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| Role of gemcitabine and cisplatin as neoadjuvant chemotherapy in muscle invasive bladder cancer: Experience over the last decade |
Sunny Goel( ),Rahul J. Sinha,Ved Bhaskar,Ruchir Aeron,Ashish Sharma,Vishwajeet Singh
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| Department of Urology, King George Medical University, Lucknow, India |
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Abstract Objective:Neoadjuvant chemotherapy followed by radical cystectomy is considered the standard of care for patients with muscle invasive bladder cancer. In the last decade, interest in neoadjuvant chemotherapy has slowly shifted from methotrexate, vinblastine, doxorubicin and cisplatin regime to gemcitabine and cisplatin regime. There are many publications on gemcitabine and cisplatin regime in literature which cover different aspects of treatment. This review aims to summarise the findings published so far on gemcitabine and cisplatin regime and present it in a concise manner. Methods: A systematic literature review was conducted searching the PubMed® database in December 2016 using the medical subject heading (MeSH) with the terms gemcitabine, cisplatin, chemotherapy, muscle invasive bladder cancer, and neoadjuvant. All relevant studies were included and results were analysed. Results: A total of 13 studies were included which published between 2007 and 2015. These 13 studies comprised of 754 subjects suffering from muscle invasive bladder cancer. The proportion of male patients ranged from 60% to 86.4% and the median age ranged from 54.2 to 77.3 years in various studies. Complete pathological response (pT0) was seen in 30.0% of patients and pathological downstaging (<pT2) was seen in 48.67% of patients. Conclusion: As per latest guidelines, neoadjuvant chemotherapy is recommended for patients with muscle invasive bladder cancer. There is substantial pathological downstaging with low toxicity in patients of muscle invasive bladder cancer who receive neoadjuvant gemcitabine and cisplatin regime.
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Received: 01 August 2017
Available online: 25 June 2018
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Corresponding Authors:
Sunny Goel
E-mail: drsunnygoel09@gmail.com
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Flowchart of materials and methods.
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| Study | Selection domain (max of 4 points) | Comparability domain (max of 2 points) | Outcome domain (max of 3 points) | Quality rating | | Kim et al. [12] | **** | *- | *-* | Fair | | van de Putte et al. [13] | **** | *- | *-* | Fair | | Galsky et al. [14] | *-** | ** | ?-- | Poor | | Gandhi et al. [15] | **** | ** | **- | Good | | Chau et al. [16] | **** | ** | ?-- | Poor | | Khaled et al. [17] | NA | NA | NA | NA | | Fairey et al. [18] | **** | *- | *-* | Fair | | Pal et al. [19] | **** | ** | *-* | Good | | Matsubara et al. [20] | **** | *- | *-* | Fair | | Scosyrev et al. [21] | **** | -- | *-* | Poor | | Kaneko et al. [22] | **** | -- | *-* | Poor | | Dash et al. [7] | **** | ** | *-* | Good | | Herchenhorn et al. [23] | NA | NA | NA | NA |
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Quality assessment of included studies using NOS tool.
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| Study | Year | Country | Type of study | Length of study | Sample size, n | Males, n (%) | Age (year, median) | | Kim et al. [12] | 2015 | Korea | Retrospective | 2003-2013 | 47 | 38 (80.9) | - | | van de Putte et al. [13] | 2015 | - | Retrospective | 1990-2014 | 51 | 36 (70.6) | 63 | | Galsky et al. [14] | 2015 | USA | Retrospective | 2005-2012 | 146 | 115 (78.8) | 63 | | Gandhi et al. [15] | 2015 | USA | Retrospective | 2000-2013 | 150 | 123 (82) | 62.5 | | Chau et al. [16] | 2015 | UK | Retrospective | 2005-2011 | 83 | 60 (72.3) | 68 | | Khaled et al. [17] | 2014 | Egypt | RCT | 2000-2002 | 59 | 44 (74.6) | 54.2 | | Fairey et al. [18] | 2013 | USA | Retrospective | 1985-2011 | 58 | 44 (75.9) | 67 | | Pal et al. [19] | 2012 | USA | Retrospective | 1995-2012 | 24 | 19 (79.2) | 77.3 | | Matsubara et al. [20] | 2012 | Japan | Retrospective | 2005-2010 | 25 | 15 (60) | 67 | | Scosyrev et al. [21] | 2012 | USA | Retrospective | 1999-2009 | 25 | 18 (72) | 65 | | Kaneko et al. [22] | 2011 | Japan | Retrospective | 2007-2011 | 22 | 16 (72.7) | 69 | | Dash et al. [7] | 2008 | USA | Retrospective | 2000-2006 | 42 | 32 (76.2) | 64 | | Herchenhorn et al. [23] | 2007 | Brazil | Prospective | 2002-2005 | 22 | 19 (86.4) | 63 |
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Demographic characteristics of the studies.
