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Chemotherapy for muscle-invasive bladder cancer in the perioperative setting: Current standards
Urologic Oncology: Seminars and Original Investigations 25 (2007) 72–75
Seminar article
Chemotherapy for muscle-invasive bladder cancer in the perioperative setting: Current standards Robert Dreicer, M.D., F.A.C.P.* Department of Solid Tumor Oncology, Taussig Cancer Center and the Glickman Urologic Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Abstract Radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. Although surgery achieves excellent local control, within 5 years, almost 50% of patients have a relapse and, subsequently, progression to systemic disease developing. Randomized trials of cisplatin-based chemotherapy regimens in the neoadjuvant setting have shown the potential to improve survival. Suboptimal trial design, insufficient numbers of patients, and lack of standardization of the chemotherapy regimens used have plagued adjuvant studies. Given the lethality of recurrent transitional cell carcinoma of the bladder, perioperative cisplatin-based chemotherapy should be considered a standard of care. © 2007 Elsevier Inc. All rights reserved. Keywords: Bladder cancer; Chemotherapy; Adjuvant; Neoadjuvant
Introduction In the United States, administration of chemotherapy in the perioperative setting for patients with muscle-invasive transitional cell carcinoma bladder cancer has become a standard of care. Data from 2 randomized trials of cisplatinbased chemotherapy administered in the neoadjuvant setting provide evidence of a survival benefit [1,2]. Despite this evidence, it appears that many if not most patients with muscle-invasive bladder cancer undergoing cystectomy who receive chemotherapy do so in the adjuvant setting. What is the current standard of care for the administration of chemotherapy for operable patients with muscle-invasive bladder cancer? How did this apparent disconnect occur, and is there a rationale to support this extrapolation from the neoadjuvant to adjuvant setting is the subject of this report. Clinicians involved in the care of patients with muscleinvasive transitional cell carcinoma of the bladder have long recognized the very aggressive nature of this epithelial cancer. The high systemic relapse rate in patients undergoing curative intent radical cystectomy with deep muscle invasion (worsened with nodal involvement) has been well described [3,4]. In the 1980s, several groups showed that cisplatin-based combination chemotherapy regimens, including methotrexate, vinblastine, doxorubicin, and cispla* Tel.: ⫹1-216-445-4623; fax: ⫹1-216-445-2360. E-mail address: [email protected]. 1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2006.05.011
tin (M-VAC), and cisplatin, methotrexate, and vinblastine, had significant activity in advanced urothelial cancer [5,6]. This observation led clinical investigators at numerous institutions around the world to evaluate the use of these agents in the adjuvant and neoadjuvant settings in patients with locally advanced disease in an attempt to decrease systemic progression [7–9].
Neoadjuvant chemotherapy The administration of systemic chemotherapy in the neoadjuvant setting has a number of theoretical advantages, including the ability to deliver effective systemic therapy, while the burden of micrometastatic disease is minimal. Chemotherapy delivered systemically preoperatively may improve drug delivery into the bladder and surrounding lymphatics. In addition, patients treated before surgery have a more optimal performance status that is widely recognized as an important prognostic factor in assessing response to chemotherapy in those with advanced urothelial cancer [10]. The potential disadvantages of therapy in the neoadjuvant setting include the potential to treat inappropriately patients whose disease is over-staged (obviated in the adjuvant setting), and the time delay (range 3– 4 months) to radical cystectomy if systemic therapy is either ineffective or results in significant therapy related toxicity, delaying or
R. Dreicer / Urologic Oncology: Seminars and Original Investigations 25 (2007) 72–75
73
Table 1 Select randomized neoadjuvant chemotherapy studies in bladder cancer Investigators
No. of patients
Local therapy
Chemotherapy
Chemotherapy survival benefit
Hall et al. [11] (Medical Research Council and European Organization for Research and Treatment of Cancer) Grossman et al. [2] (South West Oncology Group)
976
Cystectomy, radiotherapy, or combination
Cisplatin, methotrexate, and vinblastine
15% decrease in death rate at 7 yrs
317
Cystectomy
M-VAC
14% absolute survival benefit at 5 yrs
