Role of adjuvant cisplatin-based chemotherapy following radical cystectomy in locally advanced muscle-invasive bladder cancer: Systematic review and meta-analysis of randomized trials

Radical cystectomy (RC) is the standard surgical therapy for patients with muscle-invasive bladder cancer (MIBC) [1, 2]. In patients who undergo RC only, 5-year survival rate for bladder cancer can be up to 80% for lymph node–negative and organ-limited disease. Survival rate decreases to 40% in patients with extravesical extension of bladder cancer, and it can decrease to 15% to 35% if lymph node metastases are present [1, 3, 4]. The primary cause of poor survival rates in patients with locally advanced MIBC may be systemic occult micrometastatic disease present at the time of RC; preoperative imaging studies cannot detect these micrometastases [5]. These findings suggest that extended use of neoadjuvant or adjuvant systemic chemotherapies that eradicate micrometastatic disease should be considered in most patients with locally advanced MIBC, as RC alone may not be effective for disease management [6].

Level 1 evidence demonstrating a survival benefit recommended neoadjuvant cisplatin-based chemotherapy [7, 8]. However, the use of neoadjuvant chemotherapy (NAC) is low for various reasons, and clinicians must frequently decide whether to recommend adjuvant chemotherapy (ACH) for moderate-to-high-risk patients who have not received NAC [9, 10, 11]. ACH following local treatment has resulted in increases in survival rates of patients with solid tumors [12]. Although randomized clinical trials (RCTs) investigating the effect of ACH after RC in patients with MIBC have been performed [13, 14, 15, 16, 17, 18], the effects of ACH for management of MIBC remains controversial [7]. There have been several meta-analysis evaluating the effects of ACH on MIBC patients [6, 8, 9], but no study has evaluated the effects of ACH on locally advanced MIBC. Moreover, MIBC reflects very broad disease status, and locally advanced MIBC (pT3+ and/or pN+) is known to exhibit much poorer prognosis than localized MIBC (pT2pN0). For these reasons, we aimed to examine the effects of ACH on improvement of survival outcomes in patients with locally advanced MIBC following RC.

ACH has been used to manage MIBC, to eradicate micrometastatic lesions, and to enhance postoperative survival outcomes [27, 28, 29]. The main advantage of ACH after RC is that after assessing pathologic primary tumor and regional lymph node categories, clinicians can choose patients with highest risk for recurrence who are most likely to benefit from ACH without delay in definitive treatment. Several RCTs have been performed to investigate the effects of ACH in patients with MIBC [14, 26, 30, 31, 32, 33, 34]. Meta-analyses have found statistically significant evidence for the benefits of ACH use for OS and PFS in these patients [6, 8, 9]. However, these studies had limitations, such as small sample sizes, early patient entry interruption, analysis and terminology confusion, and questionable interpretation of results [35, 36]. We focused on trials regarding the effect of ACH on locally advanced MIBC patients only, and conducted a meta-analysis of these papers through systematic review.

We found a positive benefit of ACH on PFS and OS compared to no ACH, following RC in patients with locally advanced MIBC. We reported a 52% relative risk reduction in progression and a 48% reduction in the risk of death. Leow et al. [9] used a meta-analysis to examine the effects of adjuvant cisplatin-based chemotherapy after RC in patients with MIBC. They found that ACH improves disease-free survival and OS rates by 34% and 22%, respectively. Vale et al. [8] also found that ACH improves disease-free survival and OS rates of patients with MIBC by 32% and 25%, respectively. After comparing these results with ours, we found that our analysis showed ACH may be more effective in locally advanced MIBC patients than in MIBC patients. This study supports the possibility that beneficial effects of ACH may be greater for locally advanced MIBC patients.

Another difference between previous meta-analyses [6, 8, 9] and ours was the exclusion of conference abstracts. The two conference abstracts included in previous meta-analyses have not been fully published [31, 32]. Results published in abstracts were often very different from the results published in full-length articles; abstracts were generally not subjected to the strict peer review process typically required for journal articles. Therefore, unconfirmed bias may have affected the results of systematic reviews, including abstracts [37]. The Agency for Healthcare Research and Quality does not recommend the use of conference and meeting abstracts for evaluating selective outcome reporting and selective analysis reporting, given the variability in degree of agreement between conference abstracts and their subsequent full-text publications [38].

Our study did have some limitations. Since access to individual patient data was not possible, additional survival analyses could not be performed for similar covariates. There were also some between-trial differences in definitions of the endpoints (PFS and OS). Two trials defined it as time from RC until the earliest occurrence of relapse or death from any cause [14, 26]. Other trials defined it as the time from randomization [15, 18]. Another important limitation in this study was that the defects from earlier trials could have affected the outcomes. Two trials were discontinued early due to beneficial interim results [14, 15], which could have affected the results of a later meta-analysis [8]. In two trials, approximately one-quarter of the patients randomized to treatment group did not receive chemotherapy [15, 26]. Lehmann et al. [15] also had serious methodological fault. Most of control group patients with disease progression did not receive chemotherapy for recurrence; one-third of treatment group patients also did not receive chemotherapy [9]. The most significant effect of these design flaws was likely dilution of the positive and negative effects of chemotherapy.

