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carcinoma urinary bladder management

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NMIBC: non muscle invasive bladder cancer
MIBC: muscle invasive bladder cancer:
Metastatic Disease
Surgery
Chemotherapy
Immunotherapy
Radiotherapy
EORTC bladder cancer calculator
CUETO risk calculator (Spanish Urological Oncology Group).
Urinary Diversion

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carcinoma urinary bladder management

  1. 1. MANAGEMENT OF CARCINOMA URINARY BLADDER Made by:Dr Isha Jaiswal Guided by:Prof Kamal Sahni Date:04 December 2015
  2. 2. Urinary bladder cancer • NMIBC: non muscle invasive bladder cancer • MIBC: muscle invasive bladder cancer: • Metastatic Disease
  3. 3. TREATMENT OPTIONS • Surgery • Chemotherapy • Immunotherapy • Radiotherapy
  4. 4. Treatment depends on following factors Tumor related factor  TNM category  Size  Number of tumors  Grade  Presence of concurrent CIS Patient related factor  Age  Medical comorbidities  Performance status  Bladder functions  Choice
  5. 5. Non-muscle-Invasive Bladder Cancer • 70-80% of patients with bladder cancer present with NMIBC • These are classified as Tis, Ta, and T1 by the TNM classification system. • Aim of treatment: prevent recurrence & progression to MIBC • Prognostication and management strategy are based on accurate initial staging and grading of the disease.
  6. 6. TURBT: transurethral resection of bladder tumor • First-line to diagnose, stage, and treat visible tumors. • Goal: to make the correct diagnosis and completely remove all visible lesions. EUA done before & after TURBT to asses disease extent & residual tumor. Residual tumor can be as high as 53% in T1 tumors. Muscle must be seen in TURBT specimen before ruling out invasive disease Biopsies of apparently uninvolved urothelium should be obtained to rule out occult Tis. Biopsy from the prostatic urethra is necessary in some cases. tumour located on trigone or bladder neck, multiple tumours
  7. 7. TURBT Pathologist should comment on:  Size  tumour grade  depth of tumour invasion,  presence of CIS  whether the detrusor muscle is present in the specimen.  specify the presence of LVI or unusual (variant) histology  If there is uncertainty over the pathology, a further early re- resection (2-6 wk.) is indicated.
  8. 8. Second look TURBT? Indications  Residual disease after initial TURBT  When specimen contained no muscle  High-grade and/or T1 tumor Timing and strategy:  Most recommend 2-6 weeks after initial TUR  Should include resection of primary tumor site Evidence: 2nd look TURBT in T1 /HG tumor  1/2 will have residual disease on 2nd look [EAU 2010]  Under stage is more if muscle is absence (50% vs 15%) [Herr JU 1999]  1/4 will have upstage [Herr JU1999]  1/3 will have to change management [Herr JU 1999]  20% increase 5yr DFS [Germen observational study 2003] 8 European Association of Urology Guidelines 2015.
  9. 9. Predicting recurrence and progression of NMIBC • EORTC bladder cancer calculator • CUETO risk calculator.
  10. 10. • NMIBC, can be classified as low, intermediate, or high risk • It is based on combined analysis of individual pt. data of 2596 pt. from 7 EORTC trials to predict recurrence and progression in patient with stage Ta, T1 bladder cancer • Note: pt. in these trial. does not have 2nd TURBT or maintenance BCG • recurrence and progression rates reported here may be higher than those found in current clinical practice. Sylvester RJ, et al Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer Using EORTC Risk Tables: A Combined Analysis of 2596 Patients from Seven EORTC Trials. European Urology 49: 466 - 477, 2006 EORTC bladder cancer calculator
  11. 11. European Organisation for Research and Treatment of Cancer. Bladder cancer calculator. Available at: http://www.eortc.be/tools/bladdercalculator/.
