REVIEW URRENT C OPINION
Perioperative chemotherapy for muscle invasive bladder cancer Jan K. Rudzinski a, Naveen S. Basappa b, and Scott North b
Purpose of review Radical cystectomy with or without systemic chemotherapy is considered a standard of care for patients with muscle invasive bladder cancer (MIBC). The purpose of this review is to provide an update on current and recent literature published within the last 12 months reviewing the evidence for use of perioperative chemotherapy for patients with MIBC. Recent findings In the neoadjuvant chemotherapy (NAC) setting, the evidence demonstrates clinical efficacy and lower rate of toxicity with the use of high-dose methotrexate, vinblastine, doxorubicin, and cyclophosphamide (MVAC) compared with standard MVAC. Higher quality evidence for the use of gemcitabine with cisplatin is not yet available. Meta-analysis of cisplatin-based regimens in the adjuvant setting demonstrates significant benefit in overall survival and disease-free survival specifically in patients with lymph-node-positive disease. Summary The available evidence suggests that along with radical cystectomy, cisplatin-based perioperative chemotherapy should be the standard of care in patients with MIBC with a higher quality and quantity of literature in support of the NAC approach. Adoption of perioperative chemotherapy for MIBC is on the rise in North America, which is reassuring. Novel therapeutic approaches for cisplatin-ineligible patients are currently being investigated. Keywords cisplatin, muscle invasive bladder cancer, perioperative chemotherapy, radical cystectomy
INTRODUCTION Globally, bladder cancer is the ninth most common cancer with more than 330, 000 cases diagnosed annually and more than 30 000 deaths [1]. Most cases are transitional cell carcinoma (TCC), which will be the focus of this review [1,2 ,3,4]. Approximately, 20–30% of newly diagnosed patients will have muscle invasive bladder cancer (MIBC) defined as T2-T4 disease [1,2 ]. Despite surgical management with radical cystectomy, 50% of patients will develop tumor recurrence [4,5]. Mounting evidence suggests that perioperative chemotherapy administration for MIBC improves progression-free survival (PFS) and overall survival (OS). Neoadjuvant chemotherapy (NAC) has demonstrated survival benefit in patients with MIBC [6–13]. Early data to support the use of NAC comes from two Nordic trials [6–8], a combined UK Medical Research Council/European Organization of Research and Treatment of Cancer (MRC/EORTC) trial [9], and the South West Oncology Group (SWOG 8710) intergroup trial from the USA [10]. These studies enrolled patients with T2-T4a N0M0 &
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TCC disease treated with various cisplatin-based chemotherapeutic regimens. However, the OS benefit with NAC is modest. The MRC/EORTC trial consisting of 976 patients evaluated three cycles of NAC (cisplatin, methotrexate, and vinblastine) followed by radical cystectomy or radiation therapy [9]. In this study, the absolute 5year OS improvement was 5.5% (P ¼ 0.075) [9]. These results were not statistically significant initially but with further follow up, the trial is now positive with an absolute OS benefit of 6% at 10 years [9,14]. The SWOG 8710 trial was composed of 317 patients and evaluated patients who were a Division of Urology, Department of Surgery and bDivision of Medical Oncology, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
Correspondence to Scott North MD, FRCPC, Division of Medical Oncology, Department of Oncology, University of Alberta, Edmonton, Canada, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada. Tel: +17804328221; e-mail: [email protected] Curr Opin Support Palliat Care 2015, 9:249–254 DOI:10.1097/SPC.0000000000000148
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KEY POINTS Administration of perioperative chemotherapy for muscle invasive bladder cancer (MIBC) leads to improvements in overall survival (OS) for patients with MIBC. Emerging trials looking at neoadjuvant chemotherapy are focused on finding the optimal cisplatin-based regimen to provide the greatest benefit in OS with the most reasonable toxicity profile. Further research is required to best identify the cohort of patients that would be most benefit from adjuvant chemotherapy. Across North America, the use of perioperative chemotherapy for patients with MIBC is increasing. Novel therapeutic approaches for cisplatin-ineligible patients are currently being investigated.
