|Year : 2020 | Volume
| Issue : 4 | Page : 149-155
Neoadjuvant chemotherapy for bladder cancer
RB Nerli1, Manas Sharma1, Shridhar C Ghagane2, Shashank D Patil1, Pulkit Gupta1, Neeraj S Dixit2, Murigendra B Hiremath3
1 Department of Urology, JN Medical College, KLE Academy of Higher Education and Research, JNMC Campus, Karnataka, India
2 Department of Urology, Urinary Biomarkers Research Centre, KLES Dr. Prabhakar Kore Hospital and MRC, Belagavi, Karnataka, India
3 Department of Biotechnology and Microbiology, Karnatak University, Dharwad, Karnataka, India
|Date of Submission||11-May-2020|
|Date of Decision||17-Jul-2020|
|Date of Acceptance||26-Jul-2020|
|Date of Web Publication||1-Dec-2020|
Dr. R B Nerli
Department of Urology, JN Medical College, KLE Academy of Higher Education and Research (Deemed-to-be-University), JNMC Campus, Belagavi - 590 010, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Muscle invasive bladder cancer (MIBC) is an aggressive malignancy, with 5-year survival rates ranging from 36% to 48% for pT3-4/pN+ tumors. Radical cystectomy (RC) remains the gold-standard treatment for the management of MIBC. Perioperative treatment can improve overall survival (OS), with more robust evidence favoring neoadjuvant chemotherapy (NAC). Objective: This review aims to discuss the historical perspectives, recent advances, experimental therapies, and current evidence for the use of various chemotherapeutic drugs in a neo-adjuvant setting for the treatment of MIBC. Data Sources: We searched and analyzed research articles, reviews, clinical trials, and meta-analyses addressing NAC in the management of MIBC. Results: The advantages of NAC in MIBC include the delivery of chemotherapy at the earliest time point when the micrometastatic burden is presumed to be the lowest. It has improved patient compliance and better tolerability in preoperative period with more number of patients completing the therapy. It reflects in vivo chemosensitivity of urothelial cancer along with favorable pathological outcomes in individual showing response. Delay in RC in nonresponders and overtreatment in low-stage disease are the potential disadvantages. Conclusion: NAC in MIBC is associated with improved OS. Cisplatin-based NAC is the current standard of care in eligible patients.
Keywords: Bladder cancer, Neoadjuvant chemotherapy, Urothelial carcinoma
|How to cite this article:|
Nerli R B, Sharma M, Ghagane SC, Patil SD, Gupta P, Dixit NS, Hiremath MB. Neoadjuvant chemotherapy for bladder cancer. J Cancer Res Pract 2020;7:149-55
|How to cite this URL:|
Nerli R B, Sharma M, Ghagane SC, Patil SD, Gupta P, Dixit NS, Hiremath MB. Neoadjuvant chemotherapy for bladder cancer. J Cancer Res Pract [serial online] 2020 [cited 2021 Feb 26];7:149-55. Available from: https://www.ejcrp.org/text.asp?2020/7/4/149/301905
| Introduction|| |
Bladder cancer is the fourth most commonly diagnosed cancer in men and the eighth in women in the United States. The American Cancer Society's estimates for bladder cancer in the United States for 2020 are about 81,400 (62,100 in men and 19,300 in women) new cases and about 17,980 deaths (13,050 men and 4,930 women). Worldwide, bladder cancer remains the ninth most common malignancy. Estimated annual incidences of 382,660 cases and 150,282 deaths were reported in 2008., Tumors that are nonmuscle invasive (2) can be effectively treated with transurethral resection and intravesical therapy. Cystoscopic surveillance at regular intervals is required because of the high rate of recurrence and subsequent progression to more advanced disease, particularly in those with high-grade urothelial carcinoma. Tumors that are muscle invasive (approximately 20%) are usually treated with radical cystectomy (RC). However, there is a substantial rate of recurrence (56% among patients with pT3 disease), most commonly as distant metastases.
