The long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy combined with radical cystectomy versus radical cystectomy alone for bladder cancer: a propensity-score matching study

Bladder cancer is a complex disease associated with high morbidity and mortality rates. Approximately 75% of newly diagnosed patients present with non-muscle-invasive bladder cancer (MIBC), which is characterized by a high recurrence rate and 5-yr survival of ~ 90% [1]. Once the disease becomes MIBC, the 5-year overall survival is a dismal outcome at 47% compared with the 81% survival rate of patients with non-muscle-invasive disease [2]. Approximately 50% of MIBC patients will develop metastasis and have a 5-yr survival of only ~ 5% [3, 4]. Despite radical cystectomy (RC) with bilateral pelvic lymph node dissection (PLND) as the gold standard treatment, RC only permits a 5-yr survival in approximately 50% of patients [3, 5‐8]. In fact, there was no significant improvement in bladder cancer outcomes over the last three decades.

Although several high-quality clinical trials have demonstrated improved survival and pathologic downstaging with the use of chemotherapy prior to RC, adoption of neoadjuvant chemotherapy for MIBC has been slow. Several hypotheses, such as the significant toxicities and delayed surgery, especially the inability to identify which patients could derive the most benefit from neoadjuvant chemotherapy, were slow during the adoption of neoadjuvant treatment. Additionally, 25 to 33% of patients are unable to receive adjuvant chemotherapy after RC due to postoperative problems, such as perioperation complications or deterioration of renal function [9, 10]. Therefore, we hypothesized that one-shot neoadjuvant intra-arterial chemotherapy (IAC) would have less toxicity and better disease control than RC alone. Moreover, this strategy would allow patients to complete therapy quickly and move on to the next form of therapy.

Therefore, we compared the long-term efficacy of one-shot neoadjuvant IAC versus no IAC (NIAC) before RC for bladder cancer in this study.

To evaluate the long efficacy of one-shot neoadjuvant IAC versus NIAC before RC for bladder cancer, we retrospectively reviewed all patients treated with RC/PLND between October 2006 and November 2015 for urothelial carcinoma of the bladder without distant metastasis in the Department of Urology, Beijing Chao-Yang Hospital. This study was approved by the Institutional Review Board of Beijing Chao-Yang Hospital. To prevent selection bias of the learning curve, we chosen patients who operations were performed by the same laparoscopic surgeon (Xing).

A total of 26 patients underwent one-shot neoadjuvant IAC, and 123 patients were treated using RC/PLND alone. The baseline characteristics of patients enrolled are listed in Table 1. All key variables except follow-up duration (88 mo vs 26 mo, p = 0.002) were not different at baseline between the two groups. To reduce the differences between groups due to selection bias, we performed a matched analysis based on follow-up duration Additional file 2 Figure S1.

The matching algorithm was 1:3, which was the optimal weight for each key variable. The patients were followed up for a median period of 88 months in the IAC group and for 56 months in the NIAC group (p = 0.161). There were no significant differences between the groups in patient demographics and clinical characteristics. Table 1 lists the baseline characteristics for the matched cohorts.

There was no significant difference in perioperative variables between the IAC and NIAC groups (Table 2). In the type of urinary diversion, more than 50% of patients received orthotopic neobaldders in both groups. IAC treatment did not affect renal function in terms of serum creatinine (P = 0.702) or blood urea nitrogen (P = 0.119) levels. The proportion of those who remained in the intensive care unit after surgery was lower in the IA group than in the NIAC group (0% vs 10.3%; p = 0.196). The total complication rate was not significantly different between the two groups (92.3% vs 96.2%; p = 0.791). However, Clavien grade 2 complications (>80%) were more common in the perioperative period (< 30 d).