  12. 12. Scoring System To Predict 1-yr& 5-yr Recurrence & Progression 12 based on six clinical and pathological factors: most important prognostic factors for recurrence  number of tumors  size,  prior recurrence rate. for progression  T category  grade  presence of CIS
  13. 13. 13
  14. 14. predicts risks of recurrence and progression for BCG-treated patients based on an analysis of 1,062 patients from 4 CUETO trials that compared different intravesical BCG treatments. No immediate postoperative instillation or second TURB was performed The scoring system is based on evaluation of seven prognostic factors  sex  age  prior recurrence status  number of tumours  T category  associated CIS;  tumour grade. Calculated risk of recurrence is lower than EORTC.Progression risk is lower only in high risk patient. Attributed to BCG therapy in the studies CUETO risk calculator (Spanish Urological Oncology Group). CUETO risk calculator is available at: http://www.aeu.es/Cueto.html
  15. 15. Implication Of Risk Stratification • Decide adjuvant treatment • Decide follow up schedule
  16. 16. 16 Treatment recommendations in Ta, T1 tumours and CIS according to risk stratification European Association of Urology Guidelines 2015.
  17. 17. Indications of adjuvant intravesical therapy after TURBT in NMIBC • Intermediate & high risk features • Incomplete excision especially in T1 tumors • tumors rapidly recur following TURBT of the initial bladder tumor • persistent tumor cells on urine cytology during surveillance • Adjuvant therapy is given in the form of intravesical administration of immunotherapy or chemotherapy.
  18. 18. Immunotherapy • Bacillus Calmette Guerin, live attenuated form of M. bovis • Acts as immune stimulant: stimulates cellular response releasing cytokines IL-1,2,6,8,TNF and IFN gamma • Given 1-2 weeks after resection, weekly for 6 weeks f/b maintenance as 3 weekly for a 1-3 year .(3yr better) • Patient is dehydrated over night. Urine is voided completely. • 50 mg of TICE in 50cc of 0.9% NS is instilled via catheter. Patient is asked to void urine after 2 hours • S/E :  Urinary frequency ,dysuria, hematuria  Arthralgia, rash, fever  Pneumonitis, hepatitis, prostatitis, sepsis
  19. 19. Intravesical chemotherapy Chemotherapeutic agents used are mitomycin C, doxorubicin, and thiotepa. Similar efficacy in prolonging time to recurrence. Different toxicity profile • Mitomycin C may cause skin desquamation and rash • Doxorubicin may cause G.I upset and local reaction causing urinary urgency. • Thiotepa causes myelosuppression
  20. 20. BCG VS MITOMYCIN • Individual patient data (IPD) meta-analyses of nine trials that included 2820 patients • Overall, there was no difference in the time to first recurrence (p=0.09) between BCG and MMC. • In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG compared to MMC was found (p<0.0001), • In the trials without maintenance a 28% increase in risk of recurrence (p=0.006) for BCG compared to MMC • BCG with maintenance was more effective than MMC in both patients previously treated and those not previously treated with chemotherapy Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol 2009;56(2):247–256.
  21. 21. Conclusion for Adjuvant therapy in NMIBC* • Standard of care for superficial bladder cancer with a high risk of recurrence has been established as intravesical BCG with maintenance therapy up till 3 years • Patient who are at high risk of recurrence or progression and can not comply to intravesical agent can be offered either cystectomy or bladder preservation protocols as in MIBC. • Histologic persistence after 6 months indicates the need to change the intravesicular agent (may combine BCG +interferon or intravesical chemotherapy) • Disease beyond 1 year indicates the need for a different treatment approach to prevent progression to muscle-invasive cancer (cystectomy or bladder preservation protocols as in MIBC.) • Patients with persistent CIS or BCG refractory Ta/T1 disease ultimately require cystectomy or bladder preservation protocols as in MIBC. • RTOG 0926** evaluating chemoradiation for such patients who opt for an attempt at bladder preservation or are otherwise not good cystectomy candidates. **Gray PJ, Shipley WU, Efstathiou JA, et al. Recent advances and the emerging role for chemoradiation in nonmuscle invasive bladder cancer. Curr Opin Urol 2013;23:429–434 *European Association of Urology Guidelines 2015.