The stage of the disease at the presentation has a significant impact on individual outcomes and long-term survival in patients managed with primary cystectomy and lymph node dissection. In a retrospective study of 1054 patients, the 5-year and 10-year recurrence-free survival and overall survival (OS) rates in organ-confined, lymph-node-negative bladder cancer were 85% and 82%, and 78%, and 56%, respectively. Patients with lymph node-positive disease had considerably worse survival outcomes, with 5-year and 10-year recurrence-free survival rates of 35% and 35%, and OS rates of 31% and 23%, respectively. Research has focused on the early eradication of micrometastatic spread with perioperative chemotherapy, as positive lymph node status or distant metastatic disease carries an abysmal prognosis. The use of neoadjuvant chemotherapy (NAC) seems to be an attractive treatment option for muscle-invasive bladder cancer (MIBC), given the general chemosensitivity of urothelial carcinoma and the lack of NAC-associated surgical complications. Several studies have reported difficulty in administering chemotherapy in an adjuvant setting owing to surgical morbidity and postoperative complications.,
In this article, we review several clinical articles, review articles, and analyses to assess the significance of achieving a tumor response following NAC, the preferred drug combinations in a neoadjuvant setting, the role of NAC in cisplatin-ineligible patients, and a brief note on the novel agents under evaluation for neoadjuvant therapy.
| the Implications of Achieving a Tumor Response to Neoadjuvant Chemotherapy|| |
NAC is widely used in the treatment of several solid tumors, including breast, rectum, lung, and many more. The goal of using NAC in all such settings is to improve patient outcomes through tumor down-staging, elimination of micrometastatic disease, and improving the ability to administer the effective doses of chemotherapeutic agents compared with the postoperative setting. As far as bladder cancer is concerned, achieving any degree of pathological response translates into improved survival rates. This benefit was demonstrated by Splinter et al. in a retrospective analysis of patients who received NAC before RC. The 5-year survival rate for patients achieving a pathological response (2) was 75% versus 20% in the patients who did not show a pathological response (P< 0.0001). Similarly, in another retrospective study of patients receiving combination chemotherapy (methotrexate, vinblastine, adriamycin and cisplatin; MVAC) preoperatively, achieving a pathological response in organ-confined disease versus nonorgan-confined disease was associated with improved 5-year survival (61% vs. 35%, respectively). Another perceived benefit of achieving a tumor response is the application of bladder preservation protocols in the management of MIBC. The primary aim of bladder preservation is to achieve oncological outcomes comparable to RC and maintain the patient's quality of life. NAC can help realize these goals in appropriately selected patients. An ideal patient to consider for bladder preservation would be one with a unifocal tumor (≤pT2 disease) with the absence of Carcinoma in situ (CIS), absence of hydronephrosis, and macroscopically complete TURBT with good bladder capacity.
| Historical Perspective of Neoadjuvant Chemotherapy|| |
Grossman et al. assessed the capability of NAC to enhance the disease outcome in patients with locally advanced bladder cancer who were managed with RC. They enrolled 317 patients over 11 years, of whom 154 were subjected to surgery alone, and 153 were assigned to receive combination chemotherapy. In intention-to-treat analysis, the median survival times among patients assigned to the surgical and NAC arms were 46 months and 77 months, respectively (P = 0.06). In both groups, improved survival was associated with the absence of residual disease in the RC specimen. Considerably, more patients in the NAC arm had an absence of residual disease than those assigned to the cystectomy group (38% vs. 15%, P < 0.001) [Table 1].
|Table 1: Select phase III randomized controlled trials for neoadjuvant chemotherapy in muscle invasive bladder cancer|
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The Nordic Cystectomy Trial I recruited 311 eligible patients with MIBC (Stage T2-4aNXM0). The participants were randomized to receive two cycles of NAC (cisplatin and doxorubicin) at 3-weekly intervals followed by radiation therapy versus radiation and RC alone. Subset analysis revealed a 15% absolute survival benefit in patients with T3-4a disease receiving NAC (P = 0.03).