preventing potentially curative surgical intervention. Over the past 15 years, a series of cisplatin-based multiagent randomized studies have been performed, culminating in 2 recent large trials showing a survival impact of chemotherapy administered in the neoadjuvant setting (Table 1) [1,2]. The Medical Research Council and European Organization for Research and Treatment of Cancer conducted a study of 976 patients from 106 institutions in 20 countries with T2 G3, T3, T4a, N0-NX, and MO disease. A total of 491 patients were randomized to 3 cycles of neoadjuvant chemotherapy with cisplatin, methotrexate and vinblastine, or no chemotherapy (n ⫽ 485), before local definitive therapy. Definitive local therapy was selected based upon institutional preference and included radical cystectomy, external beam radiotherapy, or preoperative radiation followed by cystectomy. A total of 484 patients underwent cystectomy, 414 received external beam radiotherapy, and 77 were treated with combined modality therapy. At the initial report, there was a median follow-up was 4 years with 485 deaths, the majority (78.6%) secondary to transitional cell carcinoma. Neoadjuvant chemotherapy was associated with a higher pathologic complete-response rate in primary tumors (32.5% chemotherapy arm vs. 12.3% no chemotherapy). The hazard ratio analysis showed a 15% reduction in the risk of death, favoring the chemotherapy arm, equating to an absolute 3-year survival difference of 5.5% (95% confidence interval 0.5–11.0, P ⫽ 0.075; 55.5% for chemotherapy and 50.0% for local therapy alone). The investigators of the study concluded that the small, nonstatistically significant survival difference observed did not justify the routine use of neoadjuvant chemotherapy [1]. However, a subsequent update of this trial reported showed that the initial observation of a favorable impact of neoadjuvant chemotherapy on survival was maintained, with a median follow-up of 7 years; the difference in 5 and 8-year overall survival rates were 50% versus 44% and 43% versus 37%, respectively [11]. The U.S. Intergroup study led by investigators in the South West Oncology Group (INT-0080-SWOG 8710) evaluated the role of neoadjuvant M-VAC plus cystectomy compared with cystectomy alone [2]. Over an 11-year period, 317 patients were enrolled in this multi-institutional trial. With a median follow-up of 8.4 years, 117 patients remained alive, with 90 deaths in the chemotherapy arm and 100 deaths in the surgery arm. An intent-to-treat-analysis
showed a median survival of 46 months in the surgery alone group compared to 77 months in the combined modality arm. In addition to the improvement in survival, 48 patients from the cystectomy group had a complete pathologic response at surgery. By contrast, only 18 patients in the surgery alone group were pathologically free of disease at cystectomy. A recent meta-analysis, including all current studies with the exception of the U.S. Intergroup study, comprised data on more than 2600 patients with high-risk bladder cancer. Chemotherapy with cisplatin-based combinations showed a significant benefit in overall survival, with a 13% reduction in risk of death and a 5% absolute benefit at 5 years (P ⫽ 0.016). This survival benefit was achieved regardless of the type of local treatment [12].
Adjuvant chemotherapy In contrast to the neoadjuvant setting, clinical trials of adjuvant chemotherapy in bladder cancer have been problematic. There are 6 significantly underpowered randomized trials of chemotherapy, including 5 multiagent cisplatinbased and 1 cisplatin alone, versus observation that have been reported (Table 2) [9,13–17]. Of these studies, 2 have been interpreted as suggesting a survival benefit to adjuvant chemotherapy [9,13].
Table 2 Randomized adjuvant chemotherapy studies Investigators
No. of patients
Chemotherapy
Skinner et al. [13]
91
Cisplatin, cytoxan, doxorubicin (plus others) M-VAC/M-VEC
Stockle et al. [9]
83
Freiha et al. [14]
50
Cisplatin, methotrexate, and vinblastine
Studer et al. [15] Bono et al. [16] Otto et al. [17]
77 83 108
Cisplatin Cisplatin/methotrexate M-VEC
Chemotherapy survival benefit Yes
Yes (diseasefree survival only) Yes (freedom from progression only) No No No
74
R. Dreicer / Urologic Oncology: Seminars and Original Investigations 25 (2007) 72–75
In 1994, the German Cancer Society initiated a noninferiority phase III trial comparing cisplatin plus methotrexate to cisplatin, methotrexate, epirubicin, and vinblastine (MVEC) as adjuvant therapy in patients with pT3a– 4a and/or node-positive transitional cell carcinoma of the bladder. A noninferiority design was chosen to establish cisplatin plus methotrexate as a less toxic regimen with comparable efficacy. The results showed a median time to progression of 49.7 months for patients treated with M-VEC compared with 43.4 months for those treated with cisplatin plus methotrexate. The hazard ratio for recurrence of 1.131 (90% confidence interval 0.863–1.482) favored M-VEC. The investigators of the study suggested that the current data provided evidence that the efficacy of the less toxic regimen of cisplatin plus methotrexate cannot be considered substantially inferior to the efficacy of M-VEC [18]. Regardless of the conclusions reached from these studies, there is a widely held view that the published adjuvant studies are, as a group, severely compromised by small patient numbers, variable treatment regimens, and poor treatment compliance, and, therefore, the true utility use of adjuvant therapy remains undefined.
