H. Khaled - Bladder cancer - State of the art

Management of Urinary Bladder Cancer : State of the Art Hussein M. Khaled Prof. Medical Oncology Vice President for Post graduate Studies and Research Cairo University By:

Objectives of the presentation : For the clinical oncologist : How to manage , in general, a case of bladder cancer with special emphasis on drug therapy Having either the western , or the bilharzial subtype that is common in our region.

Ranking of ASIR of Bladder Cancer worldwide rates (Males) 0 10 20 30 40 50 60 70 80 90 100 The Gambia 1.3 Belgium 42.5 Louisiana 16.6 Egypt 26.3 Western Europe Percentiles

Most Common Cancers within EMR

BLADDER CANCER Western type Bilharzia associated Unusual tumors & pseudotumors

ETIOLOGY 1.Cigarette smoking 2.High fat diet 3.Industrial aromatic amines 4.Phenacetin 5.Cyclophosphamide

CLINICAL SETTINGS OF BLADDER CARCINOMA Organ confined: Superficial 75% M. Invasive 25% Metastatic: 5 %

HISTOPATHOLOGIC TYPES OF BLADDER CARCINOMA 1. Transitional cell carcinoma 90 % 2. Squamous cell carcinoma 5 % 3. Adenocarcinoma 2 % 4. Undifferentiated carcinoma 2 %

GROWTH PATTERN OF TRANSITINAL CELL CARCINOMA Papillary (Exophytic) Non-papillary (Endophytic)

Urothelial Tumours Overview of Treatment Options Surgery: Radical cystectomy, urinary diversion, lymphadenectomy Radiotherapy Intravesical instillations: immunotherapy or chemotherapy Transurethral resection (TUR) Chemotherapy Chemotherapy (neo-adjuvant or adjuvant) Non-muscle invasive: 70% Muscle invasive: 25% Metastatic: 5% ± palliative RT Treatment options

Contents Muscle invasive urothelial carcinoma Metastatic urothelial carcinoma Non-muscle invasive urothelial carcinoma

Non-muscle invasive TCCU Prognostic Factors * PUNLMP: Papillary Urothelial Neoplasm of Low Malignant Potential Low risk tumours Single Ta Low grade or PUNLMP* diameter < 3cm, non-recurrent Intermediate risk tumours Low-grade Ta, or PUNLMP multifocal and/or recurrent low-grade T1 High risk tumours High grade Ta (Gr3), T1 Gr3 , recurrent T1, Cis

Non-muscle invasive TCCU Prognostic Factors EORTC software used to evaluate individual risk of recurrence and progression from the first to the fifth year http://www.eortc.be/tools/bladdercalculator/download.asp

Non-muscle invasive TCCU Treatment objectives Objectives are curative Eliminate local lesion(s) and preserve the bladder Prevent development of muscle invasion and local recurrence

Non-muscle invasive TCCU Summary of Therapeutic Sequence & Monitoring Close follow-up is required Non-muscle invasive urothelial tumour Stage Treatment Monitoring Low-risk tumour Complete TUR Cystoscopy 3m, 9m, then annually for 15y (if normal) Intermediate-risk tumour CompleteTUR + local CT or BCG Cystoscopy and cytology 3m, 6m, 12m, then annually for at least 15y High-risk tumour Complete TUR + BCG with maintenance treatment Cystoscopy and cytology Every 3 months (2y) Every 4-6 months (3y), Then annually for 15 years

Contents Non-invasive urothelial carcinoma Invasive urothelial carcinoma Metastatic urothelial carcinoma

Prognostic Factors for Advanced Cases

Supervised analysis 55 genes differentially expressed with expression values significantly correlated to survival Columns: Patients Listed according to survival Rows: Genes Listed according to protein function

From gene expression to protein expression Emmprin (BSG/CD147) 19p13.3, 46.6 kDa membrane protein Anti-apoptotic via PI3K/Akt pathway Tumor progression and development of metastases Survivin (BIRC5) 17q25, 16.6 kDa protein in cytoplasm and nucleus Important anti-apoptotic protein Predictor of cisplatin-resistance in other tumor types Als AB et al. Clin Cancer Res. 2007

Chemotherapy in metastatic bladder cancer “ Old” single agents Agent ORR Cisplatin 28 % (2 6 -3 2 ) Carboplatin 15 % (11-19) Methotrexate 29 % (23-35) Ifosfamide 28 % (19-37) Doxorubicin 17 % (1 3 -2 2 ) 5-Fluorouracil 1 7 % (1 1 - 25 ) Vinblastine 16 % (4-28) Mitomycin C 13 % (3-23)