Tumor characteristics are listed in Table 3. The pathology results of all patients showed urothelial cell carcinoma of the urinary bladder. Positive surgical margins were reported in the NIAC group (3.8%). Compared with clinical TNM stages, pathological TNM staging demonstrated similar in the NIAC group after matching (P = 0.519, Additional file 1 Table S1 and Additional file 2 Figure S2); however, a significant decrease showed in the IAC group (P = 0.002): 7 (26.9%) patients had no stage change, 17 (65.4%) patients exhibited a stage decrease, and 2 (7.7%) patients exhibited a stage increase (Additional file 1 Table S2 and Additional file 2 Figure S3). There was one patient with severe gross hematuria that was diagnosed as NMIBC by CT. Conservative measures and attempts to achieve hemostasis by cystoscopy were unsuccessful at controlling bleeding. The patient therefore underwent endovascular treatment with intra-arterial chemotherapy and superselective embolization of the vesical arteries 2 weeks before RC/PLND.

Of the 26 patients in the IAC group, two (7.7%) died because of cancer, and one (3.8%) died due to another reason. Among the 78 patients in the NIAC group, eleven (14.1%) suffered cancer-specific mortality, and five (6.4%) died due to another reason. There was no significant difference in the rates along the curve for overall mortality (p = 0.354) or cancer-specific mortality (p = 0.439) between the IAC and NIAC groups (Fig. 1).

Multivariable Cox proportional hazards regression analysis (Table 4) showed that several variables have an impact on overall survival. In all samples, BMI (p = 0.005), diabetes (p = 0.002), ASA score (p = 0.005), PLN (p<0.001) and perioperative complications (p = 0.020) were influencing factors.

When these potential factors were used to calculate the Kaplan-Meier survival curve, some were associated with OS and CSS (Fig. 2). BMI less than 25 kg/m² was associated with OS (p = 0.004) but not CSS (p = 0.050), and PLN was associated with OS (p<0.001)and CSS (p = 0.010). The survival time and cumulative survival rate (1-, 5- and 10-year rates) are depicted in Table 5.

Our present results show that there was a downstaging advantage with one-shot neoadjuvant IAC before RC for MIBC (p = 0.002), but it did not significantly improve OS (p = 0.354) or CSS (p = 0.439) compared to those treated without IAC. We performed Cox regression to assess risk factors association with survival in all samples and found that BMI (less than a 25 kg/m²) significantly affected OS (p = 0.004), and PLN significantly affected both OS (p<0.001 = and CSS (p = 0.010). Besides, we are curious about the potential risk factors affecting survival outcomes in the IAC and NIAC group and their difference in the two groups. So, despite the small sample size of IAC and NIAC group, we used Cox regression to explore the risks in the both groups exploratorily. The exploratory analysis found that diabetes (P = 0.029, RR = 14.649) was an influencing factor in IAC group, whereas BMI (P = 0.015, RR = 0.802), PLN (P < 0.001, RR = 7.474) and smoking history (P = 0.043, RR = 3.388) were influencing factors in NIAC group (Additional file 1 Table S3). Furthermore, when these potential factors were used to calculate the Kaplan-Meier survival curve, some were associated with OS and CSS in IAC groups and NIAC groups (Additional file 1 Table S4-S7 and Additional file 2 Figure S4). In brief, one-shot neoadjuvant resulted in significant downstaging; for RC, only BMI and PLN correlate with survival in our long-term data.

RC usually occurs 4 to 6 weeks after MIBC diagnosis in our center, and this time offers an opportunity to preoperatively perform neoadjuvant therapy. Although standard neoadjuvant cisplatin-based combination chemotherapy followed by RC is supported by level 1 evidence for resectable (cT2-T4aN0M0) MIBC, the inability to identify which patients may derive most benefit from neoadjuvant chemotherapy was slow during the adoption of neoadjuvant treatment. Nevertheless, approximately 50% of patients with urothelial carcinoma are considered ineligible to receive cisplatin based on renal dysfunction and impaired performance status, and a subset of patients also refuse to receive neoadjuvant chemotherapy [11]. Notably, adherence to adjuvant and neoadjuvant chemotherapy regimens was observed in a similarly low proportion of patients (approximately 21% each) in the USA, and the majority of patients with resectable bladder cancer received no chemotherapy at all [12]. Therefore, the treatment algorithm for MIBC tumors in a short window before RC is still evolving.