randomized to methotrexate, vinblastine, doxorubicin, and cyclophosphamide (MVAC) followed by radical cystectomy versus radical cystectomy alone [10]. This trial demonstrated 14% improvement in OS at 5-years but with only a trend toward statistical significance in the NAC cohort (P ¼ 0.06) [10]. In addition, three separate meta-analyses composed of around 3000 patients each showed statistically significant absolute improvements in 5-year OS between 5 and 6.5% [11–13]. Currently, based on existing data, there is strong evidence to support NAC using a cisplatin-based combination in patients with MIBC. However, chemotherapy also carries the risk of significant toxicities. The SWOG 8710 reported that 73% of patients exposed to MVAC experienced more than grade 3 toxicities [10]. Attempts to find similarly effective regimens with less toxicity have been undertaken, such as the high-dose MVAC (HDMVAC) regimen administered every two weeks with growth factor support [3]. Research has also focused on combination chemotherapy with carboplatin, which is a less toxic platinum alternative. The existing evidence for the use of carboplatin-based regimens comes from small retrospective as well as prospective trials that are underpowered and demonstrate no significant difference in pathologic or survival outcomes compared with MVAC [15–20]. Therefore, the routine use of carboplatin-based regimens is not recommended at this time. There are many controversies surrounding NAC. One controversy pertains to optimal patient selection. There is an argument to reserve NAC for patients with higher stage disease as absolute OS benefit with NAC tends to be greater in those with at 250
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least T3 disease [6,10,12]. In addition, there are proponents who would argue that within the clinical T2 (cT2) cohort, NAC should be reserved for patients with higher risk features such as those with presence of hydronephrosis and/or lymphovascular invasion [21,22]. However, clinical staging is inaccurate with 43–70% of cT2 patients being upstaged on final pathology review [23–26]. Thus, excluding all cT2 patients from NAC could result in denying some higher risk patients treatment. Another debate revolves around the optimal NAC regimen. The use of MVAC or cisplatin, methotrexate, and vinblastine is considered a gold standard [9,10]. However, these regimens have been associated with unfavorable toxicity profile such as severe neutropenia, mucositis, renal, and cardiac toxicity, as well as toxic death rate of 3–4% [9,10]. In a trial of gemcitabine and cisplatin compared with MVAC, von der Maase et al. [27] reported similar efficacy and better tolerability with the use of gemcitabine and cisplatin compared with MVAC in patients with metastatic disease. Many oncologists extrapolated these data to the neoadjuvant setting [28 ]. However, the use of gemcitabine and cisplatin has not been prospectively studied in a randomized fashion and most of the evidence for its use in neoadjuvant setting comes from small single center retrospective studies or prospective case series [29 ]. Although there is no strong evidence suggesting increased surgical complication rates in those receiving NAC, there has been an argument that patients may be unnecessarily subjected to delays in definitive local therapy if they receive NAC that ends up being ineffective [3,10,30–32]. Unfortunately, there are currently no good tools to predict response to NAC [33]. Although some clinicians may employ repeat imaging or cystoscopy assessment, these are imperfect tests. Thus, failure to be able to predict who will most benefit from NAC remains one of the most important reasons to argue against its routine use. An alternate strategy to NAC is adjuvant chemotherapy administered after radical cystectomy. Despite a lack of strong data supporting clinical efficacy associated with adjuvant chemotherapy use, large multiinstitutional reviews from the USA and Europe demonstrate that more patients tend to receive adjuvant chemotherapy compared with NAC [34,35]. The existing evidence for the use of adjuvant chemotherapy is best summarized by the Advanced Bladder Cancer Meta-analysis collaboration study, which pooled six randomized controlled trials with 491 patients and demonstrated 25% relative reduction in the risk of death with absolute improvement in OS of 9% at 3 years [36,37]. However, these conclusions are limited by &
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the quality of the data used to perform the analysis. Perceived advantages of adjuvant chemotherapy include immediate definitive local therapy, lack of overtreatment of patients with good risk pathology, and that therapy could be tailored to individualized pathology [38]. Disadvantages of adjuvant chemotherapy are that it delays administering systemic therapy to deal with potential micrometastases and some patients have delayed postoperative healing such that they never have the chance to receive adjuvant chemotherapy. Finally, similar to NAC, there is no definitive way to know, which patient will benefit [38]. Despite the existing evidence suggesting that perioperative chemotherapy should be the standard of care in MIBC population, the reported concordance with clinical practice guidelines is estimated to be around 11.3–20% in North America [39– 42,43 ,44 ]. Potential reasons for its underuse are the perception of increased morbidity and toxicity of chemotherapy, modest survival benefit, delay in definitive local therapy, and concerns over the quality of data especially for adjuvant chemotherapy [39–42,43 ,44 ]. In addition, approximately, 40% with MIBC are also cisplatin ineligible mainly due to impairment in renal function [45]. Currently, the vast majority of perioperative MIBC research focuses on selection of more efficacious cisplatin-based regimens with limited number of studies looking at patients who are cisplatin ineligible [46]. &&
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REVIEW OF STUDIES Effectiveness of perioperative chemotherapy To compare the reported efficacy of NAC to its clinical effectiveness in Canada, Booth et al. [43 ] undertook an Ontario-based retrospective study aimed at evaluating the external validity of the clinical trial results for administration of perioperative chemotherapy. This retrospective analysis looked at 2044 patients who underwent definitive therapy for MIBC between 1994 and 2008. The reported 5-year OS of patients who received NAC was 26%. This differs from reported 5-year OS rates from published trials that ranges from 49 to 57% [10,14]. However, they did demonstrate that OS in the group receiving perioperative chemotherapy was superior to the group that did not receive it. &&
Neoadjuvant chemotherapy The emerging platinum-based alternatives There have been two recent prospective multicenter phase II trials that investigated the efficacy of