Chemotherapy in metastatic bladder cancer “ Old” drug combinations Cisplatin + Methotrexate CM Cisplatin + Methotrexate + Vinblastine CMV Methotrexate + Vinblastine + Adriamycin + Cisplatin MVAC

Chemotherapy in metastatic bladder cancer Mead GM et al. Br J Cancer. 1998 C MV vs. MV N 214 patients Median survival 7 months vs. 4.5 months 1-year survival 29% vs. 16% Hazard ratio 0.68

MVAC in metastatic bladder cancer Sternberg CN et al. Cancer. 1989 Overall response rate 72% CR rate 25% + 11% (surgery) Median survival 13 months

MVAC in metastatic bladder cancer Memorial Sloan-Kettering Cancer Center 5 studies with 194 evaluable patients Overall response rate 67% CR rate 24% Median survival 14.8 months Other studies Overall response rate about 50% CR rate about 15% Median survival about 12 months

MVAC in metastatic bladder cancer Phase III studies MVAC > CISCA Logothetis CJ et al. J Clin Oncol. 1990 MVAC > Cisplatin Loehrer PJ et al. J Clin Oncol. 1992

High-dose intensity MVAC vs. classic MVAC N=263 Overall response rate: 64% vs. 50% CR rate: 21% vs. 9% Median PFS: 9.5 months vs. 8.1 months Median overall survival: 15.1 vs. 14.9 months 5-year survival rate: 21.8% vs. 13.5% Sternberg CN et al. J Clin Oncol. 2001 Sternberg CN et al. Eur J Cancer. 2006

From MVAC to other cisplatin-containing regimens

Paclitaxel + Cisplatin in metastatic bladder cancer Dreicer R et al. J Clin Oncol. 2000 Burch PA et al. J Urol. 2000 Murphy BA et al. J Clin Oncol. 1996 Studies (n) Patients (n) OR rate ( % ) CR rate (%) Median survival (m onths ) 3 104 60% 19% 10.6 - 13.0

Docetaxel + Cisplatin in metastatic bladder cancer Dimopoulos MA et al. Ann Oncol. 1999 Garcia del Muro X et al. Br J Cancer. 2002 Sengelov L et al. J Clin Oncol. 1998 Studies (n) Patients (n) OR rate ( % ) CR rate (%) Median survival (m onths ) 3 129 55% 17% 8.0 - 13.6

Docetaxel + Cisplatin vs. MVAC in metastatic bladder cancer N=220 Bamias A et al. J Clin Oncol. 2004 Drug regimen Overall response Median survival D + C MVAC 37% 54% 9.3 months 14.2 months

Paclitaxel + Carboplatin in metastatic bladder cancer Studies (n) Patients (n) OR rate ( % ) CR rate (%) Median survival (m onths ) 6 165 43% 13% 8.5 - 9.5

Paclitaxel + Carboplatin vs. MVAC in metastatic bladder cancer N=85 Dreicer R et al. Cancer. 2004 Drug regimen Overall response Median survival PAC + Carbo MVAC 28% 36% 13.8 months 15.4 months

Gemcitabine + Cisplatin in metastatic bladder cancer Study Prior CT Patients (n) CR/PR (n) OR% (CR%) Survival (months) von der Maase 1999 N 38 7/9 42% (18%) 12.5 Kaufman 2000 N 46 10/9 41% (22%) 14.3 Moore 1999 N 28 6/10 57% (21%) 13.2 Lorusso 2000 N 54 8/18 48% (15%) 12.5 Wilson 2002 N 20 2/8 50% (10%) NR

Randomized phase III study in metastatic bladder cancer T4B N2, N3 M1 GC (203 patients) MVAC (202 patients) Study initiated Nov. 1996 - recruitment completed Sept. 1998

GC vs. MVAC Response Response GC (n=164) MVAC (n=151) CR 12% 12% PR 37% 34% Response Rate 49% 46%

GC versus MVAC Time to progressive disease GC: 7.4m (6.6-8.1m) MVAC: 7.4m (6.7-9.1m) HR: 1.05 (0.85-1.30) LR: p=0.659 W: p=0.995 GC 7.4 months (6.6-8.1) MVAC 7.4 months (6.7-9.1) HR: 1.05 (0.85-1.30)

