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Chemotherapy radiotherapy in Urinary bladder malignancy

This document discusses the role of chemotherapy and radiotherapy in treating carcinoma of the bladder. It provides details on neoadjuvant chemotherapy, adjuvant chemotherapy, radical radiotherapy, and combined modality treatment for locally advanced disease. Neoadjuvant chemotherapy is found to improve survival outcomes compared to cystectomy alone by treating micrometastases. For metastatic bladder cancer, platinum-based regimens such as cisplatin and gemcitabine remain the standard first-line treatment. Radiotherapy can be used for organ-sparing treatment in select patients or as adjuvant therapy before or after surgery.

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ROLE OF CHEMOTHERAPY & RADIOTHERAPY IN CARCINOMA BLADDER Dept of Urology Govt Royapettah Hospital and Kilpauk Medical College Chennai 1
Moderators: Professors: • Prof. Dr. G. Sivasankar, M.S., M.Ch., • Prof. Dr. A. Senthilvel, M.S., M.Ch., Asst Professors: • Dr. J. Sivabalan, M.S., M.Ch., • Dr. R. Bhargavi, M.S., M.Ch., • Dr. S. Raju, M.S., M.Ch., • Dr. K. Muthurathinam, M.S., M.Ch., • Dr. D. Tamilselvan, M.S., M.Ch., • Dr. K. Senthilkumar, M.S., M.Ch. Dept of Urology, GRH and KMC, Chennai. 2
OPTIONS • Chemotherapy-neoadjuvant&adjuvant • Radiotherapy-preoperative& postoperative • Bladder Conservation Protocol 3 Dept of Urology, GRH and KMC, Chennai.
Peri-operative chemotherapy Rationale • Deaths from TCC are generally not local events • Patients die as a result of metastatic disease • Local interventions will not deal with micro- metastatic disease • Systemic therapy must be given to eradicate micrometastatic disease in order to improve cure rates 4 Dept of Urology, GRH and KMC, Chennai.
Adjuvant Chemotherapy • Basis : 50% develop distant mets despite adequate local therapy within 2 years • Survival advantage seen in locally advanced disease & limited nodal metastatic disease (Skinner 1991, Stockle 1992) • Does not delay local treatment 5 Dept of Urology, GRH and KMC, Chennai.
WHEN is Adjuvant therapy indicated presence of High Risk Factors After Cystectomy • Deep muscle invasion or extravesical spread • Prostate or adjacent organ involvement • High grade or undiff histology • Lymphatic or vascular emboli • Lymph node metastases • +ve surgical cut margins (Residual) 6 Dept of Urology, GRH and KMC, Chennai.
• Stockle et al noted a difference was noted in the 80 patients who received adjuvant chemotherapy as compared with 86 patients who underwent cystectomy alone. • adjuvant chemotherapy was most effective in patients with N-1 disease • usefulness of adjuvant chemotherapy is now being tested in an EORTC/intergroup trial 7 Dept of Urology, GRH and KMC, Chennai.
Compare and Contrast Neoadjuvant • Deals with micromets sooner Concern delay in surgery Best evidence of benefit • ? Increased surgical complications • Is benefit worth it? Adjuvant • Treats only the highest risk pts. • No delay in local Rx • Evidence of benefit is weaker • Delays in healing may preclude giving therapy • Is benefit worth it? 8 Dept of Urology, GRH and KMC, Chennai.
Chemo in Invasive bladder cancer • Adjuncts to standard surgical therapy • Alternatives to standard surgical therapy 9 Dept of Urology, GRH and KMC, Chennai.
Neoadjuvant CT 10 Dept of Urology, GRH and KMC, Chennai.
Rationale for Neoadjuvant Therapy • Give systemic therapy when the pelvic blood supply is intact • in vivo chemo-sensitivity trial • Deal with micrometastatic disease immediately • Patient is fitter and more able to tolerate chemotherapy 11 Dept of Urology, GRH and KMC, Chennai.
Bladder Cancer Neoadjuvant Chemotherapy Rationale : • Treatment of micrometastases to improve overall survival • Treatment of local tumour permitting organ preservation • Determination of chemosensitivity in vivo • More efficient & higher drug delivery Problems : • Progression of disease • Delay in curative local therapies • Toxicity of chemo • Accurate staging not obtained 12 Dept of Urology, GRH and KMC, Chennai.
Advantages of Neoadjuvant Therapy • Give systemic therapy when the pelvic blood supply is intact • in vivo chemo-sensitivity trial • Deal with micrometastatic disease immediately • Patient is fitter and more able to tolerate chemotherapy 13 Dept of Urology, GRH and KMC, Chennai.
• study by Grossman et al • the Nordic Cystectomy Trial 1 • The Nordic Cystectomy Trial 2 • Raghavan et al. • Patients with muscularis propria invasive bladder cancer (stage T2 to T4a) were randomly assigned to radical cystectomy alone or three cycles of MVAC followed by radical cystectomy. 14 Dept of Urology, GRH and KMC, Chennai.
Neoadjuvant chemotherapy • MRC trial (European) – 967 patients randomized to CMV vs no chemotherapy – Definitive management of primary either cystectomy or RT – 7 yr follow shows statistically significant benefit with neoadjuvant chemotherapy Lancet 354 (9178): 533-40, 1999 15 Dept of Urology, GRH and KMC, Chennai.
• Black et al. make the case for risk-adapted neoadjuvant chemotherapy, that is, offering neoadjuvant chemotherapy to patients who are at highest risk the tumor biology, the tumor grade, the histologic subtype and biomarkers size, clinical TNM stage, location in the bladder, ureteral obstruction and extravesical extension • pTo status was the only factor independently predictive of overall survival in multivariate analyses of four trials 16 Dept of Urology, GRH and KMC, Chennai.