Current standards for perioperative chemotherapy Despite improvements in surgical techniques, a significant subset of patients with locally advanced bladder cancer remain at high risk for systemic disease developing. There are 2 well-powered randomized trials of neoadjuvant cisplatin-based chemotherapy that have shown the potential to improve the overall survival of patients with high risk transitional cell carcinoma of the bladder [2,11]. Despite the absence of similar data, many clinicians in the United States prefer to administer adjuvant chemotherapy for patients at high-risk, extrapolating the use in the neoadjuvant setting to provide a “perioperative” benefit for a more defined population. Clinicians who favor the adjuvant setting point to a recent trial conducted by investigators at the University of Texas M.D. Anderson Cancer Center. Millikan et al. [19] attempted to address several issues, including the timing of chemotherapy with respect to surgery in patients receiving the same quantity of therapy, accuracy of clinical staging information, and prognostic significance of pathologic down-staging. Their study was powered to detect a 20% improvement in survival for those patients receiving neoadjuvant/adjuvant M-VAC (2 cycles before and 3 after radical cystectomy) versus 5 cycles of M-VAC given exclusively in the adjuvant setting. After randomizing 140 patients with locally advanced disease, no significant differences in outcome were observed. Complete pathologic responses (pT0) were documented in 40% of patients receiving 2 cycles of neoadjuvant M-VAC. Toxicity was a major concern in this study, with 6 deaths in each treatment arm all considered therapy related. With a median follow-up
of 6.8 years, no differences in disease-free survival were observed [19]. In the United States, the major oncology cooperative groups recognizing the shift to the adjuvant setting have attempted to define further the use of various multiagent combination regimens. The Eastern Cooperative Oncology Group conducted a phase III trial comparing M-VAC to carboplatin and paclitaxel, and the Cancer and Leukemia Group B conducted a phase III trial comparing gemcitabine and cisplatin to a dose dense regimen developed by investigators at Memorial Sloan Kettering [20]. Both of these studies accrued less than 30 patients each and were stopped by their respective groups for lack of timely patient accrual. In an important and most likely final attempt to define the role of adjuvant chemotherapy in patients with locally advanced bladder cancer, the European Organization for Research and Treatment of Cancer is currently leading a multinational randomized phase III trial comparing immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 and/or N⫹M0 transitional cell carcinoma of the bladder. Patients with locally advanced, primarily transitional cell carcinoma will receive 1 of 3 cisplatin-based regimens (i.e., classic M-VAC regimen, gemcitabine and cisplatin, or high-dose M-VAC), as determined by the treating center. As one reviews the current status of therapy for locally advanced transitional cell carcinoma of the bladder, several observations can be made. Locally advanced bladder cancer is an aggressive and potentially lethal neoplasm. There is compelling evidence that neoadjuvant cisplatin-based chemotherapy, before radical cystectomy or definitive radiotherapy, can modestly improve survival. The role of adjuvant chemotherapy remains undefined, but urologists and medical oncologists in the United States increasingly use adjuvant chemotherapy by extrapolating a “perioperative” benefit from the neoadjuvant experience. Perioperative cisplatin-based chemotherapy, when renal function is appropriate, should now be considered a standard of care. References [1] Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. International collaboration of trialists. Lancet 1999;354:533– 40. [2] Grossman H, Natale R, Tangen C, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859 – 66. [3] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001;19:667–75. [4] Vieweg J, Gschwend J, Herr H, et al. The impact of primary stage on survival in patients with lymph node positive bladder cancer. J Urol 1999;161:72– 6. [5] Sternberg C, Yagoda A, Scher H, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985;133:403– 4. [6] Harker W, Meyers F, Freiha F, et al. Cisplatin methotrexate, and vinblastine (CMV): An effective chemotherapy regimen for meta-
R. Dreicer / Urologic Oncology: Seminars and Original Investigations 25 (2007) 72–75
[7]
[8]
[9]
[10]
[11]
[12]
[13]
