The Role of Neoadjuvant Chemotherapy in Bladder Preservation Approaches in Muscle-Invasive Bladder Cancer

At diagnosis, although most patients will present with non-muscle-invasive bladder cancer (NMIBC), approximately 25% will have muscle-invasive bladder cancer (MIBC).1 MIBC is a highly aggressive chemo-sensitive disease with nearly 50% of patients developing metastatic disease, likely owing to the presence of micrometastases at diagnosis.1 For this reason, a multidisciplinary approach to MIBC consisting of chemotherapy combined with local therapies is the key to optimizing outcomes and improving overall survival.

The mainstay of systemic treatment for patients with MIBC has traditionally been neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy (RC) with bilateral pelvic lymph node dissection.2 This is based on the randomized Phase III study by Grossman et al, showing a survival advantage for patients treated with neoadjuvant MVAC (methotrexate, vinblastine, adriamycin, cisplatin) followed by RC, compared with RC alone (77 vs 46 months,p = 0.06 by a 2-sided stratified log-rank test). In both groups, a complete pathological response was associated with improved overall survival, and this occurred more frequently in the neoadjuvant arm (38 percent vs 15 percent, p < 0.001).3 Similarly, the long-term results of the BA06 30894 trial, which will be discussed in more detail below, also documented a significant 16% reduction in the risk of death with neoadjuvant chemotherapy given either prior to surgery or radiation (HR, 0.84; 95% CI, 0.72-0.99; p=0.037).4

Dose dense MVAC (ddMVAC), which is similar to MVAC, but administered every 2 weeks with growth factor support, has also been studied in phase II clinical trials in the neoadjuvant setting, and has shown comparable efficacy, shorter duration of administration and better tolerance when indirectly compared with classic MVAC.5,6 Extrapolating from the metastatic setting, another commonly used neoadjuvant regimen is gemcitabine and cisplatin (GC). GC showed similar efficacy but better tolerability compared to classic MVAC. In the neoadjuvant setting, a retrospective multicenter study has shown that neoadjuvant GC and MVAC achieved comparable pCR rates providing further evidence to support its use in this setting.7

The first and only prospective randomized Phase 3 study in the perioperative setting to directly compare ddMVAC (6 cycles) and GC (4 cycles) is the GETUG/AFU V05 VESPER study. This study showed a statistically significant overall survival benefit for ddMVAC compared to GC, in the subset of patients treated in the neoadjuvant setting (HR 0.66, 95% CI 0.47-0.92).8 Despite these encouraging results, ddMVAC was associated with a higher toxicity and may not be the ideal choice for older patients or those with significant comorbidities, where GC would still be preferred. Currently all guidelines on the management of MIBC recommend neoadjuvant cisplatin-based combination chemotherapy for patients undergoing RC.

Despite being widely recommended, RC can be associated with significant perioperative risk as well as diminished quality of life due to urinary, gastrointestinal, and sexual dysfunction.9,10 Combined modality approaches using maximal transurethral resection of the bladder tumor (TURBT) followed by chemoradiation commonly referred to as bladder preservation (BP), is an established treatment option for patients who are medically unfit for RC or for patients that would otherwise be candidates for RC but are seeking non-surgical alternatives. For carefully selected patients who are otherwise surgical candidates, Kulkarni et al have shown that BP appears to result in similar oncologic outcomes compared to RC. Recently, the NCCN 2020 guidelines were updated to incorporate BP as a category 1 recommendation for the primary treatment of MIBC.11

Until recently, most patients undergoing BP tended to be elderly and frail with multiple comorbidities that precluded both RC and cisplatin-based NAC. However, it is very important to recognize that the demographics of patients receiving BP in 2022 is rapidly changing - with more and more patients who are fit, healthy and potentially eligible for cisplatin-based NAC opting for BP. Also, with modern anti-emetics and growth factor support, cisplatin-based NAC chemotherapy in the modern era is much better tolerated than it used to be, significantly lowering the threshold of patients who can potentially receive it. NAC works primarily by eliminating micrometastases and preventing distant recurrences and has shown an overall survival benefit in the context of RC12, 13, 14 and especially in patients achieving a complete pathological response. Since distant recurrences after BP approaches are similar to that seen with RC (in the range of 22-39%),15, 16, 17 the rationale for using NAC prior to BP is also applicable.