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HD-MVAC in the neoadjuvant setting [28 ,47 ]. In the first trial by Plimack et al. [28 ], the authors enrolled 44 patients with T2c–T4a N0-1 disease to establish whether HD-MVAC with pegfilgrastim can achieve similar rates of pathologic response to standard MVAC. The authors compared the prospectively obtained pathologic complete response rates with retrospective experience of MVAC. This study demonstrated that patients who received HD-MVAC experienced about 38% pathologic T0 rate with another 14% of patients being downstaged to nonmuscle invasive disease. When comparing the baseline clinical stage to final pathologic stage, 65% of patients were downstaged after NAC. In a second trial by Choueri et al. [47 ], the authors enrolled 39 patients with clinical T2-T4 N0-1 M0 MIBC. Patients were treated with four cycles of HD-MVAC followed by radical cystectomy. This trial found that 49% of patients achieved pathologic down staging with one-year disease-free survival (DFS) of 89%. Of particular importance is that 26% of patients achieved complete pT0 rate, and only 10% of patients experienced high-grade toxicity with no episodes of treatment-related death. Despite the small number of patients enrolled, these trials suggest that HD-MVAC achieves similar pT0 rates to standard 12-week MVAC regimen with lower rate of high-grade toxicities. As the existing evidence for the use of gemcitabine and cisplatin as a neoadjuvant regimen is confined to small retrospective single center trials or case series, there are two-registered phase III trials attempting to compare neoadjuvant gemcitabine and cisplatin with HD-MVAC [46,48]. One trial is being conducted by University Hospital in Rouen, France [49], whereas the second study is led by the SWOG group in the USA [48]. The results from these studies aim to provide higher quality evidence for the use of gemcitabine and cisplatin in the neoadjuvant setting. &
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Effect of neoadjuvant chemotherapy on surgical outcomes One of the reported limitations of the use of NAC is the perceived risk of adverse perioperative outcomes. To specifically investigate the effect of NAC on perioperative outcomes in patients who underwent radical cystectomy, Gandaglia et al. [50 ] conduced a retrospective database review of 3760 patients diagnosed with MIBC between 2000 and 2009. There was no significant difference in rates of transfusions, length of stay, hospital readmission rates, and mortality between both groups. Chau et al. [51 ] investigated the clinical outcomes following neoadjuvant cisplatin-based chemotherapy in the elderly to determine whether age is a &
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factor in determining tolerance and response to chemotherapy. This was a single institution retrospective case series analysis of 83 patients with median age of 68 with T2-T4a N0M0 TCC who were treated with gemcitabine and cisplatin between 2005 and 2011. Overall, the study found that elderly patients with good functional status and limited comorbidities have similar outcomes to their younger counterparts receiving NAC. Risk adapted approach to neoadjuvant chemotherapy Culp et al. [52 ] have reported on whether a riskadapted approach can be used to select higher risk patients for NAC, thus, sparing low-risk patients from toxicity. This was a single center retrospective analysis of 1285 patients who underwent radical cystectomy between 2000 and 2010. The presence of high-risk features was defined as the presence of hydroureteronephrosis, clinical T3b-T4a disease, and/or histological evidence of lymphovascular invasion. Overall, patients in the high-risk group had statistically worse 5-year OS, PFS, and diseasespecific survival, and when compared with low-risk patients (P < 0.001). However, within the low-risk cohort, 49.2% of patients had pathological upstaging of their disease, underscoring the problems of clinical staging. Given the challenges in clinical staging and the high rate of being upstaged at final pathology, this risk-adapted approach has not been widely adopted. &
relapse. Overall, administration of immediate adjuvant chemotherapy did not lead to significant improvement in OS (P ¼ 0.13), but was associated with significant improvement in prolonging 5-year PFS. Unfortunately, this trial was limited by a small sample size and was underpowered to detect an OS difference. In the context of existing evidence, these articles strengthen the role of adjuvant chemotherapy in MIBC. However, to improve the quality of the available data and provide better guidance to clinicians, future trials should focus on an individualized patient data meta-analysis to better elucidate the benefit of adjuvant chemotherapy in this setting.
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Hsu et al. [55 ] surveyed academic urologists and medical oncologists across Canada to better understand the factors that influence the decisions to recommend NAC for MIBC. Among the 51 respondents across Canada, the authors found that key considerations in recommending NAC were performance status, presence of comorbidities, and renal function. Also, a US retrospective cohort analysis by Reardon et al. [56 ], has shown that the use of NAC significantly increased from 10.1 to 20.1% (P ¼ 0.005) between 2006 and 2010. The multivariable analysis demonstrated that advanced age, increased number of comorbidities, geographic location, and low income was associated with lower utilization of perioperative chemotherapy. &
Adjuvant chemotherapy To further improve the statistical power of the existing data on cisplatin-based adjuvant chemotherapy, Loew et al. [53 ], conducted an updated metaanalysis from nine randomized clinical control trials, which demonstrated a statistically significant benefit in OS and DFS specifically in patients with lymph-node-positive disease. The largest prospective trial for adjuvant chemotherapy is the EORTC 30994 trial published by Sternberg et al. [54 ] in December 2014. This was a large open label, multicenter randomized phase III trial, which planned to recruit 660 patients with pathologic T3-T4 or NþM0 TCC to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy and bilateral pelvic lymph node dissection. In this trial, which was terminated early, only 284 participants were accrued between 2008 and 2010. Patients were randomized to either four cycles of adjuvant chemotherapy within 90 days of surgery (gemcitabine and cisplatin, MVAC, or HD-MVAC based on institutional preference) or six cycles of chemotherapy at &
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Novel approaches There are currently multiple phase II trials investigating the role of targeted therapy in the perioperative setting [46]. Interesting results have been seen with the use of erlotinib [57], and dasatinib [58,59] monotherapy preradical cystectomy, and with bevacizumab [60] and sunitinib [61] in combination with cisplatin-based chemotherapy. However, to firmly delineate the potential benefit of these agents we need to await phase III clinical trials.