In the largest phase III randomized clinical trial conducted to date by the International Collaboration of Trialists investigating the role of NAC in MIBC, three cycles of cisplatin, methotrexate, and vinblastine (CMV) NAC administered every 3 weeks was compared to nonneoadjuvant therapy. A total of 976 patients with Stage T2-T4aN0/XM0 urothelial bladder cancer and a glomerular filtration rate >50 ml/min were randomized to receive NAC or no therapy before definitive treatment (RC, radiotherapy or radiotherapy plus RC). In the final analysis, 43% of the patients received radiation therapy, 49% underwent RC, and 8% received a combination of the two. At 3 years of follow-up, a nonsignificant 5.5% absolute difference in survival was observed in favor of NAC (P = 0.075). However, at a longer median follow-up of 8 years, a statistically significant 16% reduction in the risk of death (P = 0.037) was demonstrated, corresponding to a 10-year survival improvement from 30% to 36%.
| Preferred Neoadjuvant Chemotherapy Drug Combinations|| |
A South West Oncology Group (SWOG) trial explored the role of four drugs in the neoadjuvant setting for chemotherapy. The MVAC regimen was originally studied at Memorial Sloan-Kettering Cancer Center (MSKCC) in the 1980s, with a significant response reported in patients with advanced disease. An early retrospective analysis of the MSKCC experience with neoadjuvant MVAC demonstrated promising activity. In this review, 111 patients with T2-3N0M0 MIBC received neoadjuvant MVAC, of whom 60 (54%) showed a complete clinical response (cCR). Of these patients, 43 (71.66%) underwent bladder-preserving surgery, and 74% were still alive after an average follow-up of 10 years, with 58% having a functioning bladder. Another prospective phase III randomized trial (SWOG 8710/INT-0080) investigated the role of neoadjuvant MVAC followed by RC. A total of 317 patients with MIBC eligible for RC and cisplatin-based chemotherapy were randomized to receive NAC (methotrexate [30 mg/m2], vinblastine [3 mg/m2], doxorubicin [30 mg/m2] and cisplatin [70 mg/m2]) for three cycles followed by RC versus RC alone. In intention-to-treat analysis of 307 patients, the median survival in the combination therapy arm was 77 months versus 46 months in surgery alone arm (P = 0.06).
The gemcitabine and cisplatin (GC) chemotherapy regimen carries significant toxicity. When given in a neoadjuvant setting, patients have been reported to experience granulocytopenia (Grade 4: 33%), stomatitis (Grade 3: 10%), and combined gastrointestinal toxicity of nausea, vomiting, diarrhea or constipation (Grade 3: 10%). For these reasons alone, the GC regimen has mostly been replaced by the MVAC regimen for metastatic disease based on a phase III trial. The use of GC stems from the desire to avoid the toxicity profile of the MVAC regimen while maintaining efficacy. The efficacy of the combination of GC for metastatic disease was established by von der Maase et al., who reported similar progression-free survival (PFS) (7.7 vs. 8.3 months) and OS (14.0 vs. 15.2 months; HR: 1.09; 95% CI: 0.88-1.34; P = 0.66) between GC and MVAC, respectively. Although an increased incidence of Grade 3 or 4 anemia (27% vs. 18%) and Grade 3 or 4 thrombocytopenia (57% vs. 21%) was noted in the GC regimen, the toxicity profile was better.
GC has also been evaluated in the neoadjuvant setting. The first retrospective analysis reported by the MSKCC group compared the outcomes of 42 patients who received GC with 54 patients who received MVAC. The proportion of patients who achieved a pathologic complete response (pCR) (26% vs. 28%) and 2 response (36% vs 35%) was equivalent between GC and MVAC, respectively. A small prospective phase II trial of neoadjuvant GC regimen including 22 patients reported a pCR rate of 26.7%. The median PFS was 26 months, and the median OS was 36 months. Comparable rates of pCR between GC and MVAC regimens indicates the long-term treatment effectiveness and improved survival. These results support the use of GC in a neoadjuvant setting.
