According to the EAU guidelines for NMIBC, BCG instillation is the standard treatment strategy for high-risk NMIBC(Babjuk et al. 2022). As many as 25–45% of patients do not benefit from intravesical BCG therapy(Pettenati and Ingersoll et al. 2018). 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(Sylvester et al. 2002, Bohle et al. 2003). 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(Tse et al. 2019). It has been suggested that RC can impair patients’ gut function and metabolism, leading to malnutrition, sarcopenia and frailty(Michel et al. 2020). 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, various alternative treatment options for high-risk NMIBC patients have emerged in recent years, including hyperthermia chemotherapy and BCG + checkpoint inhibitor therapy(Pettenati and Ingersoll et al. 2018, Veeratterapillay et al. 2016). However, there is currently a lack of rigorous evidence on the effectiveness of these strategies.
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(Eapen et al. 2004, Han et al. 2014, Miyanaga et al. 2000, Miyata et al. 2015). Our previous studies reported that IAC + IVC was superior to IVC alone in preventing tumor recurrence and progression in NMIBC(Chen et al. 2013, Huang et al. 2019, Huang et al. 2019). Another study revealed that, compared to BCG immunotherapy, IVC + IAC has almost equal effects in treating NMIBC(Huang et al. 2021). The mechanism of action of BCG is currently considered to be the inflammatory response induced by BCG (Moschini et al. 2019). Cisplatin and anthracyclines are commonly used in IAC, the former kills tumor cells via oxidative stress-mediated cytotoxicity, cell apoptosis (Dasari and Tchounwou et al. 2014), 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 our previous study (28.3% vs. 26.4%)(Huang et al. 2021). However, it was slightly lower than the rate of 35.2% reported by Tom J.H et al.(Arends et al. 2016) We attribute this to the fact that BCG-treated patients in Tom J.H et al.’s study started the treatment in at least 3 weeks after TURBT rather than in two weeks in our study, indicating that earlier instillation of BCG might be a key influence of recurrence. In contrast, within the median follow-up time of 22 months, the recurrence rate in the BCG + IAC group was 14.0%. The Kaplan-Meier survival analysis showed that the difference in recurrence rate between the two groups was remarkable (p < 0.05), suggesting 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.(Hoshi et al. 1997) 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 (7.0% vs. 25.3% and 36%)(Palou et al. 2018, Thiel et al. 2019). Unfortunately, there was no significant difference in the progression rate between the two experimental groups (p = 0.288). However, it is widely accepted that long-term accumulation of genetic alterations in cancer cells plays a crucial role in tumor progression(Yokota et al. 2000). Eradicating more residual mutated cells after TURBT at an early stage will most likely delay NMIBC progression. Moreover, according to a systematic review(van den Bosch and Alfred Witjes et al. 2011), 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, we firmly believe that IAC + BCG therapy has better clinical efficacy in delaying NMIBC progression. Continuation of follow-up and further prospective studies are required to verify our hypotheses.
Regarding the safety, routine blood changes and gastrointestinal distress were the most common complications. Approximately 46.5% of patients (20/43) 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.(Huang et al. 2019, Huang et al. 2021, Lian et al. 2019) On the contrary, including patients who previously withdrew, 86.1% patients (99/115) suffered from adverse reactions of BCG immunotherapy. Notably, eight 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 also caused a negative result in the comparison of progression rates. The median follow-up times of the two previous studies are much longer than that of our study (5.2 years and 100 months, respectively). With follow-up work continue, combination therapy will definitely show better efficacy in preventing tumor progression. What’s more, 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 no other risk factors were found to be related to recurrence, and no parameters were significantly associated with progression. We attribute this limitation to the small sample size and the finite time span. To solve these problems, further multicenter, large-scale prospective studies are recommended.