static transitional cell carcinoma of the urothelial tract: A Northern California Oncology Group study. J Clin Oncol 1985;3:1463–70. Dreicer R, Messing E, Loehrer P, et al. Perioperative methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) for poor risk transitional cell carcinoma of the bladder: An Eastern Cooperative Oncology Group Pilot Study. J Urol 1990;14:1123–7. Sternberg CN, Arena MG, Calabresi F, et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for infiltrating transitional cell carcinoma of the bladder. Cancer 1993;72:1975– 82. Stockle M, Meyenburg W, Wellek S, et al. Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): Improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 1992;148:302– 6. Bajorin D, Dodd P, Mazumdar M, et al. Long-term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17:3173– 81. Hall RR, International Collaboration of Trialist of the MRC. Updated results of a randomised controlled trial of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy for muscle invasive bladder cancer. Proc Am Soc Clin Oncol 2002;21:178a [Abstract 710]. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis. Lancet 2003;361:1927–34. Skinner D, Daniels J, Russell C, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J Urol 1991;145:459 – 64.
75
[14] Freiha F, Reese J, Torti F. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle-invasive bladder cancer. J Urol 1996;155: 495–500. [15] Studer U, Bacchi M, Biedermann C, et al. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: Results of a prospective randomized trial. J Urol 1994;152:81– 4. [16] Bono A, Benvenuti C, Reali L, et al. Adjuvant chemotherapy in advanced bladder cancer. Italian Uro-Oncologic Cooperative Group. Prog Clin Biol Res 1989;303:533– 40. [17] Otto T, Borgmann C, Krege S. Radical cystectomy ⫹/⫺ adjuvant chemotherapy in bladder cancer—A randomized phase III study. J Urol 2001;165:279 [Abstract 1147]. [18] Lehmann J, Retz M, Wiemers C, et al. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: Results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol 2005;22: 4963–74. [19] Millikan R, Dinney C, Swanson D, et al. Integrated therapy for locally advanced bladder cancer: Final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 2001;19: 4005–13. [20] Small E, Halabi S, Dalbagni G, et al. Overview of bladder cancer trials in the Cancer and Leukemia Group B. Cancer 2003;97(Suppl 8):2090 – 8.
Seminar article
Chemotherapy for muscle-invasive bladder cancer in the perioperative setting: Current standards Robert Dreicer, M.D., F.A.C.P.* Department of Solid Tumor Oncology, Taussig Cancer Center and the Glickman Urologic Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Abstract Radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. Although surgery achieves excellent local control, within 5 years, almost 50% of patients have a relapse and, subsequently, progression to systemic disease developing. Randomized trials of cisplatin-based chemotherapy regimens in the neoadjuvant setting have shown the potential to improve survival. Suboptimal trial design, insufficient numbers of patients, and lack of standardization of the chemotherapy regimens used have plagued adjuvant studies. Given the lethality of recurrent transitional cell carcinoma of the bladder, perioperative cisplatin-based chemotherapy should be considered a standard of care. © 2007 Elsevier Inc. All rights reserved. Keywords: Bladder cancer; Chemotherapy; Adjuvant; Neoadjuvant
Introduction In the United States, administration of chemotherapy in the perioperative setting for patients with muscle-invasive transitional cell carcinoma bladder cancer has become a standard of care. Data from 2 randomized trials of cisplatinbased chemotherapy administered in the neoadjuvant setting provide evidence of a survival benefit [1,2]. Despite this evidence, it appears that many if not most patients with muscle-invasive bladder cancer undergoing cystectomy who receive chemotherapy do so in the adjuvant setting. What is the current standard of care for the administration of chemotherapy for operable patients with muscle-invasive bladder cancer? How did this apparent disconnect occur, and is there a rationale to support this extrapolation from the neoadjuvant to adjuvant setting is the subject of this report. Clinicians involved in the care of patients with muscleinvasive transitional cell carcinoma of the bladder have long recognized the very aggressive nature of this epithelial cancer. The high systemic relapse rate in patients undergoing curative intent radical cystectomy with deep muscle invasion (worsened with nodal involvement) has been well described [3,4]. In the 1980s, several groups showed that cisplatin-based combination chemotherapy regimens, including methotrexate, vinblastine, doxorubicin, and cispla* Tel.: ⫹1-216-445-4623; fax: ⫹1-216-445-2360. E-mail address: [email protected]. 1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2006.05.011
tin (M-VAC), and cisplatin, methotrexate, and vinblastine, had significant activity in advanced urothelial cancer [5,6]. This observation led clinical investigators at numerous institutions around the world to evaluate the use of these agents in the adjuvant and neoadjuvant settings in patients with locally advanced disease in an attempt to decrease systemic progression [7–9].