| Meta-Analysis|| |
The Advanced Bladder Cancer Meta-Analysis Collaboration analyzed 3005 patients from 11 different trials, integrated 98% of all patients from these randomized clinical trials, and summarized the survival benefits associated with NAC. The pooled results revealed a 14% reduction in the risk of death, translating into a 5% absolute survival benefit at 5 years of follow-up (hazard ratio = 0.86; 95% confidence interval: 0.77–0.95; P = 0.003) for patients treated with cisplatin-based NAC. This benefit was consistent across various subgroups irrespective of age, clinical stage, and performance status. The Advanced Bladder Cancer meta-analysis firmly established the benefit of NAC and its role in the management of locally advanced MIBC [Figure 1] and [Figure 2].
|Figure 1: Computed tomography (a and b: Axial cuts; c and d: Sagittal cuts) of a patient presenting with gross hematuria showing multiple tumours over the anterior, posterior and lateral walls of the urinary bladder|
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|Figure 2: (a) Cystoscopic view of bladder tumours at diagnosis showing multiple sessile tumours along with increased vascularity. (b) A patient received three cycles of MVAC. Postchemotherapy cystoscopy showed marginally reduced size and decreased vascularity of the tumour and surrounding bladder mucosa|
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| Dosing Schedule Options|| |
Several alternate dosing schedules of cisplatin-based NAC have been explored as a means of further improving disease response and survival outcomes. A collective strategy has been to intensify the dosing frequency from every 3 or 4 weeks to every 2 weeks. Several studies have also evaluated the efficacy and safety of this dose-dense (DD) schedule in both advanced and the neoadjuvant settings for urothelial carcinoma.
In the advanced setting, Sternberg et al. reported an improved cCR (25% vs. 11%; P = 0.006) and PFS (9.5 vs. 8.1 months; P = 0.017) with similar safety in a 2-week versus 4-week MVAC schedule, respectively. Similarly, the Hellenic Oncology Group compared DD-MVAC and DD-GC in the advanced/metastatic setting and reported comparable PFS (8.5 vs. 7.8 months; P = 0.36) and OS (19 vs. 18 months; P = 0.098), respectively, between the regimens and improved tolerability and less toxicity with the DD-GC regimen.
Elmongy et al. reported a 50% pCR rate in a small feasibility study of 12 patients who received DD-MVAC before RC. A retrospective analysis of 80 patients with T2-4aN0-2M0 disease managed with DD-MVAC (three or four cycles) followed by RC or radiation therapy indicated that out of the 60 subjects who underwent RC, 24 (40%) were disease free. Additionally, 52% of the patients had 2 disease, and the 2-year disease-free survival and OS rates were 65% and 77%, respectively.
| Role of Neoadjuvant Chemotherapy in Cisplatin-Ineligible Patients|| |
Cisplatin-based regimens with either GC or MVAC have served as the first-line options in the treatment of advanced, unresectable, or metastatic bladder cancer and remain the standard of care. Up to 50% of cases ineligible for cisplatin-based chemotherapy are due to a number of medical comorbidities. One consensus review suggested that patients with the following conditions should be considered ineligible for chemotherapy [Figure 3]:
|Figure 3: Management algorithm for nonmetastatic muscle invasive bladder cancer|
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- Impaired renal function (CrCl <60 ml/min)
- Poor performance status (Eastern Cooperative Oncology Group of 2 or Karnofsky performance status ≤60%–70%)
- Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) Grade ≥2 hearing loss by audiometry
- CTCAE version 4 Grade ≥2 peripheral neuropathy, and
- New York Health Association Class III heart failure
Multiple randomized trials have tested the effectiveness of carboplatin-based regimens in the neoadjuvant setting. One small phase II trial assessed neoadjuvant paclitaxel, carboplatin, and gemcitabine (PCaG) in patients with CrCl > 40 ml/min, adequate bone marrow, and liver function. Patients were registered into two arms according to stage [T2-3N0M0(arm 1) or T2-4N1-3M0(arm 2)] with primary endpoints of pCR (arm 1) and resectability (arm 2), respectively. An analogous SWOG 0219 phase II trial evaluated the efficacy of three cycles of PCaG followed by surveillance or RC. Of 74 patients who were evaluable after NAC, 34 (46%) were clinically disease-free on follow-up TURBT. Of these patients, 10 underwent RC, of whom four had a pCR and the remaining six had residual pT2-4 malignancies.
