Radical Cystectomy Versus Tri-Modal Therapy for Treatment of cT2N0M0 Urinary Bladder Transitional Cell Carcinoma
Phase: NA
Conditions: Transitional Cell Bladder Cancer, Cystectomy, Radiation
Sponsor: Ain Shams University

 
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Radical Cystectomy Versus Tri-Modal Therapy 
For Treatment Of cT2N0M0 Urinary Bladder 
Transitional Cell Carcinoma                         
 
Protocol of a Thesis for partial fulfillment of 
MD in Urology 
Presented by 
 
Ahmed Himdan Abdelhamid 
Assistant Lecturer of Urology 
M.B.B.Ch., Faculty of Medicine – Ain Shams University (2015) 
Cairo – Egypt. 
 
Supervised by 
Prof.Dr. Tarek Osman Elsayed 
Professor of Urology 
Faculty of Medicine¸ 
Ain Shams University– Egypt. 
Prof.Dr Hesham Elwakil 
Professor of oncology 
Faculty of Medicine¸ 
Ain Shams University– Egypt. 
 

 
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DR. Ahmed Mohamed Emam 
Assistant professor of Urology 
Faculty of Medicine¸ 
Ain Shams University – Egypt. 
 
 
DR. Ahmed Lofty Ghazy 
Lecturer of Urology 
Faculty of Medicine¸ 
Ain Shams University – Egypt. 
 
 
              
      Faculty of Medicine, 
        Ain Shams University 
    Cairo – Egypt 
2022 
 
 
 
 
 
 
 

 
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1.What is already known on this subject?  
 
  Radical cystectomy with lymphadenectomy is classically performed in patients with 
muscle invasive transitional cell carcinoma of urinary bladder cT2N0M0. 
  
     Bladder-preserving, trimodality therapy (TMT) was suggested for patients with 
muscle-invasive urothelial bladder cancer who are not surgical candidates due to 
medical comorbidities and for those who desire to retain their native bladder. 
 
 
2. AIM / OBJECTIVES 
     The aim of this study is to compare the oncological outcome of trimodal therapy 
(TMT) with bladder preservation versus radical cystectomy with pelvic lymph node 
dissection (PLND) for treatment of muscle invasive transitional cell carcinoma of 
urinary bladder cT2N0M0. 
 
 
3. INTRODUCTION / REVIEW  
      Bladder cancer is the 11th most commonly diagnosed cancer worldwide. For localized 
 muscle-invasive bladder (MIBC), treatment includes induction chemotherapy (CT). 
 followed by radical cystectomy [1,2]. 
 
      Advances in the surgical technique and perioperative care, significantly reduced 
 complication rates. On the other hand, orthotopic neobladder may have a positive impact 
 on quality of life but has the potential of increasing short and long-term complication rates, 
 compared to standard urinary diversion [3,4].  

 
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        However, Hautmann’s study shows that among 923 patients (pts) having had an 
 orthotopic neobladder, 40% had late complications [5]. More than one-third of pts develop 
 metastasis within 3 years after surgery, particularly pts with pT3 stages. In this context, 
 alternative conservative strategies have been developed during the last decade, following 
 approaches similar to the anal canal or laryngeal cancer treatments. (5) 
 
      The usual conservative approach in localized MIBC is a trimodal therapy (TMT). It 
consists of a transurethral resection of the bladder tumor (TURBT) as complete as possible, 
followed by concomitant radiotherapy (RT) and chemotherapy.  
       
      Response to (RT) and chemotherapy is then assessed by cystoscopy and 
 biopsies. Planned surgery is proposed to non-responder patients and additional 
 chemotherapy and RT with careful regular endoscopic examination is performed 
 in responders [6]. 
 
      Except for the incomplete selective bladder preservation against radical excision 
 (SPARE) trial, there is no large and meaningful randomized trial comparing radical 
 cystectomy and TMT [7].  
 
      Several single-institution series and prospective trials conducted by radiation therapy 
 oncology group (RTOG) have shown that the conservative approach can achieve high 
 rates of complete histologic response, bladder conservation in many patients, and survival  
rates similar to recent surgery series [8–10].  

