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| A phase II study of neoadjuvant chemotherapy followed by organ preservation in patients with muscle-invasive bladder cancer |
Chinna Babu Drachama,Narendra Kumara,*( ),Santosh Kumarb,Arun Elangovana,Budhi Singh Yadava,Ravimohan S. Mavudurub,Anupam Lalc,Pramod K. Guptad,Rakesh Kapoora
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aDepartment of Radiotherapy & Oncology, PGIMER, Chandigarh, India
bDepartment of Urology, PGIMER, Chandigarh, India
cDepartment of Radiodiagnosis, PGIMER, Chandigarh, India
dDepartment of Biostatistics, PGIMER, Chandigarh, India |
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Abstract Objective: Conservative approaches in muscle-invasive bladder cancer (MIBC) have been evolved to avoid aggressive surgery, but are limited to elderly, frail, and patients medically unfit for surgery. Our study aimed to assess the response rate of neoadjuvant chemotherapy (NACT) before radiotherapy (RT) in MIBC patients.
Methods: Forty patients with urothelial carcinoma of stage T2-T4a, N0, M0 were enrolled between November 2013 and November 2015, and treated with three cycles of NACT with gemcitabine-cisplatin. Post-NACT response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Patients who achieved complete response (CR) and partial response (PR) >50% were treated with radical RT, and those who had PR <50%, stable disease (SD), and progressive disease (PD) underwent radical cystectomy (RC). Survival analysis was done with Kaplan-Meier method and point-to-time events were analyzed with Cox-proportional hazards regression model.
Results: After NACT, 35 (87.5%) patients achieved either PR >50% or CR, and were treated with RT. Five (12.5%) patients who had PR <50%, SD, or PD underwent RC. All patients who received radiation showed CR after 6 weeks. Median follow-up was 43 months (range: 10-66 months) and median overall survival (OS) was not reached. Three-year OS, local control, and disease-free survival were 70.1%, 60.9%, 50.6%, respectively, and 50% of patients preserved their functioning bladder. Three-year OS rate was 88.9% in patients who achieved CR to NACT, 73.1% in patients with PR ≥50% and 40% in patients with PR <50%.
Conclusion: NACT followed by RT provides a high probability of local response with bladder preservation in CR patients. Appropriate use of this treatment regimen in carefully selected patients may omit the need for morbid surgery.
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Received: 11 January 2020
Available online: 20 July 2022
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Corresponding Authors:
Narendra Kumar
E-mail: drnarendra74@gmail.com
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Study flowchart with a summary of methods and results. CR, complete response; NACT, neoadjuvant chemotherapy; PD, progressive disease; PR, partial response; SD, stable disease; MIBC, muscle-invasive bladder cancer; RT, radiotherapy.
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| Characteristic | Patient, n (%) | | Transitional cell carcinoma | 40 (100) | | High grade | 40 (100) | | Carcinoma in situ | 5 (12.5) | | T stage | | T2 | 18 (45) | | T3 | 16 (40) | | T4a | 6 (15) | | N stage | | N0 | 40 (100) | | Composite stage (AJCC 2010) | | II | 18 (45) | | III | 22 (55) | | Comorbidities | | Hypertension | 10 (25) | | Diabetes | 6 (15) | | Coronary artery disease | 4 (10) | | Hydroureteronephrosis | 4 (10) | | Smoking and alcohol intake | 20 (50) |
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Disease and patient characteristics.
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Survival function curves estimated by Kaplan-Meier method along with their 95% confidence interval bands (at any time point, there is a 95% chance that the interval band contains true percentage survival). (A) Overall survival; (B) Disease-free survival; (C) Local control.
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Survival function curve computed by Kaplan-Meier method. (A) For local control with tumor (T) stage; (B) With NACT response. CR, complete response; NACT, neoadjuvant chemotherapy; PD, progressive disease; PR, partial response; SD, stable disease; PostCCT-status, post-chemotherapy (NACT) status.
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Survival function curve computed by Kaplan-Meier method. (A) For disease-free survival with NACT response; (B) For overall survival with NACT response. CR, complete response; NACT, neoadjuvant chemotherapy; PD, progressive disease; PR, partial response; SD, stable disease; PostCCT-status, post-chemotherapy (NACT) status.
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| Variable (n) | Local control | Disease-free survival | Overall survival | | 3-year, % | p-Value | 3-year, % | p-Value | 3-year, % | p-Value | | Composite stage | | 0.05 | | 0.07 | | 0.22 | | II (18) | 74.0 | | 60.0 | | 77.8 | | | III (22) | 42.1 | | 51.0 | | 68.2 | | | T-stage | | 0.00 | | 0.00 | | 0.06 | | T2 (18) | 76.2 | | 60.7 | | 77.8 | | | T3 (16) | 60.0 | | 53.0 | | 65.0 | | | T4a (6) | 16.2 | | 16.7 | | 33.3 | | | Response to NACT | | 0.05 | | 0.02 | | 0.06 | | CR (9) | 85.7 | | 85.7 | | 88.9 | | | PR≥50% (26) | 57.9 | | 40.4 | | 73.1 | | | PR<50%/SD/PD (5) | 40.0 | | 26.7 | | 40.0 | |
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Local control, disease-free survival, and overall survival, analyses with Kaplan-Meier method using log-rank test.
