024, respectively). The hazard ratios which were below 1 indicated that BCG + IAC intervention were probably negatively correlated with tumor recurrence and progression. These outcomes suggest that IAC could further reduce the recurrence rate of BCG immunotherapy. It could be an effective reinforcement for the weakness of BCG immunotherapy. To explain the mechanism of IAC, Hoshi et al.[26] performed a series of animal surgeries on rabbits and found that due to direct arterial administration, antitumor drug concentrations in the plasma and bladder tumors were much higher in the IAC group. Higher drug concentrations could lead to the reduction of potential micrometastases into smooth muscle or pelvic lymph nodes and, therefore, decrease the incidence of recurrence.

Compared to two earlier studies, the progression rate of the IAC + BCG group in our study was quite lower than those of BCG groups (8.9% vs. 25.3% and 36%)[27, 28]. Besides, a significant difference was found in the progression rate between the two experimental groups (p = 0.019). It is widely accepted that long-term accumulation of genetic alterations in cancer cells plays a crucial role in tumor progression[29]. Eradicating more residual mutated cells after TURBT at an early stage will most likely delay NMIBC progression. The above mentioned could probably be the mechanism of IAC treatment in preventing tumor progression. Additionally, according to a systematic review[30], progression in high-risk NMIBC mainly occurs within 48 months, and the median follow-up times of our study haven’t reach the time limit yet. Hence, continuation of follow-up and further prospective studies are still required to verify the more authentic effect of IAC treatment in slowing tumor progression.

Regarding the safety, routine blood changes and gastrointestinal distress were the most common complications. Approximately 22.2% of patients (10/45) experienced adverse effects of IAC. According to the CTCAE v4.0 grading system, the grades of adverse reactions were limited to grade 1 to 2, meaning that they were mild enough to be managed at home or outpatient. These results consist with previous studies.[15, 17] On the contrary, including patients who previously withdrew, 81.5% patients (88/108) suffered from adverse reactions of BCG immunotherapy. Notably, four patients in the BCG + IAC group discontinued treatment because of serious side effects of BCG rather than IAC. No statistically significant difference in side effects was observed between the two groups, indicating that IAC causes reversible and tolerable adverse reactions and brings no additional toxicity to BCG instillation.

Our study has a few limitations. The study had a retrospective design, leading to inevitable bias within the data collection procedure. The follow-up time was not long enough, probably limiting the strength of the conclusion. Inadequate follow-up time and sample size also caused unsatisfactory results of univariate analyses. It is widely known that tumor grade, stage, CIS, history of recurrence, etc. are all risk factors for recurrence and progression. However, in our current study only multifocality was found to be related to recurrence, while history of recurrence was the only significantly associated factor of progression. To solve these problems, further multicenter, large-scale prospective studies are recommended.

The present study indicated that IAC + BCG combination therapy in terms of preventing recurrence, was superior to BCG alone in high-risk NMIBC. IAC is likely compatible with BCG instillation, with acceptable adverse reactions. Hence, it could be a promising auxiliary treatment for standard BCG immunotherapy in high-risk NMIBC to further reduce the recurrence and progression rates.

Disclosure of potential conflicts of interest

This study was funded by grants from the National Natural Science Foundation of China (No.81402116). The authors declare that they have no conflict of interest.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Approval was obtained from the ethics committee of the First Affiliated Hospital of Sun Yat-sen University (No. [2021]414).

Informed consent

Informed consent was obtained from all individual participants included in the study. Patients signed informed consent regarding publishing their data and photographs.

Data Availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

Author Contributions

All authors contributed to the study's conception and design. Material preparation and data collection were performed by Shuhang Luo, Rui Yang, Gaowei Huang, Wusimanjiang, Jiahao Lei, and Jinwen Liu. Data analysis was performed by Shuhang Luo, Shengjie Lin, and Zhoujing Liu. The first draft of the manuscript was written by Shuhang Luo and Rui Yang. Critical revision and supervision were performed by Bin Huang, Junxing Chen, and Lingwu Chen, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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No competing interests reported.

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Intra-arterial chemotherapy plus BCG, a promising combination adjuvant treatment for high-risk NMIBC

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Introduction

Materials And Method

Patients

Intravesical bacillus Calmette- Guérin (BCG) immunotherapy treatment protocol

BCG combined with Intra-arterial chemotherapy (IAC) treatment protocol

Follow-up and outcomes

Statistical analysis

Results

Discussion

Conclusion

Declarations

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Competing Interests

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Informed consent

Data Availability

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