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Re: A Systematic Review of Neoadjuvant and Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer
EUROPEAN UROLOGY 63 (2013) 579–584
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: A Systematic Review of Neoadjuvant and Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer Meeks JJ, Bellmunt J, Bochner BH, et al. Eur Urol 2012;62:523–33 Expert’s summary: The authors reviewed Medline databases of articles published before April 1, 2012, regarding use of perioperative chemotherapy for patients with muscle-invasive bladder cancer. In a meta-analysis of 11 randomized trials that included 3005 patients who received neoadjuvant chemotherapy with platinum-based combination regimens, there was a 5% increase in absolute overall 5-yr survival and a 9% absolute increase in 5-yr disease-free survival compared with patients who received primary cystectomy alone. More than 90% of the patients in the neoadjuvant groups received ciplatin, and the remainder received carboplatin. Current evidence does not show superiority of a specific regimen (ie, methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin [MVAC]; dose-dense MVAC; gemcitabine and cisplatin [GC]). Despite this level 1 evidence, the use of neoadjuvant chemotherapy for bladder cancer remains very low. In addition, the majority of patients who receive any perioperative chemotherapy are treated with adjuvant therapy despite the fact that evidence to support a benefit for such therapy does not exist. Expert’s comments: All can agree on certain facts regarding the staging, behavior, and outcomes for patients with muscle-invasive bladder cancer. Initial clinical staging is inadequate, and the overall accuracy is only about 57%, with overstaging in 11% and understaging in 31%. Although a well-done radical cystectomy and lymphadenectomy provide good local control and moderately good cancer-specific survival, distant relapse is the major problem limiting patient survival. Major improvements in patient survival require earlier detection and prevention of disease progression to invasion and metastatic potential (neither seems likely in the near future); better staging and identification of micrometastatic systemic disease (there is some hope for advances in imaging techniques); more effective systemic therapy at the time of gross metastatic relapse (there has been no real progress in this area in >30 yr); or earlier use of best current neoadjuvant platinum based combination chemotherapy, which has demonstrated improved patient survival. 0302-2838/$ – see back matter
Amid this background, it remains somewhat astounding that the current use of neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer in the United States remains <2% of cases. The reasons cited for not giving routine neoadjuvant chemotherapy are well known and include at least some of the following points: Patients with localized and smaller volume invasive disease enjoy good survival after a well-done cystectomy and node dissection alone. The chemotherapy may alter what had been the true initial pathologic stage. Chemotherapy delays eventual surgery and thus may allow progression in the nonresponders. Chemotherapy may increase perioperative complications. Chemotherapy is associated with morbidity, even possible mortality, increased costs, and patient inconvenience. The benefit of neoadjuvant chemotherapy has been only modest, with an increase of 5% in 5-yr patient survival. Patient preferences and comorbidities limit the use of neoadjuvant chemotherapy. Simple clinical parameters such as tumor size, hydronehprosis, lymphovascular invasion, and mixed histology may identify patients who are at highest risk for metastases and allow selective use of chemotherapy only in these patients. Progress in translational research may allow selective use of more effective chemotherapy in the patients who are at greatest risk. Allow me to respond to this litany of reasons. Even the best surgery will prove insufficient to save the significant fraction of patients who harbor systemic micrometastatic disease at the time of initial diagnosis. The ability of current best chemotherapeutic agents to save patients who are treated at the time of diagnosis of gross disease recurrence is minimal. Morbidity and mortality associated with current platinum chemotherapy has been decreased, particularly with the GC regimen. Neoadjuvant chemotherapy has not been associated with increased risks of perioperative complications. Selective and more effective use of systemic therapy is an obvious wish. The quest for methods, such as the COXEN model, to define tumor response or sensitivity to specific chemotherapy are steps in the right direction. Our group and many other investigators have identified panels of molecular
580
EUROPEAN UROLOGY 63 (2013) 579–584
markers of cell regulation that are prognostic for higher risk for disease relapse and cancer-specific mortality. Admittedly, prognostic markers may not identify patients who respond to specific chemotherapy. Even more elegant are the studies on gene profiles that may identify, at the outset, the tumors that are most prone to have early micrometastatic systemic spread. All of these approaches are steps toward more selective, intelligent, and effective use of systemic therapy. Yet, we must distinguish research from best current clinical care. We all hoped neoadjuvant chemotherapy would provide a >5% improvement in 5-yr patient survival. However, there are many forms of cancer for which medical oncologists and their patients would be thrilled to have a treatment that has level 1 evidence for a 5% improvement in