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| Variable | Number of events/number of patients | Median time in months (95% CI) | Hazard ratio (95% CI) | p-Value | | Local control (n=15) | | Age | | | 0.57 (0.19-1.71) | 0.34 | | ≤60 years | 10/22 | 29.0 (23.3-34.6) | | | | >60 years | 5/18 | 35.0 (28.8-41.3) | | | | Comorbidity | | | 0.66 (0.22-1.97) | 0.72 | | Yes | 5/12 | 30.6 (22.2-39.1) | | | | No | 10/28 | 32.4 (27.3-37.5) | | | | T stage | | | 6.93 (2.03-20.67) | 0.00 | | T2 | 4/18 | Not estimablea | | | | T3 | 5/16 | 35.9 (30.6-41.2) | | | | T4a | 6/6 | 13.5 (2.4-24.5) | | | | Composite stage | | | 0.19 (0.22-1.73) | 0.14 | | II | 4/18 | 34.8 (29.2-40.3) | | | | III | 11/22 | 29.2 (23.0-35.4) | | | | NACT response | | | 2.72 (1.17-6.31) | 0.05 | | CR | 1/9 | Not estimablea | | | | PR≥50% | 10/26 | 31.2 (25.7-36.6) | | | | PR<50%/SD/PD | 4/5 | 23.2 (7.8-38.5) | | | | Disease-free survival (n=19) | | Age | | | 0.60 (0.22-1.64) | 0.60 | | ≤60 years | 12/22 | 27.4 (22.3-32.4) | | | | >60 years | 7/18 | 32.1 (25.6-38.7) | | | | Comorbidity | | | 0.86 (0.30-2.46) | 0.86 | | Yes | 5/12 | 30.6 (22.2-39.1) | | | | No | 14/28 | 35.0 (25.6-35.6) | | | | T stage | | | 4.43 (1.44-13.6) | 0.001 | | T2 | 6/18 | Not estimablea | | | | T3 | 7/16 | 33.0 (27.3-38.6) | | | | T4a | 6/6 | 13.5 (2.4-24.7) | | | | Composite stage | | | 0.35 (0.05-2.37) | 0.28 | | II | 6/18 | 34.6 (29.3-39.8) | | | | III | 13/22 | 27.2 (21.2-33.2) | | | | NACT response | | | 2.62 (1.28-5.36) | 0.01 | | CR | 1/9 | Not estimablea | | | | PR≥50% | 14/26 | 28.3 (23.2-33.3) | | | | PR<50%/SD/PD | 4/5 | 23.2 (7.8-35.5) | | | | Overall survival (n=15) | | Age | | | 0.83 (0.28-2.45) | 0.76 | | ≤60 years | 8/22 | 44.9 (38.3-51.4) | | | | >60 years | 7/18 | 50.5 (41.0-60.7) | | | | Comorbidity | | | 0.86 (0.26-2.82) | 0.55 | | Yes | 4/12 | 39.8 (30.3-49.6) | | | | No | 11/28 | 51.0 (44.1-58.0) | | | | T stage | | | 2.01 (0.96-4.26) | 0.06 | | T2 | 4/18 | Not estimablea | | | | T3 | 7/16 | 47.0 (39.1-54.8) | | | | T4a | 4/6 | 28.3 (14.7-41.2) | | | | Composite stage | | | 0.54 (0.06-4.55) | 0.20 | | II | 4/18 | 47.0 (39.1-54.8) | | | | III | 11/22 | 47.6 (39.6-55.7) | | | | NACT response | | | 2.62 (1.06-6.47) | 0.03 | | CR | 1/9 | Not estimablea | | | | PR≥50% | 11/26 | 48.2 (40.1-56.3) | | | | PR<50%/SD/PD | 3/5 | 34.2 (20.5-47.8) | | |
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Univariate analyses for survival end points (local control, disease-free survival, and overall survival).
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| NACT response | Local control | Disease-free survival | Overall survival | | HR (95% CI) | p-Value | HR (95% CI) | p-Value | HR (95% CI) | p-Value | | CR | 1 | 0.05 | 1 | 0.01 | 1 | 0.03 | | PR ≥50% | 1.47 (0.14-1.96) | 0.46 | 1.75 (0.22-2.18) | 0.87 | 1.51 (0.14-1.88) | 0.65 | | PR <50%/SD/PD | 2.72 (1.17-6.31) | 0.02 | 2.62 (1.28-5.36) | 0.023 | 2.26 (1.06-6.47) | 0.04 |
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Multivariate analyses for survival end points with Cox-proportional hazard regression model.
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