  22. 22. Implication Of Risk Stratification Parameter Low-risk Intermediate-risk High-risk Risk of recurrence at 1 year 15% 38% 61% Risk of progression at 1 year 0.2% 5% 17% Surveillance regimen flexible cystoscopy with urine cytology is standard of bladder surveillance  flexible cystoscopy 3 months after initial resection  if negative repeated at 9 months & then annually there-after. • between that used for low- and high-risk disease • adapted according to personal and subjective factors • 3 monthly flexible cystoscopy for 2 years • 6 monthly for further 5 years • then annually thereafter.
  23. 23. Bladder Surveillance • flexible cystoscopy with urine cytology is the standard of bladder surveillance • ongoing research into improving sensitivity and specificity of flexible cystoscopy using narrow band imaging tried. • wide number of urinary biomarkers available such as NMP22, UroVysion and ImmunoCyt also tested • these agents suffer from high false-positive rates and variable sensitivity and are costly & there role in surveillance not established
  24. 24. Muscle Invasive Bladder Cancer:MIBC • Although the majority of patients present with NMIBC, 20% to 40% will either present with or ultimately develop muscle-invasive disease.
  25. 25. Goals of Treatment • Cure patient • Optimize survival • Prevention of Pelvic failure and Distant metastasis • Functional Urinary reservoir and High Quality Of Life (QoL) 25
  26. 26. MUSCLE INVASIVE BLADDER CANCER RADICAL CYSTECTOMY WITH URINARY RECONSTRUCTION BLADDER CONSERVATION PROTOCOLS RELAPSE OR PROGRESSION 26
  27. 27. SURGERY: Radical cystectomy • Indication: • Muscle invasive or locally advanced disease T2-T4a • Non muscle invasive bladder cancer T1G3 with high risk features ( multiple, recurrent ,large ,CIS) Refractory or failure to cystoscopy resection and intravesical chemotherapy or immunotherapy Non compliance to intravesical chemotherapy or immunotherapy Extensive disease not amenable to cystoscopy resection
  28. 28. Rationale For Radical Cystectomy lowest local recurrences. good long-term survival rates. provides accurate pathologic staging for determining the need for adjuvant therapy morbidity and mortality of radical cystectomy has substantially improved over the past decades.
  29. 29. Optimum Timing for cystectomy Within 3 months of TURBT.Delay of treatment beyond 90 days of primary diagnosis causes • significant increase in extravesical disease (81 vs. 52%), . • Also affect the options of urinary diversion • Hautmann RE, et al. Does the option of the ileal neobladder stimulate patient and physician decision toward earlier cystectomy?. J Urol 1998;159(6):1845-50. • decrease in overall survival, recurrence-free survival, cause-specific survival • Chang SS, et al. Delaying radical cystectomy for muscle invasive bladder cancer results in worse pathological stage. J Urol 2003;170(4 Pt 1):1085-7 29
  30. 30. Radical Cystectomy involves • Radical Cystectomy • Removal of bladder with surrounding fat • Prostate/seminal vesicles (males) • Uterus/fallopian tubes/ovaries/cervix vaginal cuff (females) • + Urethrectomy • Pelvic Lymphadenectomy • More is better • Urinary Diversion • Ileal conduit • Continent cutaneous reservoir • Orthotopic neobladder
  31. 31. • Complications – Re-operation (10%) – Bleeding (10%) – Sepsis and wound infection (10%) – Intestinal obstruction or prolong ileus (10%) – Cradio-pulmonary morbidity – Rectal injury (4%) – Complications of urinary diversion: dehydration, electrolyte abnormality,infection • Peri-operative mortality : 3% • Early complications (within 3 months of surgery) in 28% ( Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006 ) 31
  32. 32. Technique to improve QOL Level of preservation: • Anterior & membranous urethra + external sphincter • For orthotopic neobladder • Part of prostate and seminal vesicle • Fertility , potency and continence • Autonomic & sensory nerve (NVB) • soft tissue adjacent to the tips of the seminal vesicles. • Uterus & part of vagina ; • Improve antomical support for neobladder & autonomic nerves Disadvantages: • Residual Ca prostate (30%)  10% clinically significant • Increase oncological risk  need long term data 32
  33. 33. ILEAL CONDUIT (incontinent diversion to skin) CONTINENT CUTANEOUS RESERVOIR (continent diversion to skin) ORTHOTOPIC NEOBLADDER (continent diversion to urethra) Types of Urinary Diversion
  34. 34. Choice of Urinary Diversion • Disease Factors • Urethral margin • Patient Factors • Kidney function / liver function • Manual dexterity for intermittent catheterization • Preoperative urinary continence/ urethral strictures • Motivation • Surgeon Factors • Familiarity with various types of diversions
  35. 35. Rationale for L.N Dissection • From Stein series incidence of L.N metastasis: • Overall estimate ~ 25% patient undergo cystectomy have LN mets • pTis, pTa, pT1: 5% • pT2 : 15 • pT3 : 40% • pT4 : 50% 1. Stein JP. The role of lymphadenectomy in patients undergoing radical cystectomy for bladder cancer. Curr Oncol Rep 2007;9(3):213–221. 2. Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer: I. historical perspective and contemporary rationale. BJU Int2006;97(2):227–231. 3. Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer. II. technical aspects and prognostic factors. BJU Int 2006;97(2):232–237.