Molecular Markers in Neoadjuvant Chemotherapy • Takata et al studied gene expression profiles from biopsies prior to neoadjuvant MVAC and identified 14 genes that were expressed differently in responders and nonresponders. SWOG phase III trial, evaluates the therapeutic and prognostic significance of altered p53 expression by the tumor p53 following radical cystectomy in pT1 or pT2 with p53-negative tumors, the treatment is observation. with p53-positive tumors, MVAC or observation 17 Dept of Urology, GRH and KMC, Chennai.
regime • three 28-day cycles of MVAC as follows: • methotrexate (30 mg/m2 on days 1, 15, and 22), • vinblastine (3 mg/m2 on days 2, 15, and 22), • doxorubicin (30 mg/m2 on day 2), • and cisplatin (70 mg/m2 on day 2). 18 Dept of Urology, GRH and KMC, Chennai.
Conclusions of trials • (1) The survival benefit associated with MVAC related to down-staging of the tumor to pTo. • Thirty-eight percent of the chemotherapy-treated patients had no evidence of cancer at cystectomy as compared with 15% of patients in the cystectomy-only group • (2) The median survival was 77 months for the chemotherapy-treated patients compared with 46 months for the cystectomy-only group. • (3) The 5-year actuarial survival was 43% in the cystectomy group, 57% in the chemotherapy-treated group 19 Dept of Urology, GRH and KMC, Chennai.
conclusions: • single-agent neoadjuvant chemotherapy is ineffective and should not be used; • current combination chemotherapy regimens improve the 5-year survival by 5%, which reduces the risk of death by 13% compared with the use of definitive local treatment alone (i.e., from 43% to 38%). • patients should be informed of the potential benefits versus the risks of neoadjuvant chemotherapy 20 Dept of Urology, GRH and KMC, Chennai.
Adjuvant chemotherapy 21 Dept of Urology, GRH and KMC, Chennai.
Combination therapy • the combination of methotrexate, vinblastine, and cisplatin (MCV), a total of three 28-day cycles • four cycles of cisplatin, gemcitabine, and paclitaxel, 22 Dept of Urology, GRH and KMC, Chennai.
Combined Modality Treatment of Locoregionally Advanced Disease Caseselection • patients with locally advanced unresectable bladder cancer with • 1) an excellent performance status • (2) locally advanced measurable disease • (3) a normal hemogram and kidney function tests • (4) no evidence of distant metastases beyond the common iliac lymph nodes. 23 Dept of Urology, GRH and KMC, Chennai.
• four to six cycles of combination chemotherapy, usually MCV, or gemcitabine-cisplatin. • If significant regression of tumor was achieved, radiation treatment was administered in combination with radiosensitizing chemotherapy, usually cisplatin-paclitaxel. • When gemcitabine was used avoid gemcitabine- radiation interactions by using a waiting period of at least 2 months from the completion of gemcitabine treatment to the start of radiation 24 Dept of Urology, GRH and KMC, Chennai.
Metastatic Bladder Cancer • The prognosis of metastatic bladder cancer, as with other metastatic solid tumors, is poor, with a median survival of only12 Months transitional cell cancer is chemosensitive • . In phase II clinical trials, radiographic response rates -70% to 80%, and in phase III clinical trials, - 50% • duration of response in TCC is short, with a median of 4 to 6 months, and therefore the impact of chemotherapy on survival has been disappointing 25 Dept of Urology, GRH and KMC, Chennai.
Cisplatin -single drug therapy • the response rate to single-agent cisplatin has been lower than that of cisplatin-containing combination therapy. 26 Dept of Urology, GRH and KMC, Chennai.
Cisplatin-Based Combination Chemotherapy • The standard chemotherapy regimen for advanced bladder cancer • methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). • MVAC is administered in 28-day cycles methotrexate 30 mg/m2 (days 1, 15, and 22), vinblastine 3 mg/m2 (days 2, 15, and 22), doxorubicin 30 mg/m2 (day 2), cisplatin 70 mg/m2 (day 2). 27 Dept of Urology, GRH and KMC, Chennai.
CMV, regime • omits doxorubicin and has less toxicity. • Cisplatin 70 mg/m2 d 2 Methotrexate 30 mg/m2 d 1, 8 Vinblastine 4mg/m2 d 1, 8 GC regime • Gemcitabine 1000 mg/m2 d 1, 8, 15 Cisplatin 70 mg/m2 d 2 • response rate of 42% to 66% and a CR rate of 18% to 28% • . 28 Dept of Urology, GRH and KMC, Chennai.
• The response rate to MVAC is 40% to 65%and there is improved progression-free and median survival of 12 months 29 Dept of Urology, GRH and KMC, Chennai.
Toxic effects of MVAC • neutropenia, anemia, thrombocytopenia, stomatitis, nausea, and fatigue • grade 3 or 4 myelosuppression • grade 3 or 4 gastrointestinal toxicity . • neutropenic sepsis . • Primary toxicity of GC was hematologic, febrile neutropenia 30 Dept of Urology, GRH and KMC, Chennai.
• Toxic deaths (1% vs. 3%), • neutropenic fevers (2% vs. 14%), • grade 3/4 neutropenia (71% vs. 82%), grade 3/4 mucositis (1% vs. 22%), and • alopecia (11% vs. 55%), were all lower in the GC group. • Patients receiving GC gained more weight, reported less fatigue, and had better performance status than patients receiving MVAC. • GC is generally considered the current standard of care for metastatic bladder cancer. 31 Dept of Urology, GRH and KMC, Chennai.