Re: Radiotherapy With or Without Chemotherapy in Muscle-invasive Bladder Cancer James ND, Hussain SA, Hall E, et al., BC2001 Investigators N Engl J Med 2012;366:1477–88 Experts’ summary: James and colleagues report the results of a phase 3 randomized study of 360 patients with clinical T2–T4aN0M0 histologically confirmed bladder cancer who received either radiotherapy alone or concomitant chemoradiation. All patients were World Health Organization performance status 0–2. The chemotherapy regimen consisted of fluorouracil (days 1–5 and 16–20) and mitomycin C (day 1). Approximately 30% of patients received neoadjuvant platinum-based chemotherapy, which was allowed but not required. Radiographic and cystoscopic response to therapy was evaluated at 6, 9, and 12 mo after randomization and then annually. The primary end point was locoregional disease-free survival (rate of recurrence free survival in bladder and pelvic nodes). Secondary and tertiary end points included rate of adverse events, rate of salvage cystectomy, disease-free survival, and overall survival. Two-year locoregional disease-free survival was significantly better for chemoradiation (67%; 95% confidence interval [CI], 59–74) than for radiation monotherapy (54%; 95% CI, 46–62). After adjusting for neoadjuvant chemotherapy, tumor stage or grade, and performance status, the hazard ratio (HR) was 0.66 ( p = 0.03) favoring multimodal therapy. Chemoradiation trended toward a lower cystectomy rate at 2 yr (11.4% vs 16.8%, p = 0.07). HRs for 5-yr cancer-specific survival (0.77; 95% CI, 0.57–1.05, p = 0.10) and overall survival (0.82; 95% CI, 0.63–1.09, p = 0.16) supported chemoradiation but were not significant. Chemotherapy regimens were well tolerated, with 95% of patients receiving an effective dose of mitomycin C and fluorouracil. Utilizing a variety of toxicity criteria, highgrade adverse event rates varied between 8.3% and 53.8% for chemoradiation and between 15.7% and 51% for radiation over a median follow-up of 69 mo. Experts’ comments: Management options for muscle-invasive bladder cancer (MIBC) include some permutation of radical cystectomy or
survival. Five percent of the approximately 15 000 patient deaths per year from bladder cancer in the United States represents 750 lives per year, or an additional 3750 lives over 5 yr, that might be saved with neoadjuvant chemotherapy. I wonder how many of those 3750 patients or their loved ones would feel that the chemotherapy was not worth it! Conflicts of interest: The author has nothing to disclose. Arthur I. Sagalowsky Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2012.12.007
radiotherapy, with or without chemotherapy. To date, a randomized trial of radical cystectomy versus bladder preservation for MIBC has unfortunately proven to be an unrecognizable goal. Fortunately, however, we do have some answers [1]. For instance, high-quality evidence demonstrates neoadjuvant chemotherapy prior to cystectomy to be superior to cystectomy alone [2]. At first glance, it would appear that the present article by James and colleagues adds little to the existing body of literature that has already established the superiority of chemoradiation over radiotherapy alone for MIBC [3,4]. Moreover, the majority of contemporary articles regarding bladder preservation report on the efficacy of varying multimodal therapy regimens, suggesting radiation monotherapy is an option of the past [5,6]. However, closer examination reveals extremely important insights into bladder-preservation strategies for MIBC. First and foremost, James et al. report oncologic outcomes with chemoradiation utilizing combination mitomycin C and fluorouracil that are comparable with prior studies that administered synchronous platinum-based chemotherapy regimens and radiation [4,6]. The vast majority of patients in the present study were able to receive effective doses of chemotherapy (approximately 95%) with a tolerable side effect profile. In contrast, nephrotoxic platinum-based regimens are often precluded by low glomerular filtration rate or are poorly tolerated by the generally less fit population that is selected for bladder preservation. The chemoradiation regimen suggested by James and colleagues may be ideally suited to elderly, frail, and renally impaired patients that have an extremely poor prognosis with transurethral resection alone and a guarded prognosis with radiation monotherapy. At this point, we do not know how radiosensitizing mitomycin–fluorouracil combination therapy directly compares with cisplatin; the two drugs may have different clinical niches depending on patient health, renal function, and concern for micrometastatic disease. Second, the present article raises important considerations regarding the selection of a primary end point for this type of study. The authors chose locoregional control as the primary end point and found a significant difference in the two arms. Although this is certainly an important