  36. 36. Standard PLND  Proximal: Bifurcation of common iliac artery  Distal: Circumflex iliac vein  Lateral :Gentitofemoral nerve  Medial: Bladder wall  Pelvic floor and hypogastric vesse  Anything more (up to bifurcation of aorta and above) can be called an extended PLND.  Includes b/l obturator, internal, external, common iliac and presacral nodes as well as nodes at the aortic bifurcation May also Extend to IMA  Evidence[1-3] suggests that a more extended lymphadenectomy is beneficial in both lymph node–positive and lymph node–negative patients with bladder cancer, 36 36 1. Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol2002;167(3):1295–1298. 2. . Leissner J, Ghoneim MA, bol-Enein H, et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol 2004;171(1):139–144. 3. . Stein JP. The role of lymphadenectomy in patients undergoing radical cystectomy for bladder cancer. Curr Oncol Rep 2007;9(3):213–221.
  37. 37. Number of Nodes Sampled Affects Survival in Both Node Negative and Node Positive Patients Node negative Node Positive Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol2002;167(3):1295–1298
  38. 38. 38 Recommendation for adequate L.N dissection • The Bladder Cancer Collaborative Group recommends 10- 14 lymph nodes should be removed at time cystectomy  Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 2002;167(3):1295–1298
  39. 39. Results of radical cystectomy SELECTED DATA FROM THE UNIVERSITY OF SOUTHERN CALIFORNIA BLADDER CANCER STUDY OF RADICAL CYSTECTOMY Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patient JCO 2001
  40. 40. BLADDER PRESERVATION PROTOCOL
  41. 41. Bladder Conservation approach • 2 main concerns about bladder preservation compared with radical cystectomy • Toxicity of radiation therapy on bladder function • Field cancerization effect : • 30-50% of patients experience a local recurrence (~50% invasive and ~50% superficial), either in the area of tumor or in a different part of bladder • If bladder preservation is selected, close surveillance is critical 41
  42. 42. No trials have till date directly compared Cystectomy and Bladder-preservation 42
  43. 43. Methods of Conservation Conservative Surgery Partial Cystectomy Radical External Beam Radiation Therapy ±Brachytherapy boost Combined modality treatment Chemotherapy + TURBT/Partial cystectomy Trimodality Therapy: maximal TURBT, chemotherapy & radiotherapy 43
  44. 44. Partial Cystectomy • Careful patient selection • Solitary lesion • Location: allows for complete excision with a 2-cm tumor-free margin like bladder dome • Contraindications : • Bladder neck or trigone tumors • Association with carcinoma in situ • Prostatic urethral involvement • Prior recurrent bladder tumors • 6% to 19% of patients with primary, muscle-invading bladder cancer are potential candidates • Local recurrence rates : 38% to 78% • Half of the recurrences appear in the first year and two thirds by 2 years 44
  45. 45. Radical External Beam Radiation Therapy • Historically, EBRT was used as monotherapy • Factors having significant favourable effect on local control with Radiotherapy: • Early clinical stage (T2 and T3a) • Absence of ureteral obstruction • Visibly complete TURBT • Small tumor size (<5 cm) solitary , Papillary / Sessile absence of coexisting carcinoma in situ • total radiation dose used varied from 55 to 65 Gy, with 1.8- 2 Gy per fraction in North America from 50 to 55 Gy at 2.5 to 2.75 Gy per fraction in the United Kingdom. 45
  46. 46. 5-year local control rate 31% to 45% for the entire patient population 49% to 79% for the subgroup of patients with a complete response
  47. 47. Interstitial Brachytherapy • combined with EBRT to provide a radiation boost to the primary tumor • Indication: Solitary TCC with a diameter of less than 5 cm 47 • Five-year local control rates for selected patients 70% -90% • High rates of bladder preservation • Acute toxicity : • Fistula formation with wound leakage
  48. 48. Trimodality Therapy Combination of maximum TURBT Resection, Chemotherapy, and Irradiation in Bladder Preservation • Best results till date in bladder preservation when the 3 modalities are combined together • Based on both single institutional data and randomised control trials 48