Neoadjuvant chemotherapy The administration of systemic chemotherapy in the neoadjuvant setting has a number of theoretical advantages, including the ability to deliver effective systemic therapy, while the burden of micrometastatic disease is minimal. Chemotherapy delivered systemically preoperatively may improve drug delivery into the bladder and surrounding lymphatics. In addition, patients treated before surgery have a more optimal performance status that is widely recognized as an important prognostic factor in assessing response to chemotherapy in those with advanced urothelial cancer [10]. The potential disadvantages of therapy in the neoadjuvant setting include the potential to treat inappropriately patients whose disease is over-staged (obviated in the adjuvant setting), and the time delay (range 3– 4 months) to radical cystectomy if systemic therapy is either ineffective or results in significant therapy related toxicity, delaying or
R. Dreicer / Urologic Oncology: Seminars and Original Investigations 25 (2007) 72–75
73
Table 1 Select randomized neoadjuvant chemotherapy studies in bladder cancer Investigators
No. of patients
Local therapy
Chemotherapy
Chemotherapy survival benefit
Hall et al. [11] (Medical Research Council and European Organization for Research and Treatment of Cancer) Grossman et al. [2] (South West Oncology Group)
976
Cystectomy, radiotherapy, or combination
Cisplatin, methotrexate, and vinblastine
15% decrease in death rate at 7 yrs
317
Cystectomy
M-VAC
14% absolute survival benefit at 5 yrs
preventing potentially curative surgical intervention. Over the past 15 years, a series of cisplatin-based multiagent randomized studies have been performed, culminating in 2 recent large trials showing a survival impact of chemotherapy administered in the neoadjuvant setting (Table 1) [1,2]. The Medical Research Council and European Organization for Research and Treatment of Cancer conducted a study of 976 patients from 106 institutions in 20 countries with T2 G3, T3, T4a, N0-NX, and MO disease. A total of 491 patients were randomized to 3 cycles of neoadjuvant chemotherapy with cisplatin, methotrexate and vinblastine, or no chemotherapy (n ⫽ 485), before local definitive therapy. Definitive local therapy was selected based upon institutional preference and included radical cystectomy, external beam radiotherapy, or preoperative radiation followed by cystectomy. A total of 484 patients underwent cystectomy, 414 received external beam radiotherapy, and 77 were treated with combined modality therapy. At the initial report, there was a median follow-up was 4 years with 485 deaths, the majority (78.6%) secondary to transitional cell carcinoma. Neoadjuvant chemotherapy was associated with a higher pathologic complete-response rate in primary tumors (32.5% chemotherapy arm vs. 12.3% no chemotherapy). The hazard ratio analysis showed a 15% reduction in the risk of death, favoring the chemotherapy arm, equating to an absolute 3-year survival difference of 5.5% (95% confidence interval 0.5–11.0, P ⫽ 0.075; 55.5% for chemotherapy and 50.0% for local therapy alone). The investigators of the study concluded that the small, nonstatistically significant survival difference observed did not justify the routine use of neoadjuvant chemotherapy [1]. However, a subsequent update of this trial reported showed that the initial observation of a favorable impact of neoadjuvant chemotherapy on survival was maintained, with a median follow-up of 7 years; the difference in 5 and 8-year overall survival rates were 50% versus 44% and 43% versus 37%, respectively [11]. The U.S. Intergroup study led by investigators in the South West Oncology Group (INT-0080-SWOG 8710) evaluated the role of neoadjuvant M-VAC plus cystectomy compared with cystectomy alone [2]. Over an 11-year period, 317 patients were enrolled in this multi-institutional trial. With a median follow-up of 8.4 years, 117 patients remained alive, with 90 deaths in the chemotherapy arm and 100 deaths in the surgery arm. An intent-to-treat-analysis
showed a median survival of 46 months in the surgery alone group compared to 77 months in the combined modality arm. In addition to the improvement in survival, 48 patients from the cystectomy group had a complete pathologic response at surgery. By contrast, only 18 patients in the surgery alone group were pathologically free of disease at cystectomy. A recent meta-analysis, including all current studies with the exception of the U.S. Intergroup study, comprised data on more than 2600 patients with high-risk bladder cancer. Chemotherapy with cisplatin-based combinations showed a significant benefit in overall survival, with a 13% reduction in risk of death and a 5% absolute benefit at 5 years (P ⫽ 0.016). This survival benefit was achieved regardless of the type of local treatment [12].