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: A Systematic Review of Neoadjuvant and Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer Meeks JJ, Bellmunt J, Bochner BH, et al. Eur Urol 2012;62:523–33 Expert’s summary: The authors reviewed Medline databases of articles published before April 1, 2012, regarding use of perioperative chemotherapy for patients with muscle-invasive bladder cancer. In a meta-analysis of 11 randomized trials that included 3005 patients who received neoadjuvant chemotherapy with platinum-based combination regimens, there was a 5% increase in absolute overall 5-yr survival and a 9% absolute increase in 5-yr disease-free survival compared with patients who received primary cystectomy alone. More than 90% of the patients in the neoadjuvant groups received ciplatin, and the remainder received carboplatin. Current evidence does not show superiority of a specific regimen (ie, methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin [MVAC]; dose-dense MVAC; gemcitabine and cisplatin [GC]). Despite this level 1 evidence, the use of neoadjuvant chemotherapy for bladder cancer remains very low. In addition, the majority of patients who receive any perioperative chemotherapy are treated with adjuvant therapy despite the fact that evidence to support a benefit for such therapy does not exist. Expert’s comments: All can agree on certain facts regarding the staging, behavior, and outcomes for patients with muscle-invasive bladder cancer. Initial clinical staging is inadequate, and the overall accuracy is only about 57%, with overstaging in 11% and understaging in 31%. Although a well-done radical cystectomy and lymphadenectomy provide good local control and moderately good cancer-specific survival, distant relapse is the major problem limiting patient survival. Major improvements in patient survival require earlier detection and prevention of disease progression to invasion and metastatic potential (neither seems likely in the near future); better staging and identification of micrometastatic systemic disease (there is some hope for advances in imaging techniques); more effective systemic therapy at the time of gross metastatic relapse (there has been no real progress in this area in >30 yr); or earlier use of best current neoadjuvant platinum based combination chemotherapy, which has demonstrated improved patient survival. 0302-2838/$ – see back matter
Amid this background, it remains somewhat astounding that the current use of neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer in the United States remains <2% of cases. The reasons cited for not giving routine neoadjuvant chemotherapy are well known and include at least some of the following points: Patients with localized and smaller volume invasive disease enjoy good survival after a well-done cystectomy and node dissection alone. The chemotherapy may alter what had been the true initial pathologic stage. Chemotherapy delays eventual surgery and thus may allow progression in the nonresponders. Chemotherapy may increase perioperative complications. Chemotherapy is associated with morbidity, even possible mortality, increased costs, and patient inconvenience. The benefit of neoadjuvant chemotherapy has been only modest, with an increase of 5% in 5-yr patient survival. Patient preferences and comorbidities limit the use of neoadjuvant chemotherapy. Simple clinical parameters such as tumor size, hydronehprosis, lymphovascular invasion, and mixed histology may identify patients who are at highest risk for metastases and allow selective use of chemotherapy only in these patients. Progress in translational research may allow selective use of more effective chemotherapy in the patients who are at greatest risk. Allow me to respond to this litany of reasons. Even the best surgery will prove insufficient to save the significant fraction of patients who harbor systemic micrometastatic disease at the time of initial diagnosis. The ability of current best chemotherapeutic agents to save patients who are treated at the time of diagnosis of gross disease recurrence is minimal. Morbidity and mortality associated with current platinum chemotherapy has been decreased, particularly with the GC regimen. Neoadjuvant chemotherapy has not been associated with increased risks of perioperative complications. Selective and more effective use of systemic therapy is an obvious wish. The quest for methods, such as the COXEN model, to define tumor response or sensitivity to specific chemotherapy are steps in the right direction. Our group and many other investigators have identified panels of molecular
580
EUROPEAN UROLOGY 63 (2013) 579–584
markers of cell regulation that are prognostic for higher risk for disease relapse and cancer-specific mortality. Admittedly, prognostic markers may not identify patients who respond to specific chemotherapy. Even more elegant are the studies on gene profiles that may identify, at the outset, the tumors that are most prone to have early micrometastatic systemic spread. All of these approaches are steps toward more selective, intelligent, and effective use of systemic therapy. Yet, we must distinguish research from best current clinical care. We all hoped neoadjuvant chemotherapy would provide a >5% improvement in 5-yr patient survival. However, there are many forms of cancer for which medical oncologists and their patients would be thrilled to have a treatment that has level 1 evidence for a 5% improvement in