• GC was compared with standard MVAC in a multicenter phase III study • more adverse factors on the GC arm. • Median survival was 14.0 months with GC and 15.2 months with MVAC, • Median progression-free survivals were 7.7 and 8.3 months with GC and MVAC 32 Dept of Urology, GRH and KMC, Chennai.
Taxane- and Platinum-Containing Regimens Cisplatin/paclitaxel Carboplatin/paclitaxel • Cisplatin/docetaxel • Cisplatin/gemcitabine/paclitaxel • Carboplatin/gemcitabine/paclitaxel • Cisplatin/gemcitabine/docetaxel • Gemcitabine/paclitaxeL 33 Dept of Urology, GRH and KMC, Chennai.
summary • Whether bladder-sparing or cystectomy is used as local treatment, combined modality approaches are essential if treatment is to be optimal. • Neoadjuvant chemotherapy improv es survival, although further studies will be necessary before this combined approach can be considered standard treatment. • For adjuvant treatment, the data are much less convincing. • The results of studies using newer drug combinations may help to establish the role of adjuvant chemotherapy in improving survival 34 Dept of Urology, GRH and KMC, Chennai.
SUMMARY • In metastatic disease, platinum-based regimens such as cisplatin and gemcitabine remain the standard therapy • The addition of taxanes to the initial regimen or as second-line therapy may provide further activity, and lead to prolonged survival • overall survival remains poor in metastatic disease, • newer therapies such as targeted agents against tumor-specific growth factor pathways are needed 35 Dept of Urology, GRH and KMC, Chennai.
Radiotherapy 36 Dept of Urology, GRH and KMC, Chennai.
MODALITIES • Radical RT – curative • Adjuvant RT – preop / postop • Palliative RT METHODS • EBRT • INTERSTITIAL 37 Dept of Urology, GRH and KMC, Chennai.
Radical Radiation Therapy Indications : • Patients unfit / unwilling for surgery Bladder conservation protocols 38 Dept of Urology, GRH and KMC, Chennai.
RADICAL RT CURATIVE RT Indications : • Muscle invasive • Organ confined • Who retain good bladder function • No associated CIS • No significant bladder symptoms • Willingness to commit to both prolonged course of therapy & regular follow up cystoscopy SPARE – Selective Bladder preservation against radical excision 39 Dept of Urology, GRH and KMC, Chennai.
• 55-65 Gy : Target volume definition & adequate margins important • Initial CR (T0) 40-52% Bladder DF 35-45% for T2-4 at 5 years Overall survival 25-40% Excellent local control means good survival • Salvage cystectomy for residual / rec disease 40 Dept of Urology, GRH and KMC, Chennai.
Contraindications • Pt with active inflammatory bowel disease • Previous pelvic irradiation • Extensive prior pelvic surgery • Chronic pelvic infections • High risk of serious late bowel complications. • Pts with extensive bladder CIS are at high risk for tumor recurrence after radiotherapy, therefore should be considered for cystectomy 41 Dept of Urology, GRH and KMC, Chennai.
Pre-op Radiation Therapy • Moderate dose 20 Gy / 5 Fr or 40-50 Gy / 20-25 Fr • Eradication of primary & nodal disease in few patients after pre-op RT alone • No survival benefit in randomised trials • MD Anderson Trial : Reduces pelvic relapses in T3b patients (28% vs 9%) No survival benefit 42 Dept of Urology, GRH and KMC, Chennai.
Salvage Cystectomy • Cystectomy following definitive radiation therapy • Planned procedure or for progressive, residual or recurrent disease after RT or for RT related complications • Survivals comparable to radical cystectomy in 4 randomised trials • Technical challenge: Devascularisation & fibrosis • Acceptable mortality & morbidity 43 Dept of Urology, GRH and KMC, Chennai.
T2-T4 Bladder Cancer Chemo + RT+TUR No. of patients 106 • 40% Bladder preservation • 63% T2 45% T3-T4 • 66% free of distant mets • CR with TUR+Chemo+RT higher than TUR+Chemo (Zietman MGH 1998) 44 Dept of Urology, GRH and KMC, Chennai.
EBRT 2 Protocols • 64Gy – 2Gy x 32 daily doses over 6 1/2 weeks • 52.5 – 55 Gy x 20 daily doses over 4 weeks 45 Dept of Urology, GRH and KMC, Chennai.
complications • Bladder contraction – 2% • Incontinence – 6% • Bowel frequency – 20% • Rectal bleed – 2% • Impotence – 40% • Vaginal stenosis • Recurrence 10-20% (salvage cystectomy) 46 Dept of Urology, GRH and KMC, Chennai.
factors affecting Outcome • T • Size • Age • Nodal status • Pre RT RFT, Hb% • Presence of HUN • TURBT completeness 47 Dept of Urology, GRH and KMC, Chennai.
Bladder : EMPTY or FULL ??? • Empty bladder – • More comfort to patient • Overall irradiated volume is smaller. • Full bladder – • Displaces small intestine & some part of rectum out of radiation portals 48 Dept of Urology, GRH and KMC, Chennai.
Factors influencing bladder volume • Interval between voiding & T/t delivery • Pts state of hydration • Use of diuretic medications • Ingestion of diuretic beverages ( coffee, soft drinks) • Extrinsic pressure ( rectal filling, tumor mass) 49 Dept of Urology, GRH and KMC, Chennai.
Radiation portals • ANTERIOR POSTERIOR FIELDS : • Superior border- L5-S1 interface, • Inferior border – Lower border of obturator foramen • Lateral border – 1.5- 2 cm outside the bony pelvic wall • Anterior field should not include femoral heads & neck. • Upper corners can be shielded to reduce small bowel volume. 50 Dept of Urology, GRH and KMC, Chennai.
Portals for AP/PA beam arrangement 51 Dept of Urology, GRH and KMC, Chennai.