One of the first studies to address the question of NAC prior to bladder sparing approaches was the nonrandomized phase II RTOG 8802 study.18 This study enrolled 91 T2-4N0M0 patients from 1988 to 1990, who received 2 cycles of neoadjuvant MCV (methotrexate (30 mg/m2), cisplatin (70 mg/m2), and vinblastine (3 mg/m2)) followed by once-daily RT to 39.6 Gy with concurrent cisplatin (70 mg/m2 every 3 weeks). RTOG 8802 showed that NAC followed by BP was feasible and effective yielding similar survival outcomes to RC, forming the basis of the RTOG 8903 phase III randomized study.

RTOG 8903 assigned 123 patients, from 37 centers, between 1990 and 1992, with T2-4 NX M0 MIBC to 2 cycles of neoadjuvant MCV versus no MCV, followed by once-daily pelvic RT to 39.6 Gy and 2 cycles of concurrent cisplatin (100 mg/m2 given 3 weeks apart).15 Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and 1 additional dose of cisplatin. Those with less than a CR underwent cystectomy. After a median follow-up of 60 months there were no significant differences in pCR rate, or OS between the arms.

However, there are a number of important caveats related to the interpretation of these results. First, this study was stopped early, reaching only 71% of its expected accrual target (123/174), and was likely underpowered to show a difference between arms. By comparison, the Grossman study3 which showed an overall survival benefit of NAC prior to RC, accrued 317 patients; and the ABC meta-analysis which also showed a 5% absolute OS benefit from NAC, was based on patient-level data from 3005 trial patients.12 In RTOG 8903, only 67% of patients in the NAC arm actually completed treatment (due to high rates of neutropenia and sepsis), compared to 81% completing treatment in the arm without NAC.15 This led to a protocol amendment where better baseline renal function was required at study entry, which led to reduced rates of sepsis, and serves to highlight the critical importance of careful patient selection and supportive strategies when evaluating chemotherapy-based approaches in MIBC.

It should also be mentioned that MCV is not currently a standard regimen in MIBC and that typically patients receive 4 cycles of NAC with modern anti-emetics and growth factors. The latter has made contemporary NAC regimens much more tolerable with less severe hematological toxicities and raises the question of whether repeating this study with more patients, contemporary NAC regimens and enhanced supportive measures may have a different result.

Another phase III study, the BA06894, randomized 976 MIBC patients from 1989 to 1995, to receive 3 cycles of MCV or no MCV prior to their choice of surgery or radiotherapy (without radiosensitizing chemotherapy).4 After a median follow up of 8 years there was a statistically significant increase in the OS favoring the NAC arm (HR 0.84; 95% CI, 0.72-0.99; P = 0.037), translating into an increase in 10-year survival from 30% to 36%.18 NAC reduced the risk of death by 26% for patients who received RC and by 20% for patients who received radiotherapy alone. Based on a pre-planned interaction analysis, there was no evidence to suggest that the effect of NAC was impacted by the local definitive management. There was however an imbalance in baseline patient characteristics between arms, where patients in the radiotherapy arm were older and frailer, but despite this still benefited from NAC. It is unclear if the benefit of NAC would change if patients had received concurrent chemoradiotherapy, which is currently the standard of care for BP approaches4 (Table 1).

More recent retrospective reports have evaluated and confirmed both the safety and efficacy of NAC followed by concurrent chemoradiation, with CR, OS, and cancer-specific survival (CSS) rates ranging from 73% to 86%, 68% to 72%, and 76% to 79%, respectively.19, 20, 21, 22 In the BC2001 prospective trial 117 patients received NAC (mostly platinum-based regimens) and then were randomized to radiotherapy (48%) or concurrent chemoradiation with MMC-5FU (52%).23 NAC did not compromise the delivery of radical curative treatment; and despite the use of NAC, concurrent chemoradiation still showed a non-significant trend to improved locoregional disease control over radiation alone. Taken together, this data suggests that NAC and concurrent chemotherapy may improve outcomes independently in MIBC, by targeting micrometastases and local disease respectively.