  49. 49. Ideal candidates • MIBC:Solitary T2 or early T3 tumors < 6 cm; CIS -nt; TCC histology • visibly complete TURBT • No hydronephrosis • Adequate renal function to allow cisplatin concurrent with radiation • Willing for being on close surveillance • Willing for cystectomy in case of progression or relapse
  50. 50. 1. cytotoxic agents, are capable of sensitizing tumor to irradiation, therefore increasing cell kill in a synergistic fashion. 2. Patients with MIBC harbour occult metastases in approximately 50% of cases, addition of systemic chemotherapy is in an attempt to control occult distant disease. Rationale For Combining Chemotherapy With RT In Bladder Preservation
  51. 51. PIONEERING SINGLE INSTITUTION STUDIES OF TRIMODALITY TREATMENT 51 ± NACT:MCV
  52. 52. Multi-modality Treatment Evolution In RTOG trials
  53. 53. Objective of RTOG trials Primary objective: to improve cure rates, secondary objective :to improve bladder preservation rates additional objective: to evaluate the tolerance and advantage of newer chemotherapeutic agents. • During the years 1985-2001 the RTOG conducted 6 trials, of which 5 were phase I and II and the 6th a phase III trial, which tested the role of adjuvant chemotherapy with tri-modality treatment • A total of 415 patients were enrolled in these trials. five year OS was approximately 50%, with 75% of surviving patients retaining a functionally preserved bladder
  54. 54. RTOG trials
  55. 55. Results of RTOG trials • RTOG 97-06, phase III trial with NACT failed to show the survival benefit with NACT in tri-modality. This trial stopped accrual prior to the planned because of the poor tolerance of MCV regimen and 3 treatment related deaths. • Trials using neo-adjuvant or adjuvant chemotherapy, showed more grade 3-4 acute toxicities but late effects were similar • RTOG 0233, examined the role of accelerated twice-daily radiation therapy in combination with either paclitaxel/cisplatin or 5- FU/cisplatin. Both cohorts also received four cycles of adjuvant gemcitabine/paclitaxel/ cisplatin chemotherapy. Both regimens had high rates of response , completion and bladder preservation. 73% and 69% of patients had their bladder preserved at 4 years • To conclude from the RTOG data that, tri-modality treatment is an effective bladder preservation approach of patients with MIBC, with the understanding that radical cystectomy is an available option for those who fail combined modality, with no decrease in survival due to delay in cystectomy.
  56. 56. C O M P A R A B L E SURVIVAL DATA OF RADICAL CYSTECTOMY AND SELECTIVE BLADDER PRESERVATION 57
  57. 57. Survival Data Of Radical Cystectomy And Selective Bladder Preservation: non comparable!!! because of following reason: • comparisons have not been stage matched. • staging systems have changed over the years • accurate staging not possible in RT series. In contrast, surgical series will report accurate pathological stage. It is well documented that more accurate staging will bring about a paradoxical improvement in reported results by stage due to upstaging of apparently early disease cases, the so-called Will Rogers phenomenon. • imaging techniques have evolved over time so more accurate staging in non surgical patients possible • RT Techniques have evolved over time and so more conformal techniques with less toxicity in recent series • in previous RT series the pt. who were treated with bladder preservation protocol were unfit for surgery so selection bias
  58. 58. In truth, surgery and radiotherapy are not competing, but are complementary approaches to invasive bladder cancer Poor RT candidates poorly functioning bladders extensive CIS. pT1G3 disease. hydronephrosis Poor surgical candidates  older patients,  Medical comorbidities  poor anesthetic risk pts.  Non compliant to urinary diversion care
  59. 59. concurrent chemotherapy agent • cisplatin, • 5-fluorouracil (5-FU), • mitomycin C, • carboplatin, • paclitaxel, • gemcitabine.