CONCLUSION The role of perioperative chemotherapy for MIBC has been well established with the strongest literature in support of NAC. The optimal regimen is not known but cisplatin-based combination therapy should be the standard. Although perioperative chemotherapy use is still low, it is encouraging to see a trend toward increased use of chemotherapy in this setting. And increased adherence to clinical practice guidelines. Future research will need to focus on Volume 9 Number 3 September 2015
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how to manage cisplatin ineligible patients and explore how new therapeutic agents, such as molecular and immune-targeted therapies and biologics, may play a role in the MIBC-patient population. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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51. Chau C, Wheater M, Geldart T, et al. Clinical outcomes following neoadjuvant cisplatin-based chemotherapy for bladder cancer in elderly compared with younger patients. Eur J Cancer Care (Engl) 2015; 24:155–162. This report is important as it demonstrates that elderly patients can similarly benefit from chemotherapy as opposed to younger counterparts. 52. Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for & neoadjuvant chemotherapy before radical cystectomy. J Urol 2014; 191:40– 47. This retrospective trial evaluated the survival of patients with low risk versus highrisk MIBC features. This study suggests that only patient with high risk features with poor prognosis should be exposed to NAC. 53. Loew JJ, Matin-Doyle W, Rajagopal PS, et al. Adjuvant chemotherapy for & invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 2014; 66:42–54. This updated meta-analysis covers the recent evidence in support of adjuvant chemotherapy in MIBC. 54. Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred && chemotherapy after radical cystectomy in patients with pT3-T4 or NþM0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open label, randomized phase 3 trial. Lancet Oncol 2015; 16:76–86. This is a largest randomized trial of adjuvant chemotherapy in MIBC patients. It showed that immediate chemotherapy after radical cystectomy led to significant improvement in PFS with no improvement in OS. 55. Hsu T, Black PC, Chi KN, et al. Treatment of muscle-invasive bladder cancer in & Canada: a survey of genitourinary medical oncologists and urologists. Can Urol Assoc J 2014; 8 (9–10):309–316. This report is important as it was a real-world survey of what is being done in Canada for MIBC and how the data are being interpreted and implemented by treating oncologists. 56. Reardon ZD, Patel SG, Zaid HB, et al. Trend in the use of perioperative & chemotherapy for localized and locally advanced bladder cancer: a sign of changing tides. Eur Urol 2015; 67:165–170. This review highlights international adherence to guidelines and implementation of perioperative chemotherapy for MIBC. 57. Pruthi RS, Nielsen M, Heathcote S, et al. A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results. BJU Int 2010; 106:349– 352. 58. Hahn NM, Daneshmand S, Posadas EM. A phase II trial of neoadjuvant dasatinib (Neo-D) in muscle-invasive urothelial carcinoma of the bladder (miUCB): Hoosier Oncology Group GU07-122 trial [abstract]. J Clin Oncol 2012; 30:. (Suppl):abstract 4586. 59. Knudsen B, Hahn NM, Daneshmand S, et al. Biologic activity of dasatinib administered as neoadjuvant therapy preceding radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) [abstract]. J Clin Oncol 2014. 32(Suppl): abstract 324. 60. Chaudhary UB, Golshatan AR, Brisendine A, et al. Phase II trial of neoadjuvant cisplatin, gemcitabine, and bevacizumab followed by radical cystectomy (RC) in patients with muscle-invasive transitional cell carcinoma (TCC) of the bladder [abstract]. J Clin Oncol 2011. 29(Suppl):abstract 276. 61. Galsky MD, Hahn NM, Powles T, et al. Gemcitabine, Cisplatin, and Sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscleinvasive bladder cancer. Clin Genitourin Cancer 2013; 11:175–181. &
Volume 9 Number 3 September 2015
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Perioperative chemotherapy for muscle invasive bladder cancer Jan K. Rudzinski a, Naveen S. Basappa b, and Scott North b
Purpose of review Radical cystectomy with or without systemic chemotherapy is considered a standard of care for patients with muscle invasive bladder cancer (MIBC). The purpose of this review is to provide an update on current and recent literature published within the last 12 months reviewing the evidence for use of perioperative chemotherapy for patients with MIBC. Recent findings In the neoadjuvant chemotherapy (NAC) setting, the evidence demonstrates clinical efficacy and lower rate of toxicity with the use of high-dose methotrexate, vinblastine, doxorubicin, and cyclophosphamide (MVAC) compared with standard MVAC. Higher quality evidence for the use of gemcitabine with cisplatin is not yet available. Meta-analysis of cisplatin-based regimens in the adjuvant setting demonstrates significant benefit in overall survival and disease-free survival specifically in patients with lymph-node-positive disease. Summary The available evidence suggests that along with radical cystectomy, cisplatin-based perioperative chemotherapy should be the standard of care in patients with MIBC with a higher quality and quantity of literature in support of the NAC approach. Adoption of perioperative chemotherapy for MIBC is on the rise in North America, which is reassuring. Novel therapeutic approaches for cisplatin-ineligible patients are currently being investigated. Keywords cisplatin, muscle invasive bladder cancer, perioperative chemotherapy, radical cystectomy