A separate phase II trial in patients eligible for cisplatin-based therapy assessed the effectiveness of methotrexate, vinblastine, and carboplatin in the neoadjuvant setting, and it therefore serves as a potential reference for a similar regimen in cisplatin-ineligible patients. In this trial, patients with T2-4N0M0 bladder cancer received the three-drug regimen on a 28-day schedule for four cycles, with the principal outcome of pCR. A pathological response was noted in 40% of the 47 patients treated, of whom 12 (26.5%) achieved a pCR with a disease-specific survival rate of 42% at 2 years of follow-up.
In summary, cisplatin-ineligible patients can be offered alternative chemotherapy regimens; however, the survival benefit is far superior in patients who receive cisplatin-based chemotherapy. At present, numerous clinical trials are being conducted to address this issue. It would be apt to say that the results from these studies will further clarify whether cisplatin-ineligible patients benefit from novel immune-checkpoint inhibitor therapy.
| Novel Agents in the Neoadjuvant Setting|| |
Several trials have evaluated anti-VEGF therapy for urothelial carcinoma of the bladder. A phase II trial in advanced urothelial carcinoma assessed the effectiveness of GC plus bevacizumab (GC-Bev) combination therapy. A median PFS of 8.2 months, median OS, and overall response rates of 19.1 months and 72%, respectively, were reported. Based on these data, a randomized, double-blind, placebo-controlled phase III trial is presently being conducted to define the role of GC-Bev in advanced urothelial carcinoma as a first-line therapy. Researchers are also reviewing the role of neoadjuvant bevacizumab in many small, single-institutional studies. An interim analysis of a phase II trial evaluating neoadjuvant GC-Bev followed by surgery has provided some insight into the role of neoadjuvant anti-angiogenic therapy. Patients with evidence of persistent disease on RC specimens were subjected to adjuvant paclitaxel plus bevacizumab therapy.
Sunitinib is an oral multi-target receptor tyrosine kinase inhibitor with potent VEGF inhibition. It was tested in combination with GC in a neoadjuvant setting with the primary endpoint of pCR. Although closed early due to incomplete accrual (18 out of a planned 45 patients), one patient attained a pCR (6.6%), and five (33%) patients had 2 disease; and of these latter five, four exhibited pTis responses.
Single-agent erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, was studied in a small phase II trial in patients with MIBC (clinical T2N0M0) with a principal outcome of pCR. Out of the 20 evaluable patients treated with erlotinib (150 mg daily for 4 weeks), five (25%) had a pCR and seven (35%) had a ≤pT1 response and an overall organ-confined response rate of 75%. The most common side effect was rash; notably, every patient who exhibited any degree of disease down-staging also experienced a rash. More extensive phase II or confirmatory phase III trials are essential to determine the usefulness of this EGFR inhibitor in a neoadjuvant setting and also to explore the relationship between skin toxicity and response to chemotherapy.
Similarly, dasatinib, an oral tyrosine kinase inhibitor of Src-mediated signalling, was studied in a phase II neoadjuvant trial in patients unsuitable for or reluctant to accept cisplatin-based therapy. A daily oral dose of 100 mg dasatinib was used for 28 ± 7 days, followed by RC 8-24 h after the last dose of treatment. The primary endpoint was the feasibility of >60% of the patients completing RC without dose-limiting toxicity. Although the trial did reach its goal with 15 of 25 patients (68%) achieving surgical resection, the pathological response was T1 or Tis in three patients (14%) and ≥T2 in 19 patients (86%) with node-positive disease in six patients (27%).