LATERAL FIELDS : • Superior border same as in AP/PA portals • Inferior border • Anterior border- 1.5-2 cm in front of anterior bladder wall as seen on imaging study • Posterior border – 2.5 cm posterior to the most posterior aspect of the bladder and falls within the rectum 52 Dept of Urology, GRH and KMC, Chennai.
Lateral beam arrangement 53 Dept of Urology, GRH and KMC, Chennai.
Areas irradiated • The whole pelvis • The pelvic lymph nodes • The whole Bladder • Proximal urethra (trigonal invl) • Any extravesical disease spread • Any region deemed to be at risk of microscopic disease spread. 54 Dept of Urology, GRH and KMC, Chennai.
Preoperative Radiation Therapy ❖Destroys local micrometastases ❖potentially downstage otherwise unresectable tumors ❖improve local control after cystectomy. 55 Dept of Urology, GRH and KMC, Chennai.
Post operative radiotherapy Indications – i) Extravesical disease ii) Positive resection margins iii) Pelvic LN involvement • Advantage – Availability of pathologic staging • Allows administration of adjuvant irradiation to those having high probability of tumor recurrence • Disadvantage- increased small intestine toxicity (adhesions). • Dose schedule- 40-50 Gy/ 5-6 weeks @ 1.8-2Gy/ # 56 Dept of Urology, GRH and KMC, Chennai.
Palliative RT INDICATIONS • Hematuria • Severe urgency • Pain Dose • 7Gy x 3 or • 3-3.5Gy x 10 • Troublesome bowel side effects 57 Dept of Urology, GRH and KMC, Chennai.
Radiosensitisers • CT – cisplatin / gemcitabine • Hyperbaric oxygen therapy • Misonidazole no role • Carbogen (ARCO) • Carbogen nicotinamide (ARCON) – Doubles the rate of survival 58 Dept of Urology, GRH and KMC, Chennai.
Interstitial Radiation Therapy • Never as a primary therapy • After preoperative external-beam radiation therapy, partial cystectomy, or TUR • Overall survival rates for low-stage tumors (T1-T2) of 60% to 80% have been reported. • In selected cases - provide an acceptable alternative bladder preservation strategy. • Complications( 25%) • delayed wound healing, • fistula formation, • hematuria, • chronic cystitis.. 59 Dept of Urology, GRH and KMC, Chennai.
Side effects ACUTE TOXICITY : • Cystitis – frequency, urge incontinence, dysuria. • Diarrhea, anal irritation • Mild proctitis LATE SEQUELAE: • Teleangiectasia of bladder mucosa • Intractable Hematuria • Rectal bleeding • Reduced bladder capacity 60 Dept of Urology, GRH and KMC, Chennai.
POTENTIAL BLADDER PRESERVATION 61 Dept of Urology, GRH and KMC, Chennai.
Invasive Bladder Cancer Chemo : Observations (Herr 1989) • 30 patients had cystectomy post - MVAC • 10 patients had no disease in cystectomy specimens POTENTIAL BLADDER PRESERVATION 33% 62 Dept of Urology, GRH and KMC, Chennai.
Invasive Bladder Cancer Chemo : Is bladder saving possible? 20 patients refused surgery post-MVAC 6 disease free 5 required TUR-BT 4 required cystectomy 5 developed distant mets In 11/20 (55%), bladder could be saved (Herr 1989) 63 Dept of Urology, GRH and KMC, Chennai.
Bladder conservation protocol T2-3 Nx M0 TCC TUR whenever possible 2-3 cycles of neoadjuvant chemo (M-VAC / cisplat+gemcite) Cystoscopy with biopsy - 1 month Urine cytology CT scan Responders Non-responders Cons RT + chemo Rad Cystectomy 64 Dept of Urology, GRH and KMC, Chennai.
Bladder Conservation Protocol • Combination of chemo & radiotherapy • CR after TUR + chemoradiation 74% • 5 year survival with intact bladder 36-44% • Survivals comparable to radical surgery in selected patients • 20-30% develop superficial relapses • Long term regular cystoscopic follow up must 65 Dept of Urology, GRH and KMC, Chennai.
Bladder-sparing therapy for invasive bladder cancer • High probability of subsequent distant metastasis after cystectomy or radiotherapy alone (50% within 2 years) • Radiotherapy in comparison with cystectomy has inferior results (local control 40%) • Muscle-invasive bladder cancer is often a systemic disease → combined modality therapy 66 Dept of Urology, GRH and KMC, Chennai.
Bladder Conservation Approach Case Selection • T2/T3a tumours • Unifocal tumours • Absence of associated diffuse Tis • Good bladder capacity • Low chance of metastatic disease Prospective randomised trials essential to compare oncologic value with cystectomy 67 Dept of Urology, GRH and KMC, Chennai.
Bladder Conservation Approach contraindications • Hydronephrosis • Multifocal disease • Irritative bladder symptoms • Low capacity bladder 68 Dept of Urology, GRH and KMC, Chennai.
Bladder Preservation Protocols • Bimodality & trimodalities • First step is always TURBT → CT ± RT • TURBT is for tissue diagnosis (muscle invasive)and removal of all macroscopic disease. • Not advocated in CIS (severe) – requires BCG / R cystectomy 69 Dept of Urology, GRH and KMC, Chennai.
Thank you 70 Dept of Urology, GRH and KMC, Chennai.

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Chemotherapy radiotherapy in Urinary bladder malignancy

  • 1.
    ROLE OF CHEMOTHERAPY& RADIOTHERAPY IN CARCINOMA BLADDER Dept of Urology Govt Royapettah Hospital and Kilpauk Medical College Chennai 1
  • 2.