  60. 60. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–1488. • 360 patients ,MIBC • randomized to either RT alone or to CCRT with 5-FU and mitomycin C chemotherapy. • median follow-up of 70 months • Local–regional DFS was superior for those patients receiving chemotherapy (67% versus 54% at 2 years; hazard ratio [HR] 0.68, p = 0.03 • Survival at 5 years was higher with CCRT (48% versus 35%), but did not reach statistical significance (HR 0.82; p = 0.16)
  61. 61. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–1488.
  62. 62. Conclusion about agent of choice for CCRT in bladder preservation protocol • After RTOG 85-1228, and NCIC trials the efficacy and safety of cisplatin in CTRT bladder was proved. • Newer agents and combination regimens with taxanes, gemcitabine and platinum is being increasingly used in with some increase in response rates compared with platinum monotherapy • RTOG 0524 is ongoing and will evaluate the role of concurrent trastuzumab/paclitaxel in patients with human epidermal growth factor receptor 2 (her2)/neu over expression.
  63. 63. • As of now, there are no definite recommendations for any particular combination chemotherapy in tri-modality setting. • However there is a recent randomized trial BC2001 published in 2012 which suggest mitomycin & 5FU is also good alternative because of following reasons.  Although not a standard comparison but the when comparing LC it was better with 5FU+MC than single agent cisplatin  Also due to poor bladder function and deranged KFT cisplatin is contraindicated in some patients  RT alone is an inferior option  Lastly BC2001 is a recent trial with modern day conformal radiotherapy techniques
  64. 64. Radiotherapy in bladder cancer
  65. 65. • Concurrent chemo-radiation as a part of multi- modality bladder sparing protocol in T2-T4 N0 M0 • Neoadjuvant radiotherapy • Adjuvant radiotherapy Radiotherapy in bladder cancer
  66. 66. SIMULATION • CT Simulation preferred • Patient Position :supine with arms on chest. • Immobilization :knee and ankle rest • Bowel preparation: rectum should be empty of flatus and faeces, use of daily micro enemas may be considered. • Bladder preparation: empty bladder prior to scan.(Special bladder protocol can be followed for conformal planning to account for organ motion) • All planning and treatment should be carried out with the bladder empty To minimize the risk of geographic miss To keep the treated volumes as small as possible
  67. 67. Simulation: need of contrast For X Ray based planning: • catheterization f/b introduction of perurethral contrast to define bladder wall. • Conventional simulation involves: AP-PA & lateral radiographs For CT based planning • iv contrast used to facilitate nodal delineation • CT scan performed with 3 to 5-mm slice spacing from to 3 cm above the dome of the bladder or bottom of L5 (whichever is higher) to bottom of ischial tuberosity :
  68. 68. Conventional radiotherapy volumes 2 phased treatment Phase I: Field border • superior border :at the L5-S1 disc space • inferior border: below obturator foramen. • Anteriorly: 1.5 to 2 cm from the most anterior aspect of the bladder • posterior border: about 2.5-3 cm posterior to posterior aspect of the bladder. • Laterally:1.5-2 cm to the bony pelvis at its widest section • Dose:40-45 GY @ 1.8-2Gy/#
  69. 69. Boost phase • entire bladder excluding the nodes and then give a further boost to the tumor alone (3 phase treatment). • Dose:10-15 gy to entire bladder and upto 66 gy to tumor.(aim bladder receive 60 gy) OR • treat the bladdr+tumor with a 2-cm margin to a total dose of 66 gy
  70. 70. Bladder protocol to account for organ motion in conformal planning • Patient will be asked to void the urine and empty the bladder as much as possible. • Patient will be asked to drink 500 ml of water and time will be recorded. • After 60minutes of drinking the water CT simulation without contrast will be performed suggestive of full bladder. • Thereafter, patient will be asked to void the urine and empty the bladder as much as possible and CT Simulation with contrast enhancement will be performed suggestive of empty bladder • Both images (with full bladder and empty bladder) will be reviewed for tumor delineation to ensure that in all possible circumstances the PTV includes the maximum extension of the full bladder. However the CT slices with empty bladder will form the primary image for GTV and CTV delineations.