GC versus MVAC Overall survival GC: 13.8 m (12.3-15.8 m) MVAC: 14.8 m (13.2-16.8 m) HR: 1.04 (0.82-1.32) LR: p=0.746 W: p=0.908 GC 13.8 months (12.3-15.8 ) MVAC 14.8 months (13.2-16.8 ) HR: 1.04 (0.82-1.32 )

GC versus MVAC Toxicity GC MVAC Infections (grade 3-4) 3% 15% Mucositis (grade 3-4) 1% 22% Diarrhea (grade 3-4) 3% 8% Alopecia (grade 3) 11% 55% Anemia (grade 3-4) 27% 18% Thrombocytopenia (grade 4) 29% 13% Neutropenia (grade 4) 30% 65% Neutropenic fever 2% 14% Neutropenic sepsis 1% 12% Toxic deaths 1% 3%

Platinum-containing triplets in metastatic bladder cancer Author Drugs N OR rate CR rate MST Bajorin 2000 Ifos + Pac + Cis 44 68% 23% 20 mo Hussain 2001 Gem + Car + Pac 47 68% 32% 15 mo Bellmunt 2000 / 2002 Pac + Cis + Gem 58 78% 28% 16 mo Pectasides 2002 Gem + Cis + Doc 35 66% 29% 16 mo von der Maase 2003 Gem + Cis + Pac 45 60% 18% 15 mo

PCG versus GC Response Bellmunt J et al. ASCO 2007 Response PCG (n=312) GC (n=315) CR 15% 10% PR 42% 36% Response Rate 57% 46%

Progression-Free Survival Gem/Cis median 7.7 mo 1 Pac/Cis/Gem median 8.8 mo 0.87 (0.74-1.03) Bellmunt J et al. ASCO 2007 Progression-free survival

Overall Survival Gem / Cis median 12.8 mo 1 Pac / Cis / Gem median 15.7 mo 0.86 (0.72-1.03) Bellmunt J et al. ASCO 2007 Overall duration of survival

Locally advanced and metastatic transitional cell carcinoma of the urothelium Standard 1 st line chemotherapy in fit patients GC (or MVAC or HDI-MVAC)

Chemotherapy Agents for Patients Unable to Tolerate Cisplatin Phase II trial of Oxaliplatin (100 mg/m2 D 8) with Gemcitabine (1200 mg/m2 D1, D8) q21 days. N=36 in patients with advanced TCC unfit for cisplatin therapy. RR=48% (CR,19 PR) TTP = 5 months. Gemcitabine / Paclitaxel : N = 17, RR = 65%

Newer Chemotherapy Agents in Clinical Trials and as Second Line Pemetrexed : Phase II trial in patients who failed at least one prior chemotherapy. N=43, RR=30% Pemetrexed: (500 mg/m2 q 3wks) and Gemcitabine (1250 mg/m2 D1, D8) in chemo na ive pts. N=63, RR=26.5% Ixabepilone : ECOG phase II trial in pre-treated patients with advanced TCC, (40 mg/m2 q21 days), N=45, RR=11.9%, OS= 8 months Vinflunine : next slide

Trials on 2 nd line treatment of TCCU Vinflunine monotherapy in TCCU after failure of a prior platinum-containing regimen Two phase II trials Culine S et al. Br J Cancer. 2006 Vaughn DJ et al. Cancer. 2009 * PS 0 = 320 mg/m²/q3w ** PS 0 with pelvic irradiation and PS 1 = 280 mg/m²/q3w

Efficacy results * PS 0 = 320 mg/m²/q3w ** PS 0 with pelvic irradiation and PS 1 = 280 mg/m²/q3w Culine S et al. Br J Cancer. 2006 Vaughn DJ et al. Cancer. 2009 Culine et al. Vaughn et al. Number of treated patients n (%) 51 151 Initial dose (mg/m², q3w) 320 320*/280** Objective Response Rate n (%) 95% CI 9 (17.6) [8.4 - 30.9] 22 (14.6) [9.4 – 21.2] Disease control rate n (%) IRP 95% CI 34 (66.7) [52.1 - 79. 3 ] 86 (56.9) [48,7 - 65] Median Duration of response months IRP 95% CI 9.1 [4.2 - 15.0] 6.0 [5.4 – 9.5] Median PFS months 95% CI 3.0 [2.4-3.8] 2.8 [2.6 - 3.8] Median OS months 95% CI 6.6 [4.8 - 7.6] 8.2 [6.8 – 9.6]