Level 1 evidence supports the use of NAC to improve OS of patients with MIBC, but adoption rates remain low [39]. Cowan et al. [10] used a survey to determine factors related to NAC use, define reasons for low utilization, and the current rate of NAC use among urologic oncologists. They found NAC adoption rates between 30% and 57%, although the urologic oncologists discussed NAC with >90% of their patients and medical oncologists recommended NAC. Among major concerns regarding the use of NAC, age and comorbidities accounted for the greatest proportion, followed by delay in surgery, marginal benefit, prolonged diagnosis and referral, better adjuvant therapy choices, too toxic for surgical patient, and risk of surgical complications. The use of NAC can have negative effects on assessing response to therapy, due to discrepancies between interpretation of clinical and pathologic stages; patient is then more likely to receive unnecessary treatment. Despite the availability of level 1 evidence, use of NAC and ACH for bladder cancer (BCa) remains low [9, 40, 41]. Expectedly, chemotherapy use is even lower for upper tract urothelial carcinoma (UTUC), due to the absence of corresponding strong evidence [42]. Therefore, the outcome of ongoing Phase II/III clinical trial was enthusiastically anticipated, and perioperative chemotherapy versus surveillance in upper tract urothelial cancer (POUT) trial recently published the results [43]. POUT trial addresses whether ACH improves survival for patients with locally advanced or node-positive UTUC (pT2-T4, N0-3, M0). POUT trial provides a high-level of evidence for the added value of ACH in patients with locally advanced or node-positive UTUC. However, this trial was prematurely discontinued by the safety monitoring committee, due to significant improvement in disease-free survival [43]. In addition, this trial may be limited due to inadequate stratification of local or locoregional disease [42].

The National Comprehensive Cancer Network (NCCN) guidelines suggest that ACH may be given to patients with high-risk pathology who did not receive NAC (category 2A recommendation) [44]. That is, based on relatively low-level evidence, there is unified NCCN agreement that intervention is appropriate. In patients with pT3-4 and/or N+M0 disease, 5-year survival rate after RC is only 30% at most. As a result, ACH was administered to high-risk patients to delay relapse and prolong survival [45]. This approach of administering chemotherapy after local treatment increases survival in patients with many different solid tumors [46, 47]. It also prevents overtreatment for patients who are suspected of having a reasonable outcome with only surgery, that is, those with tumor localized to the bladder [45]. A more sophisticated analysis of molecular prognostic and predictive markers by available sufficient tissue is also an advantage. If micrometastases are present, a clinician can treat them when they are at a low volume rather than waiting for an overt metastatic disease [45]. ACH also has disadvantages of delayed treatment for micrometastatic disease, and results in limitation of administration of chemotherapy due to postoperative morbidity [48]. There is no accurate answer to the question of whether ACH is less effective than NAC, as they both have advantages and disadvantages. No study directly compares the effects of both. Yin et al. [49] found that NAC is associated with a survival benefit (absolute increase of 8% OS), which is equivalent to a number needed to treat of 12.5. We calculated the absolute increases in OS by ACH in MIBC patients using a study by Leow et al. [9], and found a 4% increase in results (i.e., numbers needed to treat, 25). Our study found that the absolute increases in OS for use of ACH in patients with locally advanced MIBC was 10%, respectively (i.e., numbers needed to treat, 10). Although ACH, when used for all MIBC patients, seems to have a marginal benefit (4% increase), overtreatment is a concern (number needed to treat, 25). However, if ACH were offered only to patients with locally advanced MIBC, the number needed to treat using ACH may be lower than that of NAC (10 versus 12.5). Therefore, a larger collaborative international and well-designed RCT will be needed to determine the true value of postoperative chemotherapy. The effects of ACH and NAC in patients with MIBC or locally advanced MIBC should also be compared.

Over the past 30 years, there has been no significant progress in the treatment of metastatic BCa, and chemotherapy is still the standard of care [50]. However, advances in the perception of pathophysiology provided by comprehensive genomic profiling of BCa may greatly improve the outcomes of this malignancy [51]. The relevance of PD-1 blockade in urothelial cancer has been recently confirmed by a phase I study to evaluate a human monoclonal antibody directed against PD-L1 (MPDL3280A), including 67 patients with metastatic BCa [52]. This trial verified the checkpoint PD-1 pathway as a promising therapeutic target in BCa [53]. Rapidly evolving knowledge of urothelial carcinoma pathophysiology and identified fundamental molecular alterations will provide the basis for new therapies, and apply new therapeutic effects through a well-designed trial.

Our meta-analysis of four RCTs found that ACH may provide benefits for PFS and OS in patients with locally advanced MIBC who received ACH after RC, compared to those who underwent surgery alone. Our results, compared to previously reported meta-analysis, suggest that beneficial effects of ACH may be greater in patients with locally advanced MIBC patients than in those with MIBC.