 
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4. Description of the study: 
 
        ▫   Type of Study:  
This is a randomized controlled clinical trial comparing radical cystectomy and 
trimodal therapy, included adult patients with cT2N0M0 muscle invasive localized 
urinary bladder TCC presented to our urology clinic. 
Date of study: we started recruitment of the patients from April 2021 to April 
2022 and then followed up for three years. 
Venue of study: Ain Shams University hospitals. 
All patients underwent a proper preoperative assessment including history 
taking and appropriate clinical assessment. All patients underwent cystoscopy and 
biopsy of bladder tumor. 
Ethical Considerations: - 
Permission was received from the ethical committee of Ain Shams University 
after accepting our study protocol with approval number (FMASU MD 183/2022) to 
start our study. No personal identifiers were abstracted from the medical records. 

 
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The patients were counselled and signed an informed consent to be included 
in our study. They received detailed information about both ways of management, 
advantages, disadvantages, and possible adverse effects.  
Any participant does not have to take part in or continue this research if he 
or she wanted. Patients were allowed to stop participating at any time. 
Inclusion and exclusion criteria: 
A) Inclusion Criteria:  
1) Adults of any gender, older than 18 years. 
2) Urinary bladder TCC cT2N0M0 that was proven by imaging (CT, MRI), 
cystoscopy and histopathologic examination of biopsied tumor tissue. 
B) Exclusion Criteria: -  
1) Suspected significant nodal involvement on imaging. 
2) Carcinoma in situ (CIS). 
3) Hydronephrosis caused by bladder tumor. 
4) Urinary bladder carcinoma other than TCC 
5)  Bladder TCC with atypical variants (e.g. micropapillary, plasmacytoid, 
anaplastic and sarcomatoid variants) 
6) High grade non muscle invasive bladder cancer (NMIBC).  
7) Patients not fit for surgery. 
8) Patients not fit for chemotherapy or radiotherapy. 
9) Patients who refused randomization. 
     10) Patients who received prior chemotherapy or prior radiation For treating the  
bladder tumor. 
 

 
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The Sample size was calculated according to (PASS 11) program after 
reviewing results from the previous relevant study (Chamie et al., 2017). We 
assumed an effect size difference = 0.8 between the two treatment groups 
regarding the oncologic outcome. Based on this assumption and after 10% 
adjustment for dropout rate, a sample size of 30 patients per group achieves 80% 
power to reject the null hypothesis of zero effect size when the population effect 
size is 0.8 and the significant level (alpha) is 0.05 using a two-sided z test. 
Randomization:  
Selected patients were randomized by simple 1:1 randomization by using sealed 
envelopes method ,into two main groups: 
• Group (A): underwent radical cystectomy with lymphadenectomy. 
• Group (B): underwent trimodal therapy (TMT). 
 
CONSORT Flow Diagram 

 
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Figure (9): CONSORT Flow Diagram. 
  
Preoperative work-up:  
a) Laboratory investigations:  

 
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All the patients were examined for complete blood count, serum 
biochemistry, coagulation tests, urine culture and routine viral markers before 
operation. All Patients in both arms received preoperative prophylactic antibiotic.  
b) Radiological investigations:  
Pelviabdominal ultrasound. 
-Chest, Pelviabdominal CT or pelviabdominal MRI were done for assessment 
of local staging, nodal involvement, and distant metastasis. 
Radical cystectomy group (group A): 
a) Surgical procedure: 
RC included surgical removal of the bladder, adjacent organs, and regional 
lymph nodes. In males, it included removal of urinary bladder, prostate, and seminal 
vesicles whereas in females, it included removal of urinary bladder and reproductive 
organs (ovaries, fallopian tubes, uterus, and anterior vagina).  
Standard pelvic lymph node dissection was performed to all patients in this 
group.  
The boundaries of lymphadenectomy: extended proximally to the bifurcation 
of the common iliac artery, extended laterally to the genitofemoral nerve, medially 
to the bladder and internal iliac vessels and distally by the circumflex iliac vein. 
This was followed by urinary diversion. we have utilized only two types of 
urinary diversion procedures: 
- 18 patients underwent ileal conduit, and 9 patients underwent orthotopic 
diversion (ileal neo-bladder). 
- Choosing the type of diversion and reconstruction was decided according to 
: 
1- Patient-related factors:  

