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Bladder Cancer Case presentations and discussion Target Audience : Oncology Fellows, Oncology physicians, Oncologists Archer Board Review Courses www.Ccsworkshop.com

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Case 1 Chief Complaint: 74 y/o woman with history of baldder cancer admitted for Partial Cystectomy

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HPI <ul><li>74 y/o woman with history of bladder cancer, diagnosed in May 2009 – admitted now for partial cystectomy. </li></ul><ul><li>The diagnosis of bladder cancer was made when she first presented with painless gross hematuria, cystoscopy revealed a large lesion indwelling the dome of the bladder. She underwent Trans Urethral Resection of the Bladder Tumor ( TURBT). Pathology at that time revealed a poorly differentiated (grade 3) carcinoma which was confirmed as primary urothelial carcinoma by immunohistochemistry ( T1NxMx). </li></ul>

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HPI <ul><li>The patient subsequently presented to the ER two weeks after TURBT with significant hematuria, required cystoscopy and fulguration of the biopsy site. Biopsies obtained this time involved only scar tissue that did not show malignancy ( no bladder tissue was included in the biopsy material – uncertain complete resection). </li></ul><ul><li>A decision was made to proceed with elective partial cystectomy for which the patient was admitted in 8/2009. </li></ul><ul><li>No new episodes of hematuria. No dysuria or urgency. No weightloss/ bone pain </li></ul>

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History <ul><li>PMHx/ PSHx : Type 2 DM, Hypertension, CAD s/p CABG ( 1997), Hysterectomy (fibroids) </li></ul><ul><li>Allergies : No known allergies. </li></ul><ul><li>Social History : (+) smoking one pack /day x 20 years; quit 15 years ago. Occassional ETOH. No drug use. </li></ul><ul><li>Family history : No history of cancer in the family. Mother hx of DM. </li></ul>

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Physical Exam <ul><li>VS: Afebrile, HR: 82, BP 120/88, RR : 18 </li></ul><ul><li>HEENT: no palpable lymph nodes, no icterus or pallor. </li></ul><ul><li>CVS: No S3/S4. No murmurs </li></ul><ul><li>Lungs: NVBS. Bibasilar creps+ </li></ul><ul><li>Abd: Soft, NT, ND, BS +, No inguinal adenopathy </li></ul><ul><li>Extremities: No LE edema </li></ul>

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Labs <ul><li>WBC 8.7 </li></ul><ul><li>Hb 14.2 </li></ul><ul><li>Hct 40.8 </li></ul><ul><li>MCV 92.3 </li></ul><ul><li>RDW 13.4 </li></ul><ul><li>Plts 257 </li></ul><ul><li>PT/PTT WNL </li></ul>

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Radiology <ul><li>CT chest/abdomen/ pelvis from 05/20/09 (performed for staging work up)  </li></ul><ul><ul><ul><ul><li>Bilateral pleural effusions ( chronic) with bibasilar atelectasis and chronic changes. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No evidence of retroperitoneal lymhadenopathy or mass lesion . </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Normal liver, spleen and pancreas </li></ul></ul></ul></ul>

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Hospital Course <ul><li>Partial cystectomy was performed with out any complications. </li></ul><ul><li>Specimens were sent for pathology. </li></ul>

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Pathology <ul><li>Bladder Tumor, Partial Cystectomy </li></ul><ul><ul><ul><ul><li>Poorly differentiated infiltrating carcinoma ( 0.4 cm in greatest dimension), favor primary urothelial carcinoma with focal glandular differentiation. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No evidence of muscularis propria ( detrusor) invasion </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No evidence of lymphovascular invasion </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Margins of excision are free of tumor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pathological stage p-T1NxMx </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Clinical – T1N0M0 – Stage I </li></ul></ul></ul></ul><ul><ul><ul><ul><li>The carcinoma is histomorphologically similar to that reported in the previous TURBT specimen ( 5/2009) </li></ul></ul></ul></ul>

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Final Diagnosis Bladder cancer, T1N0M0 Stage I

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Treatment Decisions <ul><li>No role for radiation or adjuvant chemotherapy in this setting ( Non muscle invasive Stage I bladder cancer) </li></ul><ul><li>Partial Cystectomy will suffice ( the lesion was amenable to partial cystectomy because it was in the dome) . Will need adjuvant intravesical BCG. </li></ul><ul><li>Patient will be enrolled in to cystoscopic surveillance as recommended for high risk superficial bladder cancer ( high risk of recurrence because she is grade 3 – poorly differentiated) </li></ul><ul><ul><ul><li>Cystoscopy at 3 months from now </li></ul></ul></ul><ul><ul><ul><li>If no recurrence, Cystoscopy+Cytology every 6 months for 4 years and then every year. </li></ul></ul></ul><ul><ul><ul><li>Upper tract imaging to exclude metachronous lesions of upper tract every one to two years </li></ul></ul></ul>