Adjuvant chemotherapy In contrast to the neoadjuvant setting, clinical trials of adjuvant chemotherapy in bladder cancer have been problematic. There are 6 significantly underpowered randomized trials of chemotherapy, including 5 multiagent cisplatinbased and 1 cisplatin alone, versus observation that have been reported (Table 2) [9,13–17]. Of these studies, 2 have been interpreted as suggesting a survival benefit to adjuvant chemotherapy [9,13].
Table 2 Randomized adjuvant chemotherapy studies Investigators
No. of patients
Chemotherapy
Skinner et al. [13]
91
Cisplatin, cytoxan, doxorubicin (plus others) M-VAC/M-VEC
Stockle et al. [9]
83
Freiha et al. [14]
50
Cisplatin, methotrexate, and vinblastine
Studer et al. [15] Bono et al. [16] Otto et al. [17]
77 83 108
Cisplatin Cisplatin/methotrexate M-VEC
Chemotherapy survival benefit Yes
Yes (diseasefree survival only) Yes (freedom from progression only) No No No
74
R. Dreicer / Urologic Oncology: Seminars and Original Investigations 25 (2007) 72–75
In 1994, the German Cancer Society initiated a noninferiority phase III trial comparing cisplatin plus methotrexate to cisplatin, methotrexate, epirubicin, and vinblastine (MVEC) as adjuvant therapy in patients with pT3a– 4a and/or node-positive transitional cell carcinoma of the bladder. A noninferiority design was chosen to establish cisplatin plus methotrexate as a less toxic regimen with comparable efficacy. The results showed a median time to progression of 49.7 months for patients treated with M-VEC compared with 43.4 months for those treated with cisplatin plus methotrexate. The hazard ratio for recurrence of 1.131 (90% confidence interval 0.863–1.482) favored M-VEC. The investigators of the study suggested that the current data provided evidence that the efficacy of the less toxic regimen of cisplatin plus methotrexate cannot be considered substantially inferior to the efficacy of M-VEC [18]. Regardless of the conclusions reached from these studies, there is a widely held view that the published adjuvant studies are, as a group, severely compromised by small patient numbers, variable treatment regimens, and poor treatment compliance, and, therefore, the true utility use of adjuvant therapy remains undefined.