Neoadjuvant IAC is not a new concept. In the 1980s–1990s, multiple efforts were made to improve oncological outcomes by adding various IAC treatment modalities plus RC to treatment regimens for MIBC. A summary of the published neoadjuvant IAC papers, including key information on chemotherapy regimens, is provided in Table 6 (Additional file 2 Figure S5) [13‐21]. Although most of the literature is early in its use, the drugs also have differences, but all show varying degrees of pathological downstaging or even complete response (CR; pT0). Pathological downstaging or pathological CR to neoadjuvant chemotherapy is a well-recognized biomarker of improved OS [22]. Because it was such a short period of therapy, we felt that achieving pathological CR would be quite challenging in our study. Although OS and CSS for the study cohort remained disappointing, one-shot neoadjuvant IAC showed an encouraging pathological downstaging rate of greater than 60% (P = 0.002). Meanwhile, the safety and tolerability profile for IAC was quite favorable. In particular, no chemotherapy-related adverse events have been reported in the IAC group, which did not delay planned surgery. Moreover, no differences in perioperative, short-term or long-term complications were recorded compared with patients undergoing RC only. Similarly, intraoperative performance (operating time, estimated blood loss, blood transfusion, number of nodes removed and surgical margins) was not compromised by neoadjuvant IAC. Therefore, our treatment produced major pathologic responses, indicating that the side effects of chemotherapy can be reliably avoided when using one-shot IAC.

Bladder cancer is a heterogeneous disease, which means that only single treatment is not enough. Current research is actively exploring novel combinations and ideal sequencing with various treatment modalities, especially immunotherapy combined with chemotherapy, radiotherapy or targeted therapies. Although bladder cancer carries the third highest mutation rate of all studied cancers, suggesting the possibility of increased immunogenicity via the development of neoantigens, it is clear from existing data that the majority of patients will not respond to monotherapy [23‐25]. Interestingly, chemotherapeutic agents have direct cytotoxic effects on tumor cells that release tumor antigens but also have positive effects on immune effector T cells [26]. Therefore, in theory, one-shot IAC can play a synergistic role as a single immunotherapy. Moreover, chemotherapy may substantially prolong the total duration of neoadjuvant immunotherapy [27]. However, patient selection must be optimized. In addition to having good renal function, it is also necessary to pay attention to the patient’s nutritional status and immune system, which may be hampered by an aged-related reduction in functional decline. With an average age of 73 years at diagnosis, perioperative immunonutrition has a significant impact on surgery and the efficacy of immunotherapy [28]. According to our findings, BMI, diabetes and ASA score were associated with survival and may be the modifiable predictors in older and sicker patient populations. Additionally, the optimization of toxicity and tolerability of combination therapies through appropriate dosing and sequencing should be determined using well-designed clinical trials.

The strengths of our study are the selection of only one surgeon’s cases for minimizing the influence of different levels of maturity and the use of propensity-score matching to reduce the inherent biases. As a result, patients who were matched only on the basis of key variables were selected. However, an important limitation is our drawing conclusions from small sample and highly selected patients with retrospective, nonrandomized data, which might introduce possible selection biases that we did not control for. Another limitation of the present study was that there was no consistent record of recurrence-free survival (RFS) in the long-term follow-up period. Although the final pathology showed no difference between the cohorts, the proportion of positive surgical margins was higher in NIAC cohort. It is possible that NIAC cohort had lower stage disease to begin with which would affect the RFS of patients. However, it should be noted that OS is the gold standard and the most dependable end point in clinical cancer research to support treatment algorithms. Furthermore, CSS may be a surrogate endpoint for RFS. Nevertheless, we were not able to detect statistically significant differences between the groups in OS or CSS. At the same time, more than half of our patients were from all over the country, and some proportion of patients did not have clear data on disease recurrence. Therefore, RFS is not as important. Finally, we should know that there was not a specific marker to judge the safety, tolerability, or clinical benefit of the treatments in the subgroups of patients. Answers to some of these questions will become clearer as these studies begin to mature with clinical readouts.

This long-term follow-up, retrospective study of one-shot neoadjuvant IAC in patients who underwent RC from 2006 to 2015 shows significant advantages in pathological downstaging but not in OS or CSS. Moreover, this study demonstrates the safety and tolerability of this treatment and provides a basis for combination therapy. Future efforts to improve survival in patients with bladder cancer is warranted and further study of the ideal neoadjuvant therapeutic strategies followed by RC is needed.