INTRODUCTION Globally, bladder cancer is the ninth most common cancer with more than 330, 000 cases diagnosed annually and more than 30 000 deaths [1]. Most cases are transitional cell carcinoma (TCC), which will be the focus of this review [1,2 ,3,4]. Approximately, 20–30% of newly diagnosed patients will have muscle invasive bladder cancer (MIBC) defined as T2-T4 disease [1,2 ]. Despite surgical management with radical cystectomy, 50% of patients will develop tumor recurrence [4,5]. Mounting evidence suggests that perioperative chemotherapy administration for MIBC improves progression-free survival (PFS) and overall survival (OS). Neoadjuvant chemotherapy (NAC) has demonstrated survival benefit in patients with MIBC [6–13]. Early data to support the use of NAC comes from two Nordic trials [6–8], a combined UK Medical Research Council/European Organization of Research and Treatment of Cancer (MRC/EORTC) trial [9], and the South West Oncology Group (SWOG 8710) intergroup trial from the USA [10]. These studies enrolled patients with T2-T4a N0M0 &
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TCC disease treated with various cisplatin-based chemotherapeutic regimens. However, the OS benefit with NAC is modest. The MRC/EORTC trial consisting of 976 patients evaluated three cycles of NAC (cisplatin, methotrexate, and vinblastine) followed by radical cystectomy or radiation therapy [9]. In this study, the absolute 5year OS improvement was 5.5% (P ¼ 0.075) [9]. These results were not statistically significant initially but with further follow up, the trial is now positive with an absolute OS benefit of 6% at 10 years [9,14]. The SWOG 8710 trial was composed of 317 patients and evaluated patients who were a Division of Urology, Department of Surgery and bDivision of Medical Oncology, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
Correspondence to Scott North MD, FRCPC, Division of Medical Oncology, Department of Oncology, University of Alberta, Edmonton, Canada, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada. Tel: +17804328221; e-mail: [email protected] Curr Opin Support Palliat Care 2015, 9:249–254 DOI:10.1097/SPC.0000000000000148
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KEY POINTS Administration of perioperative chemotherapy for muscle invasive bladder cancer (MIBC) leads to improvements in overall survival (OS) for patients with MIBC. Emerging trials looking at neoadjuvant chemotherapy are focused on finding the optimal cisplatin-based regimen to provide the greatest benefit in OS with the most reasonable toxicity profile. Further research is required to best identify the cohort of patients that would be most benefit from adjuvant chemotherapy. Across North America, the use of perioperative chemotherapy for patients with MIBC is increasing. Novel therapeutic approaches for cisplatin-ineligible patients are currently being investigated.
randomized to methotrexate, vinblastine, doxorubicin, and cyclophosphamide (MVAC) followed by radical cystectomy versus radical cystectomy alone [10]. This trial demonstrated 14% improvement in OS at 5-years but with only a trend toward statistical significance in the NAC cohort (P ¼ 0.06) [10]. In addition, three separate meta-analyses composed of around 3000 patients each showed statistically significant absolute improvements in 5-year OS between 5 and 6.5% [11–13]. Currently, based on existing data, there is strong evidence to support NAC using a cisplatin-based combination in patients with MIBC. However, chemotherapy also carries the risk of significant toxicities. The SWOG 8710 reported that 73% of patients exposed to MVAC experienced more than grade 3 toxicities [10]. Attempts to find similarly effective regimens with less toxicity have been undertaken, such as the high-dose MVAC (HDMVAC) regimen administered every two weeks with growth factor support [3]. Research has also focused on combination chemotherapy with carboplatin, which is a less toxic platinum alternative. The existing evidence for the use of carboplatin-based regimens comes from small retrospective as well as prospective trials that are underpowered and demonstrate no significant difference in pathologic or survival outcomes compared with MVAC [15–20]. Therefore, the routine use of carboplatin-based regimens is not recommended at this time. There are many controversies surrounding NAC. One controversy pertains to optimal patient selection. There is an argument to reserve NAC for patients with higher stage disease as absolute OS benefit with NAC tends to be greater in those with at 250
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least T3 disease [6,10,12]. In addition, there are proponents who would argue that within the clinical T2 (cT2) cohort, NAC should be reserved for patients with higher risk features such as those with presence of hydronephrosis and/or lymphovascular invasion [21,22]. However, clinical staging is inaccurate with 43–70% of cT2 patients being upstaged on final pathology review [23–26]. Thus, excluding all cT2 patients from NAC could result in denying some higher risk patients treatment. Another debate revolves around the optimal NAC regimen. The use of MVAC or cisplatin, methotrexate, and vinblastine is considered a gold standard [9,10]. However, these regimens have been associated with unfavorable toxicity profile such as severe neutropenia, mucositis, renal, and cardiac toxicity, as well as toxic death rate of 3–4% [9,10]. In a trial of gemcitabine and cisplatin compared with MVAC, von der Maase et al. [27] reported similar efficacy and better tolerability with the use