Current standards for perioperative chemotherapy Despite improvements in surgical techniques, a significant subset of patients with locally advanced bladder cancer remain at high risk for systemic disease developing. There are 2 well-powered randomized trials of neoadjuvant cisplatin-based chemotherapy that have shown the potential to improve the overall survival of patients with high risk transitional cell carcinoma of the bladder [2,11]. Despite the absence of similar data, many clinicians in the United States prefer to administer adjuvant chemotherapy for patients at high-risk, extrapolating the use in the neoadjuvant setting to provide a “perioperative” benefit for a more defined population. Clinicians who favor the adjuvant setting point to a recent trial conducted by investigators at the University of Texas M.D. Anderson Cancer Center. Millikan et al. [19] attempted to address several issues, including the timing of chemotherapy with respect to surgery in patients receiving the same quantity of therapy, accuracy of clinical staging information, and prognostic significance of pathologic down-staging. Their study was powered to detect a 20% improvement in survival for those patients receiving neoadjuvant/adjuvant M-VAC (2 cycles before and 3 after radical cystectomy) versus 5 cycles of M-VAC given exclusively in the adjuvant setting. After randomizing 140 patients with locally advanced disease, no significant differences in outcome were observed. Complete pathologic responses (pT0) were documented in 40% of patients receiving 2 cycles of neoadjuvant M-VAC. Toxicity was a major concern in this study, with 6 deaths in each treatment arm all considered therapy related. With a median follow-up
of 6.8 years, no differences in disease-free survival were observed [19]. In the United States, the major oncology cooperative groups recognizing the shift to the adjuvant setting have attempted to define further the use of various multiagent combination regimens. The Eastern Cooperative Oncology Group conducted a phase III trial comparing M-VAC to carboplatin and paclitaxel, and the Cancer and Leukemia Group B conducted a phase III trial comparing gemcitabine and cisplatin to a dose dense regimen developed by investigators at Memorial Sloan Kettering [20]. Both of these studies accrued less than 30 patients each and were stopped by their respective groups for lack of timely patient accrual. In an important and most likely final attempt to define the role of adjuvant chemotherapy in patients with locally advanced bladder cancer, the European Organization for Research and Treatment of Cancer is currently leading a multinational randomized phase III trial comparing immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 and/or N⫹M0 transitional cell carcinoma of the bladder. Patients with locally advanced, primarily transitional cell carcinoma will receive 1 of 3 cisplatin-based regimens (i.e., classic M-VAC regimen, gemcitabine and cisplatin, or high-dose M-VAC), as determined by the treating center. As one reviews the current status of therapy for locally advanced transitional cell carcinoma of the bladder, several observations can be made. Locally advanced bladder cancer is an aggressive and potentially lethal neoplasm. There is compelling evidence that neoadjuvant cisplatin-based chemotherapy, before radical cystectomy or definitive radiotherapy, can modestly improve survival. The role of adjuvant chemotherapy remains undefined, but urologists and medical oncologists in the United States increasingly use adjuvant chemotherapy by extrapolating a “perioperative” benefit from the neoadjuvant experience. Perioperative cisplatin-based chemotherapy, when renal function is appropriate, should now be considered a standard of care. References [1] Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. International collaboration of trialists. Lancet 1999;354:533– 40. [2] Grossman H, Natale R, Tangen C, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859 – 66. [3] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001;19:667–75. [4] Vieweg J, Gschwend J, Herr H, et al. The impact of primary stage on survival in patients with lymph node positive bladder cancer. J Urol 1999;161:72– 6. [5] Sternberg C, Yagoda A, Scher H, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985;133:403– 4. [6] Harker W, Meyers F, Freiha F, et al. Cisplatin methotrexate, and vinblastine (CMV): An effective chemotherapy regimen for meta-
R. Dreicer / Urologic Oncology: Seminars and Original Investigations 25 (2007) 72–75
[7]
[8]
[9]
[10]
[11]
[12]
[13]
static transitional cell carcinoma of the urothelial tract: A Northern California Oncology Group study. J Clin Oncol 1985;3:1463–70. Dreicer R, Messing E, Loehrer P, et al. Perioperative methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) for poor risk transitional cell carcinoma of the bladder: An Eastern Cooperative Oncology Group Pilot Study. J Urol 1990;14:1123–7. Sternberg CN, Arena MG, Calabresi F, et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for infiltrating transitional cell carcinoma of the bladder. Cancer 1993;72:1975– 82. Stockle M, Meyenburg W, Wellek S, et al. Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): Improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 1992;148:302– 6. Bajorin D, Dodd P, Mazumdar M, et al. Long-term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17:3173– 81. Hall RR, International Collaboration of Trialist of the MRC. Updated results of a randomised controlled trial of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy for muscle invasive bladder cancer. Proc Am Soc Clin Oncol 2002;21:178a [Abstract 710]. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis. Lancet 2003;361:1927–34. Skinner D, Daniels J, Russell C, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J Urol 1991;145:459 – 64.
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