    Moderators: Professors: • Prof. Dr.G. Sivasankar, M.S., M.Ch., • Prof. Dr. A. Senthilvel, M.S., M.Ch., Asst Professors: • Dr. J. Sivabalan, M.S., M.Ch., • Dr. R. Bhargavi, M.S., M.Ch., • Dr. S. Raju, M.S., M.Ch., • Dr. K. Muthurathinam, M.S., M.Ch., • Dr. D. Tamilselvan, M.S., M.Ch., • Dr. K. Senthilkumar, M.S., M.Ch. Dept of Urology, GRH and KMC, Chennai. 2
  • 3.
    OPTIONS • Chemotherapy-neoadjuvant&adjuvant • Radiotherapy-preoperative&postoperative • Bladder Conservation Protocol 3 Dept of Urology, GRH and KMC, Chennai.
  • 4.
    Peri-operative chemotherapy Rationale • Deathsfrom TCC are generally not local events • Patients die as a result of metastatic disease • Local interventions will not deal with micro- metastatic disease • Systemic therapy must be given to eradicate micrometastatic disease in order to improve cure rates 4 Dept of Urology, GRH and KMC, Chennai.
  • 5.
    Adjuvant Chemotherapy • Basis: 50% develop distant mets despite adequate local therapy within 2 years • Survival advantage seen in locally advanced disease & limited nodal metastatic disease (Skinner 1991, Stockle 1992) • Does not delay local treatment 5 Dept of Urology, GRH and KMC, Chennai.
  • 6.
    WHEN is Adjuvanttherapy indicated presence of High Risk Factors After Cystectomy • Deep muscle invasion or extravesical spread • Prostate or adjacent organ involvement • High grade or undiff histology • Lymphatic or vascular emboli • Lymph node metastases • +ve surgical cut margins (Residual) 6 Dept of Urology, GRH and KMC, Chennai.
  • 7.
    • Stockle etal noted a difference was noted in the 80 patients who received adjuvant chemotherapy as compared with 86 patients who underwent cystectomy alone. • adjuvant chemotherapy was most effective in patients with N-1 disease • usefulness of adjuvant chemotherapy is now being tested in an EORTC/intergroup trial 7 Dept of Urology, GRH and KMC, Chennai.
  • 8.
    Compare and Contrast Neoadjuvant •Deals with micromets sooner Concern delay in surgery Best evidence of benefit • ? Increased surgical complications • Is benefit worth it? Adjuvant • Treats only the highest risk pts. • No delay in local Rx • Evidence of benefit is weaker • Delays in healing may preclude giving therapy • Is benefit worth it? 8 Dept of Urology, GRH and KMC, Chennai.
  • 9.
    Chemo in Invasivebladder cancer • Adjuncts to standard surgical therapy • Alternatives to standard surgical therapy 9 Dept of Urology, GRH and KMC, Chennai.
  • 10.
    Neoadjuvant CT 10 Dept ofUrology, GRH and KMC, Chennai.
  • 11.
    Rationale for NeoadjuvantTherapy • Give systemic therapy when the pelvic blood supply is intact • in vivo chemo-sensitivity trial • Deal with micrometastatic disease immediately • Patient is fitter and more able to tolerate chemotherapy 11 Dept of Urology, GRH and KMC, Chennai.
  • 12.
    Bladder Cancer Neoadjuvant Chemotherapy Rationale: • Treatment of micrometastases to improve overall survival • Treatment of local tumour permitting organ preservation • Determination of chemosensitivity in vivo • More efficient & higher drug delivery Problems : • Progression of disease • Delay in curative local therapies • Toxicity of chemo • Accurate staging not obtained 12 Dept of Urology, GRH and KMC, Chennai.
  • 13.
    Advantages of NeoadjuvantTherapy • Give systemic therapy when the pelvic blood supply is intact • in vivo chemo-sensitivity trial • Deal with micrometastatic disease immediately • Patient is fitter and more able to tolerate chemotherapy 13 Dept of Urology, GRH and KMC, Chennai.
  • 14.
    • study byGrossman et al • the Nordic Cystectomy Trial 1 • The Nordic Cystectomy Trial 2 • Raghavan et al. • Patients with muscularis propria invasive bladder cancer (stage T2 to T4a) were randomly assigned to radical cystectomy alone or three cycles of MVAC followed by radical cystectomy. 14 Dept of Urology, GRH and KMC, Chennai.
  • 15.
    Neoadjuvant chemotherapy • MRCtrial (European) – 967 patients randomized to CMV vs no chemotherapy – Definitive management of primary either cystectomy or RT – 7 yr follow shows statistically significant benefit with neoadjuvant chemotherapy Lancet 354 (9178): 533-40, 1999 15 Dept of Urology, GRH and KMC, Chennai.
  • 16.
    • Black etal. make the case for risk-adapted neoadjuvant chemotherapy, that is, offering neoadjuvant chemotherapy to patients who are at highest risk the tumor biology, the tumor grade, the histologic subtype and biomarkers size, clinical TNM stage, location in the bladder, ureteral obstruction and extravesical extension • pTo status was the only factor independently predictive of overall survival in multivariate analyses of four trials 16 Dept of Urology, GRH and KMC, Chennai.
  • 17.
    Molecular Markers inNeoadjuvant Chemotherapy • Takata et al studied gene expression profiles from biopsies prior to neoadjuvant MVAC and identified 14 genes that were expressed differently in responders and nonresponders. SWOG phase III trial, evaluates the therapeutic and prognostic significance of altered p53 expression by the tumor p53 following radical cystectomy in pT1 or pT2 with p53-negative tumors, the treatment is observation. with p53-positive tumors, MVAC or observation 17 Dept of Urology, GRH and KMC, Chennai.