Randomised phase III trial of influnine (VFL) plus Best Supportive Care (BSC) versus BSC alone as 2nd line therapy after a platinum-containing regimen Progression after 1 st line platinum-based treatment T4b N0 M0 or AnyT N2-3 M0 or AnyT AnyN M1 ECOG/WHO PS 0-1 Prior (neo-)adjuvant CT not permitted Vinflunine + Best Supp. Care until evidence of PD (N=253) 320 mg/m 2 , q3w: PS 0 280 mg/m 2 (Cy.1)  320 mg/m 2 (  Cy.2): PS 0 & RTx (pelvic) / PS 1 2:1 Randomisation (N = 370) Best Supp ortive Care until evidence of PD (N = 117) Palliative RTx, antibiotics, analgesics, steroids, transfusions Primary Endpoint : OS Secondary Endpoints : ORR, DCR, PFS, QoL, Safety

> 3.5 -year follow-up Eur Urol Suppl. 2010;9(2):38 Updated survival analysis - ITT population VFL + BSC arm BSC arm 2.3 months Overall Survival [months]

Bladder Guidelines Recommend Vinflunine Use as Second Line Therapy † Based on one good quality RCT ‡ Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial Post failure of a platinum based combination Level 1b recommendation † Recommended as second line therapy after platinum failure

Metastatic TCCU Therapeutic Principles TCCU is a chemosensitive tumour, particularly sensitive to cisplatin 1 st line treatment Cisplatin-based combinations in “fit” patients, but 50% are “unfit” 2 nd line treatment Up to 2009, no standard recommendation as 2 nd line treatment for advanced or metastatic TCCU. In 2011 : Vin.,antiangiogenic agents,Pac., Gem.

Era of "molecularly targeted therapy" Sorafenib 2006 Sunitinib 2006 Bevacizumab + IFN 2007 Temsirolimus 2007 Everolimus 2008 Sunitinib 2006 Imatinib 2002 Sorafenib 2008 Cetuximab + radiotherapy 2006 Bevacizumab + chemotherapy 2006 Cetuximab + chemotherapy 2008 Erlotinib 2005 Trastuzumab + chemotherapy 2001 Lapatinib + capecitabine 2006 Cetuximab 2007 Panitumumab 2007 Bevacizumab + chemotherapy 2004 Bevacizumab + paclitaxel 2007 HCC GIST RCC NSCLC CRC Breast cancer MM = malignant melanoma - HCC = hepatocellular carcinoma - GIST = gastrointestinal stromal tumour - RCC = renal cell carcinoma - NSCLC = non-small cell lung cancer - CRC = colorectal cancer - IFN = interferon Cetuximab + chemotherapy 2008 Ipilimumab 2010 MM Pazopanib 2009 Head and neck cancer … ERA OF MOLECULAR TARGETED THERAPY

Metastatic bladder cancer Integration of biologically targeted agents

Metastatic bladder cancer Integration of biologically targeted agents - only as part of a clinical trial -

Biologic Agents in Clinical Trials EGFR overexpressed in 21-48% of bladder cancers. It is associated with more aggressive tumors and poor prognosis. Single agent phase II gefitinib : lack of responses. CG + Gefitinib : phase II trial by CALGB in patients with locally advanced TCC: N=24, RR=50% A trial of CG +/- Cetuximab is ongoing.

Biologic Agents in Clinical Trials Her2-neu is overexpressed in 54% of invasive bladder cancer by IHC (only 13% had gene amplification). Carbo/Gem/Taxol + Trastuzumab: N=44, RR=73% (CR=11%) in front-line therapy. Dual ErbB1 ErbB2 inhibitor Lapatinib: N=30, RR=10% in relapsed disease, 3 patients stable disease>6 months. Bortezomib in phase II clinical trial 1.3 mg/m2 D1, D4, D8, D11 q 21 days, N=11, no responses.

VEGF Trap Treatment Plan Patients receive a dose of VEGF Trap 4 mg/kg IV administered over 1 hour on D1 of each 14 day cycle

Treatment of Metastatic Bladder Cancer Systemic chemotherapy is the main therapeutic option for metastatic bladder cancer. Despite good response , disease continues to recur and long term survival is rare. Median survival with supportive care is 4-6 months , with chemotherapy is 12-14 months .