Similar results were also seen in a prospective cohort study by Thompson and colleagues.24 In this study, patients were selected for NAC on the basis of performance status, comorbidities and renal function; all patients received 3-6 cycles of platinum-based therapy followed by concurrent chemoradiation with gemcitabine as the radiosensitizer. Of the 78 patients, 38 received NAC and 40 did not. There was no additional toxicity seen in the NAC arm, treatment completion rates were acceptable and DFS and OS were similar. The performance-status-based patient selection for NAC is used in many UK cancer centers today, similar to selection criteria for NAC prior to RC. The use of NAC followed by BP is supported by UK national guidelines, published in 2015 based on the results of BA06 30894, in which NAC is recommended regardless of the local therapy of choice – RC or BP. This is in stark contrast to the NCCN guidelines which do not discuss NAC prior to concurrent chemoradiation.11

Since contemporary NAC in appropriately selected patients, using standard platinum-based regimens is well tolerated, some leading North American institutions have also started to incorporate this strategy into their standard clinic protocols. A retrospective analysis from the Princess Margaret Cancer Center, reported on 57 MIBC patients who were treated initially with 2-4 cycles of GC, then evaluated by a multidisciplinary team to determine tumor response using imaging and cystoscopy.16 Patients with stable disease or clinical response received concurrent chemoradiation with weekly cisplatin 40 mg/m2 for 6 weeks. Most patients (95%) completed planned NAC though about half required dose reductions or delays, but still suggesting better tolerance than CMV or MVAC. All patients completed radiation therapy, and 84% completed at least 60% of the planned concurrent weekly cisplatin doses. Despite the fact that patients were elderly, a quarter had hydronephrosis and mean tumor size was 4cm, bladder-intact and OS curves were remarkably similar to both surgical series and RTOG bladder preservation series. Of note, presence of hydronephrosis was a significant factor affecting OS but not bladder preservation rates, whereas presence of residual disease in the bladder after NAC was associated with an almost 5-fold higher risk of in-bladder recurrence. Most relapses were locoregional and distant relapse rates were lower than what was observed in other series, occurring in only 11% of patients,16 which underscores the possible benefit of NAC in treating occult micrometastases.

In selecting patients for NAC followed by BP, it is important to ensure adequate renal function so patients can receive cisplatin-based treatment, which is superior to carboplatin-based approaches.25 A recently published algorithm provides important guidance in assessing cisplatin- eligibility specifically in MIBC, and can be applied regardless of local definitive management.26,27 Since many patients do respond to NAC, with a proportion even having a CR, some patients who would initially not be considered suitable for BP, may become eligible after NAC, and be spared from having a RC.12 In the Jiang study, a number of patients had higher risk disease features prior to NAC, including 25% with hydronephrosis, 28% with CIS and 11% with nodal metastasis, and yet the study still described encouraging results, comparable with RC series.16 Finally, there is likely no better way to select patients for BP than based on tumor biology, and response after NAC. Since absence of response negatively impacts outcomes with BP,28, 29, 30 the use of both imaging and cystoscopic evaluation is important to accurately determine response post NAC.16

There have been significant advances in the field of bladder cancer over the last 5 years. In particular, the immune checkpoint inhibitors (ICI), antibody drug conjugates and FGFR inhibitors have revolutionized treatment in advanced disease. These drugs are now being evaluated in earlier disease settings.31,32 For example, in cisplatin-ineligible MIBC patients, neoadjuvant ICI monotherapy has shown pCR rates ranging from 31% to 38%, in patients undergoing RC.33, 34, 35 This response rate is similar to the overall response rates but superior to the pCR rates observed with carboplatin-based regimens.25,36 Despite an unpredictability of late immune-related side effects, in general neoadjuvant ICIs were well tolerated. These results have in part paved the way for other neoadjuvant trials in cisplatin-eligible and ineligible MIBC patients combining chemotherapy and ICIs, or combining antibody drug conjugates and ICIs.37,38 Although these trials initially focused only on patients undergoing RC, newer trials are beginning to incorporate patients undergoing BP approaches as well. If these novel strategies do increase response rates and specifically pCR rates, some MIBC patients may not require any local therapy at all, and a number of ongoing studies are underway addressing this important question (Table 2).

There have also been recent advances in our understanding of bladder cancer at the molecular level. There are now 4 independent classification systems, with broad similarities between them and 2 major subtypes in common, luminal, and basal. Prognosis and response to chemotherapy have varied among subtypes,39 therefore future prospective studies taking molecular classification into consideration are important and may help further selecting patients for the most appropriate treatment strategy.

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