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| Study | No. of cycles | Schedule (3/4 weekly) | Dose of gemcitabine | Dose of cisplatin | DI for gemcitabine (%) | DI for cisplatin (%) | | Kim et al. [12] | 3.2 | - | - | - | - | - | | van de Putte et al. [13] | 3 | 3 | 1000 mg/m2 | 70 mg/m2 | - | - | | Galsky et al. [14] | 3 | - | - | - | - | - | | Gandhi et al. [15] | 3,4 | 3,4 | 1000 mg/m2 | 70/35 mg/m2 | - | - | | Chau et al. [16] | 3,4 | 3 | 1000 mg/m2 | 70 mg/m2 | - | - | | Khaled et al. [17] | 3 | 3 | 1250 mg/m2 | 70 mg/m2 | - | - | | Fairey et al. [18] | 4 | 3 | - | - | - | - | | Pal et al. [19] | 3,4 | 4,3 | - | - | 93 | 93 | | Matsubara et al. [20] | 4 | 4 | 1000 mg/m2 | 70 mg/m2 | - | - | | Scosyrev et al. [21] | 2,3,4 | 3 | 2000 mg/m2 | 70 mg/m2 | - | - | | Kaneko et al. [22] | 2 | 4 | 1000 mg/m2 | 70 mg/m2 | 83.8 | 95.4 | | Dash et al. [7] | 4 | 3 | 615 mg/m2 weekly | 21 mg/m2 weekly | 90 | 91 | | Herchenhorn et al. [23] | 3 | 3 | 1200 mg/m2 | 75 mg/m2 | - | - |
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Variation in chemotherapy regimen among various studies.
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| Study | T2 n (%) | T3 n (%) | T4 n (%) | | Kim et al. [12] | - | - | - | | van de Putte et al. [13] | 11 (21.5) | 25 (49) | 15 (29.4) | | Galsky et al. [14] | 90 (62) | 40 (27) | 16 (11) | | Gandhi et al. [15] | 97 (65) | 38 (25) | 15 (10) | | Chau et al. [16] | 43 (51.8) | 33 (39.8) | 7 (8.4) | | Khaled et al. [17] | 1 (2) | 45 (76) | 13 (22) | | Fairey et al. [18] | 28 (49) | 18 (31) | 12 (20) | | Pal et al. [19] | 19 (91.7) | 2 (8.3) | 0 (0) | | Matsubara et al. [20] | 9 (36) | 16 (64) | | Scosyrev et al. [21] | 6 (24) | 19 (76) | | Kaneko et al. [22] | 15 (68.2) | 6 (27.3) | 1 (4.5) | | Dash et al. [7] | 19 (45) | 19 (45) | 4 (10) | | Herchenhorn et al. [23] | 11 (52.4) | 2 (9.5) | 8 (38.1) |
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Distribution of patients based on pre-chemotherapy staging (T stage).
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| Study | pT0 (%) | <pT2 (%) | | Kim et al. [12] | 12.5 | - | | van de Putte et al. [13] | 31.4 | 43.2 | | Galsky et al. [14] | 31 | - | | Gandhi et al. [15] | 35-63 | - | | Chau et al. [16] | 36.9 | - | | Khaled et al. [17] | 25.6 | - | | Fairey et al. [18] | 27.3 | 45.5 | | Pal et al. [19] | 25 | 58 | | Matsubara et al. [20] | 40 | 44 | | Scosyrev et al. [21] | 20 | 44 | | Kaneko et al. [22] | 50 | 63.6 | | Dash et al. [7] | 26 | 36 | | Herchenhorn et al. [23] | 26.7 | - |
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Pathological response after neo-adjuvant chemotherapy and definitive surgery.
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| Study | Overall survival (%) | Disease free survival (%) | | Galsky et al. [14] | 26.8 months | - | | Gandhi et al. [15] | - | 58% (5-year) | | Chau et al. [16] | 65.8% (3-year) (age≥70 years) 63.2% (3-year) (age <70 years) | - | | Khaled et al. [17] | 51.9% (3-year) | 31.8% (3-year) | | Fairey et al. [18] | 24.8 months | - | | Pal et al. [19] | 104.3 months | - | | Matsubara et al. [20] | - | 66.7% | | Scosyrev et al. [21] | 68% | - | | Dash et al. [7] | - | 67.5% | | Herchenhorn et al. [23] | 36 months | 57.2% |
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Survival analysis.
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| Study | Toxicity profile (Grade 3/4) | | Anemia, n (%) | Neutropenia, n (%) | Thrombocyto-penia, n (%) | Nausea/Vomiting, n (%) | Diarrhea, n (%) | | Van de Putte et al. [13] | 1 (2.6) | 2 (5.1) | 0 (0.0) | 1 (2.6) | - | | Khaled et al. [17] | 2 (3.4) | 3 (5.2) | 3 (5.2) | 22 (40) | 1 (1.7) | | Matsubara et al. [20] | 8 (32) | 10 (40) | 10 (40) | - | - | | Kaneko et al. [22] | 1 (2.4) | 6 (14.3) | 9 (21.4) | 0 (0) | 0 (0) | | Herchenhorn et al. [23] | 0 (0) | 7 (33.3) | 1 (4.76) | 6 (28.6) | - |
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Toxicity profile.
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