of gemcitabine and cisplatin compared with MVAC in patients with metastatic disease. Many oncologists extrapolated these data to the neoadjuvant setting [28 ]. However, the use of gemcitabine and cisplatin has not been prospectively studied in a randomized fashion and most of the evidence for its use in neoadjuvant setting comes from small single center retrospective studies or prospective case series [29 ]. Although there is no strong evidence suggesting increased surgical complication rates in those receiving NAC, there has been an argument that patients may be unnecessarily subjected to delays in definitive local therapy if they receive NAC that ends up being ineffective [3,10,30–32]. Unfortunately, there are currently no good tools to predict response to NAC [33]. Although some clinicians may employ repeat imaging or cystoscopy assessment, these are imperfect tests. Thus, failure to be able to predict who will most benefit from NAC remains one of the most important reasons to argue against its routine use. An alternate strategy to NAC is adjuvant chemotherapy administered after radical cystectomy. Despite a lack of strong data supporting clinical efficacy associated with adjuvant chemotherapy use, large multiinstitutional reviews from the USA and Europe demonstrate that more patients tend to receive adjuvant chemotherapy compared with NAC [34,35]. The existing evidence for the use of adjuvant chemotherapy is best summarized by the Advanced Bladder Cancer Meta-analysis collaboration study, which pooled six randomized controlled trials with 491 patients and demonstrated 25% relative reduction in the risk of death with absolute improvement in OS of 9% at 3 years [36,37]. However, these conclusions are limited by &
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the quality of the data used to perform the analysis. Perceived advantages of adjuvant chemotherapy include immediate definitive local therapy, lack of overtreatment of patients with good risk pathology, and that therapy could be tailored to individualized pathology [38]. Disadvantages of adjuvant chemotherapy are that it delays administering systemic therapy to deal with potential micrometastases and some patients have delayed postoperative healing such that they never have the chance to receive adjuvant chemotherapy. Finally, similar to NAC, there is no definitive way to know, which patient will benefit [38]. Despite the existing evidence suggesting that perioperative chemotherapy should be the standard of care in MIBC population, the reported concordance with clinical practice guidelines is estimated to be around 11.3–20% in North America [39– 42,43 ,44 ]. Potential reasons for its underuse are the perception of increased morbidity and toxicity of chemotherapy, modest survival benefit, delay in definitive local therapy, and concerns over the quality of data especially for adjuvant chemotherapy [39–42,43 ,44 ]. In addition, approximately, 40% with MIBC are also cisplatin ineligible mainly due to impairment in renal function [45]. Currently, the vast majority of perioperative MIBC research focuses on selection of more efficacious cisplatin-based regimens with limited number of studies looking at patients who are cisplatin ineligible [46]. &&
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REVIEW OF STUDIES Effectiveness of perioperative chemotherapy To compare the reported efficacy of NAC to its clinical effectiveness in Canada, Booth et al. [43 ] undertook an Ontario-based retrospective study aimed at evaluating the external validity of the clinical trial results for administration of perioperative chemotherapy. This retrospective analysis looked at 2044 patients who underwent definitive therapy for MIBC between 1994 and 2008. The reported 5-year OS of patients who received NAC was 26%. This differs from reported 5-year OS rates from published trials that ranges from 49 to 57% [10,14]. However, they did demonstrate that OS in the group receiving perioperative chemotherapy was superior to the group that did not receive it. &&
Neoadjuvant chemotherapy The emerging platinum-based alternatives There have been two recent prospective multicenter phase II trials that investigated the efficacy of
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HD-MVAC in the neoadjuvant setting [28 ,47 ]. In the first trial by Plimack et al. [28 ], the authors enrolled 44 patients with T2c–T4a N0-1 disease to establish whether HD-MVAC with pegfilgrastim can achieve similar rates of pathologic response to standard MVAC. The authors compared the prospectively obtained pathologic complete response rates with retrospective experience of MVAC. This study demonstrated that patients who received HD-MVAC experienced about 38% pathologic T0 rate with another 14% of patients being downstaged to nonmuscle invasive disease. When comparing the baseline clinical stage to final pathologic stage, 65% of patients were downstaged after NAC. In a second trial by Choueri et al. [47 ], the authors enrolled 39 patients with clinical T2-T4 N0-1 M0 MIBC. Patients were treated with four cycles of HD-MVAC followed by radical cystectomy. This trial found that 49% of patients achieved pathologic down staging with one-year disease-free survival (DFS) of 89%. Of particular importance is that 26% of patients achieved complete pT0 rate, and only 10% of patients experienced high-grade toxicity with no episodes of treatment-related death. Despite the small number of patients enrolled, these trials suggest that HD-MVAC achieves similar pT0 rates to standard 12-week MVAC regimen with lower rate of high-grade toxicities. As the existing evidence for the use of gemcitabine and cisplatin as a neoadjuvant regimen is confined to small retrospective single center trials or case series, there are two-registered phase III trials attempting to compare neoadjuvant gemcitabine and cisplatin with HD-MVAC [46,48]. One trial is being conducted by University Hospital in Rouen, France [49], whereas the second study is led by the SWOG group in the USA [48]. The results from these studies aim to provide higher quality evidence for the use of gemcitabine and cisplatin in the neoadjuvant setting. &