  • 18.
    regime • three 28-daycycles of MVAC as follows: • methotrexate (30 mg/m2 on days 1, 15, and 22), • vinblastine (3 mg/m2 on days 2, 15, and 22), • doxorubicin (30 mg/m2 on day 2), • and cisplatin (70 mg/m2 on day 2). 18 Dept of Urology, GRH and KMC, Chennai.
  • 19.
    Conclusions of trials •(1) The survival benefit associated with MVAC related to down-staging of the tumor to pTo. • Thirty-eight percent of the chemotherapy-treated patients had no evidence of cancer at cystectomy as compared with 15% of patients in the cystectomy-only group • (2) The median survival was 77 months for the chemotherapy-treated patients compared with 46 months for the cystectomy-only group. • (3) The 5-year actuarial survival was 43% in the cystectomy group, 57% in the chemotherapy-treated group 19 Dept of Urology, GRH and KMC, Chennai.
  • 20.
    conclusions: • single-agent neoadjuvantchemotherapy is ineffective and should not be used; • current combination chemotherapy regimens improve the 5-year survival by 5%, which reduces the risk of death by 13% compared with the use of definitive local treatment alone (i.e., from 43% to 38%). • patients should be informed of the potential benefits versus the risks of neoadjuvant chemotherapy 20 Dept of Urology, GRH and KMC, Chennai.
  • 21.
    Adjuvant chemotherapy 21 Dept ofUrology, GRH and KMC, Chennai.
  • 22.
    Combination therapy • thecombination of methotrexate, vinblastine, and cisplatin (MCV), a total of three 28-day cycles • four cycles of cisplatin, gemcitabine, and paclitaxel, 22 Dept of Urology, GRH and KMC, Chennai.
  • 23.
    Combined Modality Treatmentof Locoregionally Advanced Disease Caseselection • patients with locally advanced unresectable bladder cancer with • 1) an excellent performance status • (2) locally advanced measurable disease • (3) a normal hemogram and kidney function tests • (4) no evidence of distant metastases beyond the common iliac lymph nodes. 23 Dept of Urology, GRH and KMC, Chennai.
  • 24.
    • four tosix cycles of combination chemotherapy, usually MCV, or gemcitabine-cisplatin. • If significant regression of tumor was achieved, radiation treatment was administered in combination with radiosensitizing chemotherapy, usually cisplatin-paclitaxel. • When gemcitabine was used avoid gemcitabine- radiation interactions by using a waiting period of at least 2 months from the completion of gemcitabine treatment to the start of radiation 24 Dept of Urology, GRH and KMC, Chennai.
  • 25.
    Metastatic Bladder Cancer •The prognosis of metastatic bladder cancer, as with other metastatic solid tumors, is poor, with a median survival of only12 Months transitional cell cancer is chemosensitive • . In phase II clinical trials, radiographic response rates -70% to 80%, and in phase III clinical trials, - 50% • duration of response in TCC is short, with a median of 4 to 6 months, and therefore the impact of chemotherapy on survival has been disappointing 25 Dept of Urology, GRH and KMC, Chennai.
  • 26.
    Cisplatin -single drugtherapy • the response rate to single-agent cisplatin has been lower than that of cisplatin-containing combination therapy. 26 Dept of Urology, GRH and KMC, Chennai.
  • 27.
    Cisplatin-Based Combination Chemotherapy •The standard chemotherapy regimen for advanced bladder cancer • methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). • MVAC is administered in 28-day cycles methotrexate 30 mg/m2 (days 1, 15, and 22), vinblastine 3 mg/m2 (days 2, 15, and 22), doxorubicin 30 mg/m2 (day 2), cisplatin 70 mg/m2 (day 2). 27 Dept of Urology, GRH and KMC, Chennai.
  • 28.
    CMV, regime • omitsdoxorubicin and has less toxicity. • Cisplatin 70 mg/m2 d 2 Methotrexate 30 mg/m2 d 1, 8 Vinblastine 4mg/m2 d 1, 8 GC regime • Gemcitabine 1000 mg/m2 d 1, 8, 15 Cisplatin 70 mg/m2 d 2 • response rate of 42% to 66% and a CR rate of 18% to 28% • . 28 Dept of Urology, GRH and KMC, Chennai.
  • 29.
    • The responserate to MVAC is 40% to 65%and there is improved progression-free and median survival of 12 months 29 Dept of Urology, GRH and KMC, Chennai.
  • 30.
    Toxic effects ofMVAC • neutropenia, anemia, thrombocytopenia, stomatitis, nausea, and fatigue • grade 3 or 4 myelosuppression • grade 3 or 4 gastrointestinal toxicity . • neutropenic sepsis . • Primary toxicity of GC was hematologic, febrile neutropenia 30 Dept of Urology, GRH and KMC, Chennai.
  • 31.
    • Toxic deaths(1% vs. 3%), • neutropenic fevers (2% vs. 14%), • grade 3/4 neutropenia (71% vs. 82%), grade 3/4 mucositis (1% vs. 22%), and • alopecia (11% vs. 55%), were all lower in the GC group. • Patients receiving GC gained more weight, reported less fatigue, and had better performance status than patients receiving MVAC. • GC is generally considered the current standard of care for metastatic bladder cancer. 31 Dept of Urology, GRH and KMC, Chennai.
  • 32.
    • GC wascompared with standard MVAC in a multicenter phase III study • more adverse factors on the GC arm. • Median survival was 14.0 months with GC and 15.2 months with MVAC, • Median progression-free survivals were 7.7 and 8.3 months with GC and MVAC 32 Dept of Urology, GRH and KMC, Chennai.
  • 33.