 
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-Performance status and life expectancy. 
- Body built 
- Renal and liver functions. 
- Debilitating diseases and dexterity. 
2- Oncologic factors:  
-Location of the bladder tumor. 
-Positivity of the urethral margin on frozen section. 
3- Surgeon’s preference. 
b) Early postoperative events were recorded. 
 
c) Follow up visits: 
Initially after one month then every 3 months for 1 year then every 6 months for 
2 years: 
1) Early postoperative visit: 
After 1 month, included proper assessment of overall health including 
general, local examination and assessment of stoma. Blood test for renal, liver 
functions and electrolytes + CBC. 
2) 3-month visit: 
As before + pelviabdominal ultrasound. Proper functional assessment 
including potency and urinary continence. 
3) 6-month visit: 
-Clinical examination, renal functions, CBC 

 
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-Chest, Pelviabdominal CT with contrast to detect any local or distant 
metastasis. 
4) Imaging repeated every 6 months for 2 years then at 3 years. 
 
Trimodal therapy group (group B): 
a) In this group, the patients underwent maximal TURBT, where as much tumor as 
possible was completely resected using bipolar resectoscope. The goal was to 
remove all visible tumor including the underlying muscle layer and tumor edges. 
b) This is followed by radio-sensitizing chemotherapy and RT.  
Chemotherapy consisted of weekly administration of iv infusion of cisplatin 
(40mg/m2) + 500 ml normal saline. This was administered weekly on day 1 or 2 of 
each week of radiation therapy. If renal function got impaired, cisplatin was 
replaced by weekly administration of carboplatin or gemcitabine with adjusted 
doses according to creatinine clearance.  
RT was delivered as external beam radiotherapy (EBRT). aimed at delivering 
approximately 44– 46 Gy to the urinary bladder and pelvic lymph followed by 
additional boost to the bladder 54 GY and a final boost to the tumor 64-65 GY. 
Radiation therapy delivered in daily fractions (5 days per week) over a period of 5 
to 7 weeks. 
 
c) Follow up visits:  
One week postoperative then every 3 months for 2 years then every 6months at 
the third year. 
1) Early postoperative visit, one week after tumor resection: 

 
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This included proper history taking, patient asked about any hematuria or 
storage symptoms, with review of the histopathology report. 
Proper clinical assessment included general and local examination. Follow up 
CBC, renal functions. 
Patients were referred to the clinical oncology and radiation units for proper 
assessment, and to start the chemo-radiation protocol. 
5) 3-month visits: 
- Proper clinical assessment, physical examination 
- Diagnostic cystoscopy (with or without biopsies) every 3 months for 2 years. 
- Computed tomography (CT) or magnetic resonance imaging (MRI) scans for 
the chest, abdomen, and pelvis was performed at 6-month intervals for 2 
years then at 3 years.  
- Salvage radical cystectomy was offered for any invasive tumor recurrence 
during follow up.  
 
Data analysis: 
All previously mentioned data were collected and analyzed. This included the 
preoperative, postoperative data and oncological outcome of both groups. The 
main focus was to compare the oncological outcome of the two treatment 
modalities. 
• Group A: Radical cystectomy with pelvic lymphadenectomy. 
• Group B: Trimodal therapy.  
 
 

 
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Statistical Analysis 
Data were collected, revised, coded and entered to the Statistical Package for 
Social Science (IBM SPSS) (IBM Corp. Released 2020. IBM SPSS Statistics for 
Windows, Version 27.0. Armonk, NY: IBM Corp). The quantitative data were 
presented as mean, standard deviations and ranges when parametric and median, 
inter-quartile range (IQR) when data found non-parametric. Also qualitative 
variables were presented as number and percentages.  
The comparison between groups regarding qualitative data was done by 
using Chi-square test and/or Fisher exact test when the expected count in any cell 
found less than 5.  
The comparison between two groups regarding quantitative data and 
parametric distribution was done by using Independent t-test while with non 
parametric distribution was done by using Mann-Whitney test. 
Kaplan-Meier analysis using Log Rank test was used to compare between 
the two studied groups regarding overall and disease free survival (months). 
The confidence interval was set to 95% and the margin of error accepted was 
set to 5%. So, the p-value was considered significant as the following: 
P-value > 0.05: Non-significant (NS) 
P-value < 0.05: Significant (S) 
P-value < 0.01: Highly significant (HS).  
 
 
 

 
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