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Effect of neoadjuvant chemotherapy on surgical outcomes One of the reported limitations of the use of NAC is the perceived risk of adverse perioperative outcomes. To specifically investigate the effect of NAC on perioperative outcomes in patients who underwent radical cystectomy, Gandaglia et al. [50 ] conduced a retrospective database review of 3760 patients diagnosed with MIBC between 2000 and 2009. There was no significant difference in rates of transfusions, length of stay, hospital readmission rates, and mortality between both groups. Chau et al. [51 ] investigated the clinical outcomes following neoadjuvant cisplatin-based chemotherapy in the elderly to determine whether age is a &
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factor in determining tolerance and response to chemotherapy. This was a single institution retrospective case series analysis of 83 patients with median age of 68 with T2-T4a N0M0 TCC who were treated with gemcitabine and cisplatin between 2005 and 2011. Overall, the study found that elderly patients with good functional status and limited comorbidities have similar outcomes to their younger counterparts receiving NAC. Risk adapted approach to neoadjuvant chemotherapy Culp et al. [52 ] have reported on whether a riskadapted approach can be used to select higher risk patients for NAC, thus, sparing low-risk patients from toxicity. This was a single center retrospective analysis of 1285 patients who underwent radical cystectomy between 2000 and 2010. The presence of high-risk features was defined as the presence of hydroureteronephrosis, clinical T3b-T4a disease, and/or histological evidence of lymphovascular invasion. Overall, patients in the high-risk group had statistically worse 5-year OS, PFS, and diseasespecific survival, and when compared with low-risk patients (P < 0.001). However, within the low-risk cohort, 49.2% of patients had pathological upstaging of their disease, underscoring the problems of clinical staging. Given the challenges in clinical staging and the high rate of being upstaged at final pathology, this risk-adapted approach has not been widely adopted. &
relapse. Overall, administration of immediate adjuvant chemotherapy did not lead to significant improvement in OS (P ¼ 0.13), but was associated with significant improvement in prolonging 5-year PFS. Unfortunately, this trial was limited by a small sample size and was underpowered to detect an OS difference. In the context of existing evidence, these articles strengthen the role of adjuvant chemotherapy in MIBC. However, to improve the quality of the available data and provide better guidance to clinicians, future trials should focus on an individualized patient data meta-analysis to better elucidate the benefit of adjuvant chemotherapy in this setting.
Guideline concordance &
Hsu et al. [55 ] surveyed academic urologists and medical oncologists across Canada to better understand the factors that influence the decisions to recommend NAC for MIBC. Among the 51 respondents across Canada, the authors found that key considerations in recommending NAC were performance status, presence of comorbidities, and renal function. Also, a US retrospective cohort analysis by Reardon et al. [56 ], has shown that the use of NAC significantly increased from 10.1 to 20.1% (P ¼ 0.005) between 2006 and 2010. The multivariable analysis demonstrated that advanced age, increased number of comorbidities, geographic location, and low income was associated with lower utilization of perioperative chemotherapy. &
Adjuvant chemotherapy To further improve the statistical power of the existing data on cisplatin-based adjuvant chemotherapy, Loew et al. [53 ], conducted an updated metaanalysis from nine randomized clinical control trials, which demonstrated a statistically significant benefit in OS and DFS specifically in patients with lymph-node-positive disease. The largest prospective trial for adjuvant chemotherapy is the EORTC 30994 trial published by Sternberg et al. [54 ] in December 2014. This was a large open label, multicenter randomized phase III trial, which planned to recruit 660 patients with pathologic T3-T4 or NþM0 TCC to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy and bilateral pelvic lymph node dissection. In this trial, which was terminated early, only 284 participants were accrued between 2008 and 2010. Patients were randomized to either four cycles of adjuvant chemotherapy within 90 days of surgery (gemcitabine and cisplatin, MVAC, or HD-MVAC based on institutional preference) or six cycles of chemotherapy at &
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Novel approaches There are currently multiple phase II trials investigating the role of targeted therapy in the perioperative setting [46]. Interesting results have been seen with the use of erlotinib [57], and dasatinib [58,59] monotherapy preradical cystectomy, and with bevacizumab [60] and sunitinib [61] in combination with cisplatin-based chemotherapy. However, to firmly delineate the potential benefit of these agents we need to await phase III clinical trials.