  71. 71. Conformal RT Volumes 72
  72. 72. Contouring Gross Tumor Volume (GTV): macroscopic tumor visible on radiological imaging/ cystoscopy findings provided by the urologist during TURBT. This may be GTV_Primary or GTV_LN (Lymph Node) Clinical target volume (CTV):- It shall include: CTV_Primary +CTV_LN • CTV_Primary: – GTV + whole bladder – In patient with tumors at the bladder base, the proximal urethra(in both genders), and the prostate and the prostatic urethra(in males) to be included in the CTV. CTV_lymph node (CTV_LN): – External iliac lymph.Internal iliac lymph nodes-, along its branches (obturator, hypogastric)Presacral lymph Planning target volume (PTV_Primary): • CTV_Primary will be given a 1-1.5 isotropic margin to create the PTV_Primary. • PTV_LN: 1 cm isotropic margin will be given to CTV_LN. • PTV_Primary may be Booleaned (added) with PTV_LN to produce a PTV_Total in order to facilitate treatment planning. • Both images (with full bladder and empty bladder) will be reviewed for tumor delineation to ensure that in all possible circumstances the PTV includes the maximum extension of the full bladder. However the CT slices with empty bladder will form the primary image for GTV and CTV delineations.
  73. 73. Controversy regarding PTV margin • Organ motion is the dominant source of error • Magnitude of the error depends on the region of the bladder being treated. • Some institute prefer Isotropic 2-cm margins around either the bladder (first phase of treatment) or tumor (boost) • Studies have shown that greatest degree of bladder wall positional change occurred in the cranial direction, with the least variation in the anteroinferior direction, limited by the pubic symphysis. • Few authors recommended anisotropic margin widths of 1.6 cm anteriorly and posteriorly, 1.4 cm laterally, 3 cm superiorly, and 1.4 cm inferiorly. • The problem is that these margins incorporate much normal tissue. • Image-guided radiation therapy with CBCT is away to reduce these margins significantly • Correction for errors detected on CBCT is practically achieved by a Foley's catheter. Most of the variation is due to bladder filling, so we catheterize the patient and change the bladder status to that at simulation by draining/filling it up as necessary.
  74. 74. Radiation Therapy Doses • Optimal radiotherapy schedule is yet to be established • commonly used schedule : • SPLIT SCHEDULE • In U.S split schedules often used are 39 or 40 Gy in 1.8- or 2-Gy fractions with an interval cystoscopy; • patients with responding disease proceed to a total dose of 64 to 66 Gy. • SINGLE PHASE TREATMENT • In the United Kingdom, single radical course, usually to the whole bladder, only • typical dose schedules would be 64 Gy in 32 fractions • or hypo fractionated schedules such as 55 Gy in 20 fractions 75
  75. 75. Pre-operative Radiotherapy The aims of preoperative radiotherapy include: • down staging and make surgery easier, • Increase rate of pT0 • Improve local control • No increase in the incidence of surgical complications. • DOSE: 40 Gy in 20 fractions or 20 Gy in 5 fractions followed by cystectomy 4wks later • Role of preop RT waning • Most of the studies in the literature using preop RT are old, .(1980-1990) retrospective, nonrandomized or few randomized comparisons and little can be concluded from them
  76. 76. Post-operative Radiotherapy • Limited data from randomized trials • Indication: pT3-T4, positive surgical margins , pN + (only in patients having incontinent cutaneous urinary diversion because in continent case the bowel toxicity is high) • Rationale: decreases probability of tumor recurrence following radical cystectomy. • Dose:  Areas at risk for harbouring residual microscopic disease should receive 45 to 50.4 Gy EBRT.  Involved resection margins and areas of extranodal extension should be boosted to 54 to 60 Gy if feasible based on normal tissue constrains.  Areas of gross residual disease should be boosted to 66 to 70 Gy, if feasible based on normal tissue constrains. • Concurrent chemotherapy can be considered for added tumor cytotoxicity. • CAUTIO However morbidity of post operative radiation is high due to small bowel toxicity that occupies pelvis after cystectomy.