Contents Non-invasive urothelial carcinoma Metastatic urothelial carcinoma Invasive urothelial carcinoma

Muscle invasive TCCU Treatment objectives Main objectives: Patient survival Treatment of micro-metastases

Muscle invasive TCCU Treatment Strategy Median survival of patients with muscle invasive urothelial carcinoma Huge variation according to the extent of the disease Ghoneim MA et al, Eur Urol 2004 Lerner SP et al, Urol Clin North Am 1992 Wieweg K et al, J Urol 1999 Stein JP et al, J Clin Oncol 2001 Author, year Specific survival at 5 years (%, pts) Ghoneim 2004 Disease confined to the organ ( ≤ pT2b) Disease not confined to the organ ( ≥ pT3) Lerner et al, 1992 50% 18% Vieweg et al, 1999 57.5% 24.4% Stein et al, 2003 46% 30.8%

Neoadjuvant chemotherapy Limitations: Low number of patients Multiple different regimens Sub-optimal regimens Several local treatment modalities Two Main Trials

Muscle invasive TCCU Neo-adjuvant chemotherapy Randomised phase III trials of neoadjuvant CT Modified from Sternberg Sem Oncol, 2007 ADM: Doxorubicine; E: Epirubicine; Cyst: Cystectomy Grossman et al, N Engl J Med 2003 Consistent with the 2 meta-analysis Most of the studies used earlier generation chemotherapies Most of the published phase III randomised studies included limited numbers of patients except for the EORTC study CMV = Cisplatin+Methotrexate+vinblastine M-VAC = Methotrexate+Vinblastine+Adriamycin+Cisplatin Study group Neoadjuvant arm Standard arm N° pts Survival benefit

Neoadjuvant Chemotherapy : current status Survival benefit : 5 % Bladder preservation : 20 % Included in the guidelines : EAU, NCCN,and ESMO Final words : still a debatable issue: - selected patients (not in real life): PS 0 or 1 , Cr.Cl. >50ml/min, adequate local control - optimal regimen : debatable but must contain DDP So, needs parameters to select patients

Adjuvant Chemotherapy Two advantages over neoadjuvant : - local treatment is not delayed - good selection However : - 30 % become unfit post surgery - lack of evidence based medicine

Muscle invasive TCCU Adjuvant Chemotherapy Clinical Studies and results 6 selected published randomised phase II studies including cisplatin-containing regimen The results of these studies were not consistent enough to provide recommendations on the use of adjuvant chemotherapy even if there is a favourable trend Adjuvant Chemotherapy in Invasive Bladder Cancer, Eur Urol 2005 Sternberg, “ Neo-adjuvant and adjuvant chemotherapy of bladder cancer: Is there a role? ” Medical Oncology, Vincenzo Pansadoro Foundation, Clinic Pio XI, Rome, Italy A=doxorubicin, DDP or C=cisplatin, E=epirubicin, M=methothrexate, V=vinblastine, CISCA=cytoxan+adriamycin+cisplatin, CAP=cisplatin+doxorubicin+cyclophosphamide

Muscle invasive TCCU Summary of treatment recommendations Adjuvant chemotherapy is not routinely recommended apart from trials There is no consensus in the choice of the neoadjuvant CT protocol apart from CDDP-containing regimen that provides a 5% benefit in MS ± ±

Magnitude of Cancer In Egypt National Cancer Registry

EGYPT Gharbia Population–based registry, 1999 – 2001 report

5 Most Common sites of cancer Egypt, 1999-2001, Males *ASIR: / 100,000 ASIR* R.F % Site 26.3 21.3 15.0 14.0 5.6 15.4 13.0 10.9 8.2 3.9 1. Bladder 2. Liver 3. NHL 4. Lung 5. Colon Rectum

Cancer Profile in Aswan, Egypt Methodology and Results Chart book 2008

Age-standardized Incidence rates / 100,000 By Governorate, all sites Males

Age-standardized Incidence rates / 100,000 By Governorate, all sites, Females

Age-standardized Incidence rates / 100,000 selected sites, Males Minia 2009 Damietta 2009 Aswan 2009 Aswan 2008 CI5C-IX 1999-2002 179.0 163.2 133.8 140.7 156.1 All sites ASR 116.2 126.6 97.5 96.2 93.0 All sites Crude rate 28.0 18.0 19.1 18.2 27.9 Bladder 38.8 71.5 17.4 17.4 21.9 Liver 11.7 8.8 11.8 11.2 14.0 Lung 5.5 6.8 6.9 9.2 8.5 Prostate 5.8 4.8 6.5 5.0 6.3 Colo-rectal 1.8 6.4 4.0 2.2 16.9 NHL