| Future Perspectives|| |
NAC represents a standard of care for the treatment of muscle-invasive urothelial cancer. Immune checkpoint inhibitors, including anti-PD1 and anti-PDL1 agents (targeted therapy), have shown efficacy in the treatment of advanced bladder cancer, and the use of these drugs in a neoadjuvant setting seems reasonable. These agents are currently under clinical trials. Given the dismal prognosis of patients with advanced disease, the neoadjuvant setting represents a critical opportunity to prevent the development of metastatic urothelial cancer and/or eradicate preexisting micro-metastases. Several studies are underway to identify whether molecular profiles or biologic markers can identify which patients are more likely to respond or should be excluded from NAC based on predicted resistance. One such approach is the co-expression extrapolation (COXEN) methodology which utilizes gene expression models derived fromin vitro drug testing of established cell line panels, such as NCI-60, to generate the predictive biomarkers of response to standard chemotherapy., If successful, COXEN could represent a patient-specific biomarker that can be used to predict a response to neoadjuvant treatment and survival.
| Conclusion|| |
Cisplatin-based NAC is the current standard of care in eligible patients. There are several advantages of NAC before RC in patients with MIBC. The most prominent advantage is delivering chemotherapy at the earliest time-point when the burden of micro-metastatic disease is expected to be the lowest. This ensures better tolerability and patient compliance in the preoperative period, which in turn ensures that more patients can complete the planned chemotherapy. NAC also reflects thein vivo chemosensitivity of bladder tumours. Patients responding to NAC have a favorable prognosis and long-term survival as determined by pathological staging of RC specimens. Novel immunotherapeutic agents targeting VEGF and EGFR inhibition also have shown promising results.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15-36.
Tully CM, Iyer G, Bajorin DF. Neoadjuvant chemotherapy in bladder cancer. Clin Invest 2013;3:991-1002.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.
Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, et al
. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ
transitional cell carcinoma of the bladder: A randomized Southwest Oncology Group Study. J Urol 2000;163:1124-9.
Nerli RB, Ghagane SC, Shankar K, Sanikop AC, Hiremath MB, Dixit NS, et al
. Low-grade, multiple, ta non-muscle-invasive bladder tumors: Tumor recurrence and worsening progression. Indian J Surg Oncol 2018;9:157-61.
Skinner DG, Lieskovsky G. Contemporary cystectomy with pelvic node dissection compared to preoperative radiation therapy plus cystectomy in management of invasive bladder cancer. J Urol 1984;131:1069-72.
Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al
. Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001;19:666-75.
Donat SM, Shabsigh A, Savage C, Cronin AM, Bochner BH, Dalbagni G, et al
. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: A high-volume tertiary cancer center experience. Eur Urol 2009;55:177-85.
Hudis C, Modi S. Preoperative chemotherapy for breast cancer: Miracle or mirage? JAMA 2007;298:2665-7.
Schrag D, Weiser MR, Goodman KA, Gonen M, Cercek A, Reidy DL, et al
. Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer. J Clin Oncol 2010;28 Suppl 15:3511.
Song WA, Zhou NK, Wang W, Chu XY, Liang CY, Tian XD, et al
. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: An updated meta-analysis of 13 randomized control trials. J Thorac Oncol 2010;5:510-6.
Splinter TA, Scher HI, Denis L, Bukowski R, Simon S, Klimberg I, et al
. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. European Organization for Research on Treatment of Cancer-Genitourinary Group. J Urol 1992;147:606-8.
Schultz PK, Herr HW, Zhang ZF, Bajorin DF, Seidman A, Sarkis A, et al
. Neoadjuvant chemotherapy for invasive bladder cancer: Prognostic factors for survival of patients treated with M-VAC with 5-year follow-up. J Clin Oncol 1994;12:1394-401.
Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al
. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N
Engl J Med 2003;349:859-66.
Pentyala S, Nerli RB, Ghagane SC, Hiremath MB. Bladder preservation protocols in the management of muscle-invasive bladder cancer: A systematic review. J Sci Soc 2018;45:84-9. [Full text]
Malmström PU, Rintala E, Wahlqvist R, Hellström P, Hellsten S, Hannisdal E. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 1996;155:1903-6.
Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. International collaboration of trialists. Lancet 1999;354:533-40.
International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, Australian Bladder Cancer Study Group, National Cancer Institute of Canada Clinical Trials Group, Finnbladder, et al
. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial. J Clin Oncol 2011;29:2171-7.
Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: Ten-year outcome. J Clin Oncol 1998;16:1298-301.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al
. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23:4602-8.