  77. 77. Role of systemic chemotherapy • Neoadjuvant • Adjuvant • Palliative
  78. 78. Neo-Adjuvant Chemotherapy • Aim: to reduce micro metastasis and improve survival in MIBC • Advantage: • Decrease micrometastatic spread • Potentially downstaging the tumor • Disadvantage: • 50% without micrometastasis will be overtreated • Staging error may lead to overtreatment • Delay in cystectomy may compromise outcome • Chemo therapy may have SE that affect outcome of surgery 79
  79. 79. Randomized Phase III Trials of Neoadjuvant Chemotherapy 80 (Overall Survival) Single agent
  80. 80. Metaanalysis • Advanced Bladder Cancer (ABC) Meta-analysis. [Lancet 2003] • Update in 2005 [EAU 2005]
  81. 81. • Advanced Bladder Cancer (ABC) Meta-analysis. [Lancet 2003] • Analysis of 11 trial • 2688 individual patients from ten available randomised trials • Cisplatin-containing chemotherapy : • 5% (45% vs. 50%) absolute improvement 5yr OS • 9% improvement in 5yr DFS • 13% reduction in risk of death • Combination is better than single agent • Complete tumor response in 30% • effect was observed irrespective of the type of local treatment, 82 Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis Vale, C The Lancet , Volume 361 , Issue 9373 , 1927 – 1933, 2003
  82. 82. 83
  83. 83. 84 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. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration, Eur Urol 48:202-205, 2005. Update in 2005 [EAU 2005] • Absolute OS benefit of 6.5% (95% CI 1-9%, from 45-50%) • Significant DFS benefit (HR 0.78, 95% CI 0.71-0.86, p<0.0001) with 9% improvement in 5 years • Platinum combination significantly better than platinum single agent
  84. 84. • Neoadjuvant chemotherapy is still not considered as standard of care for Muscle Invasive Bladder cancer – Unlike other malignancies • Reasons : • Selection of patients in the trial setting is different from the patients seen in clinical setting • Most are old with impaired renal functioning & poor tolerance to chemotherapy • Newer chemotherapeutic combinations that have activity in patients with metastatic disease and more favorable toxicity profiles, such as gemcitabine and cisplatin, are being investigated. 85 Conclusion
  85. 85. Adjuvant Chemotherapy After Definite Local Therapy • No randomized trials have compared neoadjuvant to adjuvant chemotherapy in patients undergoing definitive local therapy. • Not enough evidence supporting adjuvant chemo in UB cancer • It is justified in patients with high risk for relapse, if neoadj chemo was not given 1. pT3 or more 2. Node positive
  86. 86. • In three studies, a significant progression-free survival (PFS) benefit at 3 and 5 years was observed • Patients in the observation group received chemotherapy at relapse, except in the study by Stöckle • PFS benefit does not translate into OS benefit if patients receive salvage chemotherapy. PFS benefit
  87. 87. Metastatic Bladder Cancer • The prognosis of metastatic bladder cancer, is poor, with a median survival on the order of only 12 months. • Nevertheless, platinum-containing agents have significant antitumor effect ,there has been great interest in the use of chemotherapy for advanced disease. • In phase III clinical trials, response rates to CT are often on the order of 50% • However, the duration of response in TCC is short, with a median of 4 to 6 months, • Therefore, the impact of chemotherapy on survival has been disappointing
  88. 88. The MVAC regimen has superior activity to other cisplatin-containing regimens. response rate to MVAC is 40% to 65%, complete response is seen in 15% to 25% of patients, expected median survival of 12 months However MVAC is associated with substantial toxicity GC, has similar efficacy & significantly less toxicity and improved tolerability
  89. 89. Thank you

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