Age-standardized Incidence rates / 100,000, selected sites, Females Minia 2009 Damietta 2009 Aswan 2009 Aswan 2008 CI5C-IX 1999-2002 136.3 136.4 131.2 164.0 119.3 All sites ASR 99.6 120.1 97.5 115.2 91.8 All sites Crude rate 37.4 41.4 41.3 63.9 42.5 Breast 5.3 5.1 3.9 6.6 5.4 Bladder 5.0 5.2 7.4 9.1 5.2 Ovary 13.8 24.6 8.8 8.7 4.5 Liver 4.7 3.1 5.5 4.8 4.3 Colo-rectal 0.9 3.3 1.6 1.6 9.9 NHL

The National Cancer Institute Cairo University www.nci.edu.eg Cairo University National Cancer Institute

What happened to bilharziasis and to Bladder Cancer in Egypt in the past three decades?

Oral Antibilh. AbdelWahab, 7% El-Khoby, 0.5% Miller, 30% MPH, 45% Scott, 60% THE DECLINE OF PREVALENCE OF S. HEMATOBIUM IN THE NILE DELTA IN 70 YEARS (POPULATION SURVEYS BY URINE ANALYSIS) High dam Anti-Bilh.

TIME TREND ANALYSIS OF BLADDER CANCER IN 37 YEARS (NCI, 9843 Pts.) 1970- 1974 1985- 1989 2003- 2007 A B C 3212 3988 2643 Gouda, Mokhtar, Belal & El-Bolkainy, J. Egypt. NCI, 2007 .

Bladder cancer Eggs positive 82% 55% 28% 12% THE DECLINE OF BLADDER CANCER & BILHARZIAL ASSOCIATION IN 37 YEARS (NCI – 9843 PATIENTS)

Squamous Transitiona l Others 76% 28% 16% 66% 8% 6% THE CHANGE OF HISTOLOGIC PROFILE OF BLADDER CARCINOMA IN 37 YEARS (NCI – 9843 PATIENTS)

THE CHANGE OF DEMOGRAPHIC FEATURES OF BLADDER CANCER IN 37 YEARS No. of cases 3212 2643 NCI, Pathology Registry Years 1970-1974 2003-2007 Mean Age 47.4 60.5 M/F ratio 5.4 3.3

What are the prognostic factors of bilharzial related invasive bladder cancer ?

Three prognostic factors T stage Grade Lymph node status

The Role of Systemic Therapy in Urinary Bladder Cancer (Bilharzial & non-Bilharzial) Treatment of metastatic disease Role of adjuvant and neoadjuvant chemotherapy Role of combined chemo-radiotherapy

The Role of Systemic Therapy in Urinary Bladder Cancer (Biharzial & non-Bilharzial) Treatment of metastatic disease Role of adjuvant and neoadjuvant chemotherapy Role of combined chemo-radiotherapy

Results of therapy Drug No. of patients Evalu- CR PR (CR+PR) Imp. SD PD able Bleomycin 21 0 0 (0 %) 2 6 13 Doxorubicin 27 0 0 (0 %) 2 4 21 Tenoposide 26 0 1 (4 %) 2 6 17 5-fluorouracil 32 0 2 (6 %) 3 17 10 Methotrexate 14 0 1 (7 %) 0 2 11 Cisplatin 18 1 2 (16 %) 0 3 12 Dibromodulcitol 22 1 3 (13 %) 0 6 12 Cyclophosphamide 21 1 3 (19 %) 2 9 6 Pentamethylmelamine 25 1 7 (32 %) 2 9 6 Etoposide` 19 0 7 (36 %) 3 5 4 Hexamethylmelamine 26 0 10 (38 %) 12 0 4 Ifosfamide 20 0 8 (40 %) 2 2 8 Vincristine 25 2 9 (44 %) 0 8 6 Vindesine 18 3 10 (41 %) 0 9 10 Epidoxorubicin 18 0 9 (50 %) 0 7 2 18 0 11 (60 %) 0 7 0