    Taxane- and Platinum-Containing Regimens Cisplatin/paclitaxel Carboplatin/paclitaxel •Cisplatin/docetaxel • Cisplatin/gemcitabine/paclitaxel • Carboplatin/gemcitabine/paclitaxel • Cisplatin/gemcitabine/docetaxel • Gemcitabine/paclitaxeL 33 Dept of Urology, GRH and KMC, Chennai.
  • 34.
    summary • Whether bladder-sparingor cystectomy is used as local treatment, combined modality approaches are essential if treatment is to be optimal. • Neoadjuvant chemotherapy improv es survival, although further studies will be necessary before this combined approach can be considered standard treatment. • For adjuvant treatment, the data are much less convincing. • The results of studies using newer drug combinations may help to establish the role of adjuvant chemotherapy in improving survival 34 Dept of Urology, GRH and KMC, Chennai.
  • 35.
    SUMMARY • In metastaticdisease, platinum-based regimens such as cisplatin and gemcitabine remain the standard therapy • The addition of taxanes to the initial regimen or as second-line therapy may provide further activity, and lead to prolonged survival • overall survival remains poor in metastatic disease, • newer therapies such as targeted agents against tumor-specific growth factor pathways are needed 35 Dept of Urology, GRH and KMC, Chennai.
  • 36.
    Radiotherapy 36 Dept of Urology,GRH and KMC, Chennai.
  • 37.
    MODALITIES • Radical RT– curative • Adjuvant RT – preop / postop • Palliative RT METHODS • EBRT • INTERSTITIAL 37 Dept of Urology, GRH and KMC, Chennai.
  • 38.
    Radical Radiation Therapy Indications: • Patients unfit / unwilling for surgery Bladder conservation protocols 38 Dept of Urology, GRH and KMC, Chennai.
  • 39.
    RADICAL RT CURATIVE RT Indications: • Muscle invasive • Organ confined • Who retain good bladder function • No associated CIS • No significant bladder symptoms • Willingness to commit to both prolonged course of therapy & regular follow up cystoscopy SPARE – Selective Bladder preservation against radical excision 39 Dept of Urology, GRH and KMC, Chennai.
  • 40.
    • 55-65 Gy: Target volume definition & adequate margins important • Initial CR (T0) 40-52% Bladder DF 35-45% for T2-4 at 5 years Overall survival 25-40% Excellent local control means good survival • Salvage cystectomy for residual / rec disease 40 Dept of Urology, GRH and KMC, Chennai.
  • 41.
    Contraindications • Pt withactive inflammatory bowel disease • Previous pelvic irradiation • Extensive prior pelvic surgery • Chronic pelvic infections • High risk of serious late bowel complications. • Pts with extensive bladder CIS are at high risk for tumor recurrence after radiotherapy, therefore should be considered for cystectomy 41 Dept of Urology, GRH and KMC, Chennai.
  • 42.
    Pre-op Radiation Therapy •Moderate dose 20 Gy / 5 Fr or 40-50 Gy / 20-25 Fr • Eradication of primary & nodal disease in few patients after pre-op RT alone • No survival benefit in randomised trials • MD Anderson Trial : Reduces pelvic relapses in T3b patients (28% vs 9%) No survival benefit 42 Dept of Urology, GRH and KMC, Chennai.
  • 43.
    Salvage Cystectomy • Cystectomyfollowing definitive radiation therapy • Planned procedure or for progressive, residual or recurrent disease after RT or for RT related complications • Survivals comparable to radical cystectomy in 4 randomised trials • Technical challenge: Devascularisation & fibrosis • Acceptable mortality & morbidity 43 Dept of Urology, GRH and KMC, Chennai.
  • 44.
    T2-T4 Bladder Cancer Chemo+ RT+TUR No. of patients 106 • 40% Bladder preservation • 63% T2 45% T3-T4 • 66% free of distant mets • CR with TUR+Chemo+RT higher than TUR+Chemo (Zietman MGH 1998) 44 Dept of Urology, GRH and KMC, Chennai.
  • 45.
    EBRT 2 Protocols • 64Gy– 2Gy x 32 daily doses over 6 1/2 weeks • 52.5 – 55 Gy x 20 daily doses over 4 weeks 45 Dept of Urology, GRH and KMC, Chennai.
  • 46.
    complications • Bladder contraction– 2% • Incontinence – 6% • Bowel frequency – 20% • Rectal bleed – 2% • Impotence – 40% • Vaginal stenosis • Recurrence 10-20% (salvage cystectomy) 46 Dept of Urology, GRH and KMC, Chennai.
  • 47.
    factors affecting Outcome •T • Size • Age • Nodal status • Pre RT RFT, Hb% • Presence of HUN • TURBT completeness 47 Dept of Urology, GRH and KMC, Chennai.
  • 48.
    Bladder : EMPTYor FULL ??? • Empty bladder – • More comfort to patient • Overall irradiated volume is smaller. • Full bladder – • Displaces small intestine & some part of rectum out of radiation portals 48 Dept of Urology, GRH and KMC, Chennai.
  • 49.
    Factors influencing bladdervolume • Interval between voiding & T/t delivery • Pts state of hydration • Use of diuretic medications • Ingestion of diuretic beverages ( coffee, soft drinks) • Extrinsic pressure ( rectal filling, tumor mass) 49 Dept of Urology, GRH and KMC, Chennai.
  • 50.
    Radiation portals • ANTERIORPOSTERIOR FIELDS : • Superior border- L5-S1 interface, • Inferior border – Lower border of obturator foramen • Lateral border – 1.5- 2 cm outside the bony pelvic wall • Anterior field should not include femoral heads & neck. • Upper corners can be shielded to reduce small bowel volume. 50 Dept of Urology, GRH and KMC, Chennai.