CONCLUSION The role of perioperative chemotherapy for MIBC has been well established with the strongest literature in support of NAC. The optimal regimen is not known but cisplatin-based combination therapy should be the standard. Although perioperative chemotherapy use is still low, it is encouraging to see a trend toward increased use of chemotherapy in this setting. And increased adherence to clinical practice guidelines. Future research will need to focus on Volume 9 Number 3 September 2015
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how to manage cisplatin ineligible patients and explore how new therapeutic agents, such as molecular and immune-targeted therapies and biologics, may play a role in the MIBC-patient population. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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Renal and urological problems 40. Porter MP, Kerrigan MC, Donato BM, et al. Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol 2011; 29:252–258. 41. David KA, Milowsky MI, Ritchey J, et al. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. J Urol 2007; 178:452–454. 42. Fedeli U, Fedewa SA. Ward EM: treatment of muscle invasive bladder cancer – evidence from the National Cancer Database, 2003 to 2007. J Urol 2011; 185:72–78. 43. Booth CM, Siemens DR, Li G, et al. Perioperative chemotherapy for muscle&& invasive bladder cancer: a population-based outcomes study. Cancer 2014; 120:1630–1638. This report of population-based outcomes using perioperative chemotherapy for MIBC is very important for it discusses real world use of the treatment and adherence to guidelines. 44. Reardon ZD, Patel SG, Zaid HB, et al. Trends in the use of perioperative & chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol 2015; 67:165–170. This study highlights the increasing use of perioperative chemotherapy and adherence to guidelines. 45. Canter D, Viterbo R, Kutikov A, et al. Baseline renal function status limits patients eligibility to receive perioperative chemotherapy for invasive bladder cancer and is minimally affected by radical cystectomy. Urology 2011; 77:160–165. 46. Vashistha V, Quinn DI, Dorff TB, et al. Current and recent clinical trials for perioperative systemic therapy for muscle invasive bladder cancer: a systematic review. BMC Cancer 2014; 14:966. 47. Choueri. Jacobus S, Bellmunt J, et al. Neoadjuvant dose-dense methotrexate, & vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscleinvasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol 2014; 32:1889–1894. This study reports on the usefulness and success of ddMVAC in MIBC patients and this regimen is increasingly being used in this context. 48. Kumar Pal S, Southwest Oncology Group: Examining the Pre-Metastatic Niche in Muscle Invasive Bladder Cancer. [http://www.swog.org/Visitors/ Fall13GpMtg/plenary/04-McConkey-plenaryI-october-2013.pdf] [Accessed 20 March 2015] 49. University Hospital, Rouen. Randomized Phase III Study of Gemcitabine/ Cisplatin (GC) Versus High-dose Intensity Methotrexate, Vinblastine, Doxorubicine, and Cisplatin (HD-MVAC) in Perioperative Setting for Patients With Locally Advanced Transitional Cell Cancer of the Bladder. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 – [cited 2015 Apr 6]. Available from: https://clinicaltrials.gov/ct2/ show/NCT01812369?term¼NCT01812369&rank¼1 NLM Identifier: NCT01812369. [Accessed 20 March 2015] 50. Gandaglia G, Popa I, Abdollah F, et al. The effect of neoadjuvant chemother& apy on perioperative outcomes in patients who have bladder cancer treated with radical cystectomy: a population based study. Eur Urol 2014; 66:561– 568. This was a retrospective trial comparing perioperative outcomes between patients receiving NAC and those treated with radical cystectomy alone. The use of perioperative chemotherapy was not associated with higher risk of postoperative outcomes.
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51. Chau C, Wheater M, Geldart T, et al. Clinical outcomes following neoadjuvant cisplatin-based chemotherapy for bladder cancer in elderly compared with younger patients. Eur J Cancer Care (Engl) 2015; 24:155–162. This report is important as it demonstrates that elderly patients can similarly benefit from chemotherapy as opposed to younger counterparts. 52. Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for & neoadjuvant chemotherapy before radical cystectomy. J Urol 2014; 191:40– 47. This retrospective trial evaluated the survival of patients with low risk versus highrisk MIBC features. This study suggests that only patient with high risk features with poor prognosis should be exposed to NAC. 53. Loew JJ, Matin-Doyle W, Rajagopal PS, et al. Adjuvant chemotherapy for & invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 2014; 66:42–54. This updated meta-analysis covers the recent evidence in support of adjuvant chemotherapy in MIBC. 54. Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred && chemotherapy after radical cystectomy in patients with pT3-T4 or NþM0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open label, randomized phase 3 trial. Lancet Oncol 2015; 16:76–86. This is a largest randomized trial of adjuvant chemotherapy in MIBC patients. It showed that immediate chemotherapy after radical cystectomy led to significant improvement in PFS with no improvement in OS. 55. Hsu T, Black PC, Chi KN, et al. Treatment of muscle-invasive bladder cancer in & Canada: a survey of genitourinary medical oncologists and urologists. Can Urol Assoc J 2014; 8 (9–10):309–316. This report is important as it was a real-world survey of what is being done in Canada for MIBC and how the data are being interpreted and implemented by treating oncologists. 56. Reardon ZD, Patel SG, Zaid HB, et al. Trend in the use of perioperative & chemotherapy for localized and locally advanced bladder cancer: a sign of changing tides. Eur Urol 2015; 67:165–170. This review highlights international adherence to guidelines and implementation of perioperative chemotherapy for MIBC. 57. Pruthi RS, Nielsen M, Heathcote S, et al. A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results. BJU Int 2010; 106:349– 352. 58. Hahn NM, Daneshmand S, Posadas EM. A phase II trial of neoadjuvant dasatinib (Neo-D) in muscle-invasive urothelial carcinoma of the bladder (miUCB): Hoosier Oncology Group GU07-122 trial [abstract]. J Clin Oncol 2012; 30:. (Suppl):abstract 4586. 59. Knudsen B, Hahn NM, Daneshmand S, et al. Biologic activity of dasatinib administered as neoadjuvant therapy preceding radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) [abstract]. J Clin Oncol 2014. 32(Suppl): abstract 324. 60. Chaudhary UB, Golshatan AR, Brisendine A, et al. Phase II trial of neoadjuvant cisplatin, gemcitabine, and bevacizumab followed by radical cystectomy (RC) in patients with muscle-invasive transitional cell carcinoma (TCC) of the bladder [abstract]. J Clin Oncol 2011. 29(Suppl):abstract 276. 61. Galsky MD, Hahn NM, Powles T, et al. Gemcitabine, Cisplatin, and Sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscleinvasive bladder cancer. Clin Genitourin Cancer 2013; 11:175–181. &
Volume 9 Number 3 September 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