Bilharzial Bladder Cancer Active Single Agents Epidoxorubicine 60% Vincristine 44% Ifosfamide 40% Etoposide 36% hexamethylmelamine 38% Vindesine 46% Acta Oncol. (89) , 28 , 1 : 73

Bilharzial Bladder Cancer Combination Chemotherapy ( EV - IE ) Epidoxorubicin - Vincristine Alternating with Etoposide – Ifosfamide Ann. Oncol. (96) , 7, 751

Treatment Results of the 22 Evaluable Bladder Cancer Patients CR 1 (4.5 %) PR 8 (36.5 %) Improvement 3 (13.6 %) S.D. 6 (27.2 %) I.D. 4 (18.2 %) TOTAL 22 (100 %)

GEMZAR + Cisplatin in Bilharzial Bladder Cancer NCI - Cairo Treatment Schedule Gemcitabine 1000 mg/m 2 I.V. days 1,8 & 15 Cisplatin 70 mg/m 2 I.V. day 2 Every 28 days

GEMZAR + Cisplatin in Bilharzial Bladder Cancer NCI - Cairo Treatment Summary : Evaluable 33 Response Rate : CR 8 PR 10 (54%) Improvement 3 Responses Include Liver and Lung metastases

Gemcitabine plus Cisplatin is an active combination for Bilharzial related bladder cancer ( Response rate 54 %), with a moderate toxicity profile European J. Cancer (2000) , 36: s34-s37

Treatment Schedule Gemcitabine 250 mg/m 2 over 6 hours infusion days 1,and 8 Cisplatin 70 mg/m 2 day 2 Every 21 days

RESULTS Treatment Summary Evaluable patients 55 Total cycle number 240 Median cycle number 4 ( range:1–6 cycles ) Response Rate CR 5 (9 %) PR 23 (42%) Minor response 4 (7 %) Responses were observed in all disease sites

CAIRO: BLADDER CANCER, ST III/IV Khaled , et al. Urologic Oncology (2008)

Egyptian Bladder Cancer Cooperative gp T2b,3,4a N0-2 Bladder Cancer Cystectomy 3 Courses Gem+Cis SD PR CR 3 courses Gem+Cis Cystectomy 3 courses Gem+Cis Cystectomy Radical Radiotherapy

Egyptian Bladder Cancer Cooperative Group 59 SCC, 50 TCC and 5 adenocarcinoma. T2b:29 (25%),T3: 55 (48%) & T4: 30 (27%). Arm I: RR in 28 /50(56%) ,CR in 15 (30%) Bladder preservation was successful in 11(22%) for 10-24 months so far. Grade III&IV toxicities were infrequent. Arm II: Radical cystectomy in 52 patients (4 irresectable). One- year survival was 54% for cystectomy & 69% for neoadjuvant arm.

Adjuvant Systemic Treatment in High Risk Group A prospective randomized study performed at NCI Cairo. No added benefits were observed for the used systemic treatment. (El-Sebaie M. et al., 1999) Radical cystectomy P4a, G3 and/or LN+ 3-6 weeks Randomized PORT 4500 cGy/3 weeks PORT + Sequential half body PORT + 4 courses VCR + Epirubicin

Adjuvant Chemoradiotherapy High Risk Patients (P3b,4a,G3+/-LN+) Radical Cystectomy PORT 4500cGy/3wks/30 F 2 Courses (Gem Cis ) 1000 mg/m2 D1&D8 70 mg /m2 D1 PORT 4500cGy/3wks/30F 2 Courses (Gem Cis ) Same regimen

Bilharzial Bladder Cancer Drug Therapy Invasive Tumors Superficial Tumors Advanced, metastatic, and recurrent Invasive operable Single agent phase II trials 1975 now Neoadjuvant Pilot study Phase III trial Combination Chemotherapy phase II trials Epi VCR - Ifo VP16 Gemz – DDP (2) Phase III trial (combination vs single agent) Adjuvant Classic surgery Modified surgery Little experience CT-RT

THE FUTURE Tumor Repository: Bladder tumor tissue touch print frozen paraffin block Bladder Bilharzial tissue Bladder Normal Tissue Patients’ Serum Patients’ Urine Patients’ Lymphocytes (500 Cases )

Differentially Expressed Genes Differentially Expressed EST

Bilharzias VS Non MALE VS FEMALE FARMER VS NON

Upper Vs lower Egypt Low Vs high grade

Chemotherapy in bladder cancer We are approaching a new era!

H. Khaled - Bladder cancer - State of the art

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