  • 51.
    Portals for AP/PAbeam arrangement 51 Dept of Urology, GRH and KMC, Chennai.
  • 52.
    LATERAL FIELDS : •Superior border same as in AP/PA portals • Inferior border • Anterior border- 1.5-2 cm in front of anterior bladder wall as seen on imaging study • Posterior border – 2.5 cm posterior to the most posterior aspect of the bladder and falls within the rectum 52 Dept of Urology, GRH and KMC, Chennai.
  • 53.
    Lateral beam arrangement 53 Deptof Urology, GRH and KMC, Chennai.
  • 54.
    Areas irradiated • Thewhole pelvis • The pelvic lymph nodes • The whole Bladder • Proximal urethra (trigonal invl) • Any extravesical disease spread • Any region deemed to be at risk of microscopic disease spread. 54 Dept of Urology, GRH and KMC, Chennai.
  • 55.
    Preoperative Radiation Therapy ❖Destroyslocal micrometastases ❖potentially downstage otherwise unresectable tumors ❖improve local control after cystectomy. 55 Dept of Urology, GRH and KMC, Chennai.
  • 56.
    Post operative radiotherapy Indications– i) Extravesical disease ii) Positive resection margins iii) Pelvic LN involvement • Advantage – Availability of pathologic staging • Allows administration of adjuvant irradiation to those having high probability of tumor recurrence • Disadvantage- increased small intestine toxicity (adhesions). • Dose schedule- 40-50 Gy/ 5-6 weeks @ 1.8-2Gy/ # 56 Dept of Urology, GRH and KMC, Chennai.
  • 57.
    Palliative RT INDICATIONS • Hematuria •Severe urgency • Pain Dose • 7Gy x 3 or • 3-3.5Gy x 10 • Troublesome bowel side effects 57 Dept of Urology, GRH and KMC, Chennai.
  • 58.
    Radiosensitisers • CT –cisplatin / gemcitabine • Hyperbaric oxygen therapy • Misonidazole no role • Carbogen (ARCO) • Carbogen nicotinamide (ARCON) – Doubles the rate of survival 58 Dept of Urology, GRH and KMC, Chennai.
  • 59.
    Interstitial Radiation Therapy •Never as a primary therapy • After preoperative external-beam radiation therapy, partial cystectomy, or TUR • Overall survival rates for low-stage tumors (T1-T2) of 60% to 80% have been reported. • In selected cases - provide an acceptable alternative bladder preservation strategy. • Complications( 25%) • delayed wound healing, • fistula formation, • hematuria, • chronic cystitis.. 59 Dept of Urology, GRH and KMC, Chennai.
  • 60.
    Side effects ACUTE TOXICITY: • Cystitis – frequency, urge incontinence, dysuria. • Diarrhea, anal irritation • Mild proctitis LATE SEQUELAE: • Teleangiectasia of bladder mucosa • Intractable Hematuria • Rectal bleeding • Reduced bladder capacity 60 Dept of Urology, GRH and KMC, Chennai.
  • 61.
  • 62.
    Invasive Bladder Cancer Chemo: Observations (Herr 1989) • 30 patients had cystectomy post - MVAC • 10 patients had no disease in cystectomy specimens POTENTIAL BLADDER PRESERVATION 33% 62 Dept of Urology, GRH and KMC, Chennai.
  • 63.
    Invasive Bladder Cancer Chemo: Is bladder saving possible? 20 patients refused surgery post-MVAC 6 disease free 5 required TUR-BT 4 required cystectomy 5 developed distant mets In 11/20 (55%), bladder could be saved (Herr 1989) 63 Dept of Urology, GRH and KMC, Chennai.
  • 64.
    Bladder conservation protocol T2-3Nx M0 TCC TUR whenever possible 2-3 cycles of neoadjuvant chemo (M-VAC / cisplat+gemcite) Cystoscopy with biopsy - 1 month Urine cytology CT scan Responders Non-responders Cons RT + chemo Rad Cystectomy 64 Dept of Urology, GRH and KMC, Chennai.
  • 65.
    Bladder Conservation Protocol •Combination of chemo & radiotherapy • CR after TUR + chemoradiation 74% • 5 year survival with intact bladder 36-44% • Survivals comparable to radical surgery in selected patients • 20-30% develop superficial relapses • Long term regular cystoscopic follow up must 65 Dept of Urology, GRH and KMC, Chennai.
  • 66.
    Bladder-sparing therapy forinvasive bladder cancer • High probability of subsequent distant metastasis after cystectomy or radiotherapy alone (50% within 2 years) • Radiotherapy in comparison with cystectomy has inferior results (local control 40%) • Muscle-invasive bladder cancer is often a systemic disease → combined modality therapy 66 Dept of Urology, GRH and KMC, Chennai.
  • 67.
    Bladder Conservation Approach CaseSelection • T2/T3a tumours • Unifocal tumours • Absence of associated diffuse Tis • Good bladder capacity • Low chance of metastatic disease Prospective randomised trials essential to compare oncologic value with cystectomy 67 Dept of Urology, GRH and KMC, Chennai.
  • 68.
    Bladder Conservation Approach contraindications •Hydronephrosis • Multifocal disease • Irritative bladder symptoms • Low capacity bladder 68 Dept of Urology, GRH and KMC, Chennai.
  • 69.
    Bladder Preservation Protocols •Bimodality & trimodalities • First step is always TURBT → CT ± RT • TURBT is for tissue diagnosis (muscle invasive)and removal of all macroscopic disease. • Not advocated in CIS (severe) – requires BCG / R cystectomy 69 Dept of Urology, GRH and KMC, Chennai.
  • 70.
    Thank you 70 Dept ofUrology, GRH and KMC, Chennai.