Dash A, Pettus IV JA, Herr HW, Bochner BH, Dalbagni G, Donat SM, et al
. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: A retrospective experience. Cancer 2008;113:2471-7.
Herchenhorn D, Dienstmann R, Peixoto FA, de Campos FS, Santos VO, Moreira DM, et al
. Phase II trial of neoadjuvant gemcitabine and cisplatin in patients with resectable bladder carcinoma. Int Braz J Urol 2007;33:630-8.
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: Update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48:202-5.
Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al
. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006;42:50-4.
Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, et al
. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: A Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol 2013;24:1011-7.
Elmongy MB, Kaag M, Reese CT, Algood CB. Feasibility and efficacy of neoadjuvant chemotherapy with dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC) in patients with high-grade urothelial cancer with muscle invasion. J Clin Oncol 2011;29 Suppl 15:E15189.
Blick C, Hall P, Pwint T, Al-Terkait F, Crew J, Powles T, et al
. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder. Cancer 2012;118:3920-7.
De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al
. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012;30:191-9.
Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al
. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol 2011;29:2432-8.
Smith DC, Mackler NJ, Dunn RL, Hussain M, Wood D, Lee CT, et al
. Phase II trial of paclitaxel, carboplatin and gemcitabine in patients with locally advanced carcinoma of the bladder. J Urol 2008;180:2384-8.
deVere White RW, Lara PN Jr., Goldman B, Tangen CM, Smith DC, Wood DP Jr., et al
. A sequential treatment approach to myoinvasive urothelial cancer: A phase II Southwest Oncology Group trial (S0219). J Urol 2009;181:2476-80.
Bellmunt J, Ribas A, Albanell J, Bermejo B, Vera R, De Torres JA, et al
. M-CAVI, a neoadjuvant carboplatin-based regimen for the treatment of T2-4N0M0 carcinoma of the bladder. Am J Clin Oncol 1996;19:344-8.
Hahn NM, Stadler WM, Zon RT, Waterhouse D, Picus J, Nattam S, et al
. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. J Clin Oncol 2011;29:1525-30.
Chaudhary UB, Golshayan AR, Brisendine A, Kraft AS, Clarke H, Keane TE. 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. J Clin Oncol 2011;29 Suppl 7:276.
Balar AV, Iyer G, Apolo AB, Regazzi AM, Garcia-Grossman IR, Pendse D. Phase II trial of neoadjuvant gemcitabine (G) and cisplatin © with sunitinib in patients (pts) with muscle-invasive bladder cancer (MIBC). ASCO Meeting Abstracts 2012;30 Suppl 15:4581.
Pruthi RS, Nielsen M, Heathcote S, Wallen EM, Rathmell WK, Godley P, 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;106:349-54.
Hahn NM, Daneshmand S, Posadas EM, Koch MO, Bihrle R, Foster R, et al
. A phase II trial of neoadjuvant dasatinib (Neo-D) in muscle-invasive urothelial carcinoma of the bladder (miUCB): Hoosier Oncology Group GU07-122 trial 2012:4586.
Lee JK, Havaleshko DM, Cho H, Weinstein JN, Kaldjian EP, Karpovich J, et al
. A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc Natl Acad Sci U S A 2007;104:13086-91.
Smith SC, Baras AS, Lee JK, Theodorescu D. The COXEN principle: Translating signatures of in vitro
chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. Cancer Res 2010;70:1753-8.
Nerli RB, Ghagane SC, Musale A, Deole S, Mohan S, Dixit NS, et al
. Chemotherapy in a patient with advanced carcinoma of the bladder with renal insufficiency. J Sci Soc 2018;45:139. [Full text]
Sengeløv L, von der Maase H, Lundbeck F, Barlebo H, Colstrup H, Engelholm SA, et al
. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol 2002;41:447-56.
Sherif A, Holmberg L, Rintala E, Mestad O, Nilsson J, Nilsson S, et al
. Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: A combined analysis of two Nordic studies. Eur Urol 2004;45:297-303.
Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, et al
. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol 2014;25:1192-8.
[Figure 1], [Figure 2], [Figure 3]