Re: Radiotherapy With or Without Chemotherapy in Muscle-invasive Bladder Cancer James ND, Hussain SA, Hall E, et al., BC2001 Investigators N Engl J Med 2012;366:1477–88 Experts’ summary: James and colleagues report the results of a phase 3 randomized study of 360 patients with clinical T2–T4aN0M0 histologically confirmed bladder cancer who received either radiotherapy alone or concomitant chemoradiation. All patients were World Health Organization performance status 0–2. The chemotherapy regimen consisted of fluorouracil (days 1–5 and 16–20) and mitomycin C (day 1). Approximately 30% of patients received neoadjuvant platinum-based chemotherapy, which was allowed but not required. Radiographic and cystoscopic response to therapy was evaluated at 6, 9, and 12 mo after randomization and then annually. The primary end point was locoregional disease-free survival (rate of recurrence free survival in bladder and pelvic nodes). Secondary and tertiary end points included rate of adverse events, rate of salvage cystectomy, disease-free survival, and overall survival. Two-year locoregional disease-free survival was significantly better for chemoradiation (67%; 95% confidence interval [CI], 59–74) than for radiation monotherapy (54%; 95% CI, 46–62). After adjusting for neoadjuvant chemotherapy, tumor stage or grade, and performance status, the hazard ratio (HR) was 0.66 ( p = 0.03) favoring multimodal therapy. Chemoradiation trended toward a lower cystectomy rate at 2 yr (11.4% vs 16.8%, p = 0.07). HRs for 5-yr cancer-specific survival (0.77; 95% CI, 0.57–1.05, p = 0.10) and overall survival (0.82; 95% CI, 0.63–1.09, p = 0.16) supported chemoradiation but were not significant. Chemotherapy regimens were well tolerated, with 95% of patients receiving an effective dose of mitomycin C and fluorouracil. Utilizing a variety of toxicity criteria, highgrade adverse event rates varied between 8.3% and 53.8% for chemoradiation and between 15.7% and 51% for radiation over a median follow-up of 69 mo. Experts’ comments: Management options for muscle-invasive bladder cancer (MIBC) include some permutation of radical cystectomy or
survival. Five percent of the approximately 15 000 patient deaths per year from bladder cancer in the United States represents 750 lives per year, or an additional 3750 lives over 5 yr, that might be saved with neoadjuvant chemotherapy. I wonder how many of those 3750 patients or their loved ones would feel that the chemotherapy was not worth it! Conflicts of interest: The author has nothing to disclose. Arthur I. Sagalowsky Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2012.12.007
radiotherapy, with or without chemotherapy. To date, a randomized trial of radical cystectomy versus bladder preservation for MIBC has unfortunately proven to be an unrecognizable goal. Fortunately, however, we do have some answers [1]. For instance, high-quality evidence demonstrates neoadjuvant chemotherapy prior to cystectomy to be superior to cystectomy alone [2]. At first glance, it would appear that the present article by James and colleagues adds little to the existing body of literature that has already established the superiority of chemoradiation over radiotherapy alone for MIBC [3,4]. Moreover, the majority of contemporary articles regarding bladder preservation report on the efficacy of varying multimodal therapy regimens, suggesting radiation monotherapy is an option of the past [5,6]. However, closer examination reveals extremely important insights into bladder-preservation strategies for MIBC. First and foremost, James et al. report oncologic outcomes with chemoradiation utilizing combination mitomycin C and fluorouracil that are comparable with prior studies that administered synchronous platinum-based chemotherapy regimens and radiation [4,6]. The vast majority of patients in the present study were able to receive effective doses of chemotherapy (approximately 95%) with a tolerable side effect profile. In contrast, nephrotoxic platinum-based regimens are often precluded by low glomerular filtration rate or are poorly tolerated by the generally less fit population that is selected for bladder preservation. The chemoradiation regimen suggested by James and colleagues may be ideally suited to elderly, frail, and renally impaired patients that have an extremely poor prognosis with transurethral resection alone and a guarded prognosis with radiation monotherapy. At this point, we do not know how radiosensitizing mitomycin–fluorouracil combination therapy directly compares with cisplatin; the two drugs may have different clinical niches depending on patient health, renal function, and concern for micrometastatic disease. Second, the present article raises important considerations regarding the selection of a primary end point for this type of study. The authors chose locoregional control as the primary end point and found a significant difference in the two arms. Although this is certainly an important