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Case 2 85 y/o woman with history of bladder cancer and carcinoma in-situ

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Case Summary <ul><li>85 y/o woman who was diagnosed with carcinoma in-situ ( Tis, Grade 3, right lateral bladder wall) in August 2008, treated with a course of Intra-vesical BCG, was then enrolled in to cystoscopic surveillance with biopsies. Seven months after initial diagnosis (3/09), the patient was found to have high grade papillary urothelial carcinoma ( Ta, G3) at a different site ( left bladder neck). </li></ul>

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Radiology <ul><li>CT abdomen performed for staging work up </li></ul><ul><ul><ul><ul><li>No lymphadenopathy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Unremarkable ureter and urinary bladder </li></ul></ul></ul></ul>

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Pathology <ul><li>Initial diagnosis ( 8/08) </li></ul><ul><ul><ul><ul><li>Right Lateral Wall Bladder Biopsy </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Urothelial carcinoma in-situ ( Flat type) ( Tis) in a background of high-grade dysplasia. </li></ul></ul></ul></ul></ul><ul><li>Surveillance cystoscopy with biopsy (3/09) </li></ul><ul><ul><ul><ul><li>Left Bladder Neck Biopsy </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Papillary urothelial carcinoma ( Ta), high grade (G3) </li></ul></ul></ul></ul></ul>

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Treatment Decisions <ul><li>Initially, as per recommendations for Tis, she was treated with a course of intra vesical BCG and enrolled in cystoscopic surveillance. </li></ul><ul><li>Recurrent cancer in 3/09 – was Ta ( papillary with out muscle invasion)  TURBT is done. Usually, no intravesical BCG needed for this type of tumor. </li></ul><ul><ul><ul><li>However, this tumor was Grade 3 which is associated with higher rates of recurrence and progression to muscle invasive tumor. So, patient was chosen for adjuvant intravesical immunotherapy with BCG. </li></ul></ul></ul><ul><ul><ul><li>Patient will follow with Urology for BCG </li></ul></ul></ul><ul><ul><ul><li>No role for chemotherapy in this setting since there is no muscle invasion or nodal involvement ( Stage 0a disease) </li></ul></ul></ul>

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Case 3 73 y/o man with initially diagnosed carcinoma in-situ later presenting with muscle invasive bladder cancer.

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Case Summary <ul><li>73 y/o man who was diagnosed with carcinoma in-situ ( Tis, Grade 3) in April 2004, treated with a course of Intra-vesical BCG, was then enrolled in to cystoscopic surveillance with biopsies. One year after initial diagnosis (4/2005), the patient was found to have high grade muscle invasive urothelial carcinoma ( T2, G3). </li></ul>

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Staging Work up <ul><li>Labs were normal except for mildly elevated alkaline phosphatase ( 152)  bone scan performed did not reveal metastatic lesions. </li></ul><ul><li>CT Abdomen showed no evidence of lymphadenopathy or any collection. </li></ul><ul><li>CXR normal </li></ul>

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Treatment decisions <ul><li>Stage II T2N0M0 – Muscle invasive bladder cancer. </li></ul><ul><li>Treatment of choice is Radical cystectomy. </li></ul><ul><li>Not a candidate for bladder preservation strategies because this is a recurrent cancer. </li></ul><ul><li>Patient was offered cystectomy  however, he refused and hence given Chemoradiation ( Taxol + carboplatin/ concurrent RT) . </li></ul><ul><li>Cystoscopy performed in 8/05 showed excellent response so, patient continued on chemoRT. </li></ul><ul><li>Surveillance Cystoscopies (Q6months) since then have been normal. </li></ul>

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Case 4 88 y/o man with hx of metastatic bladder cancer.

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Case Summary <ul><li>88 y/o man with hx of Renal Cell Carcinoma s/p Right Nephrectomy (2003), developed hematuria in mid-2008 and cystoscopy revealed bladder tumor, subsequent TURBT (8/08) demonstrated Muscle invasive high grade urothelial carcinoma ( G3, T2), treated with Radical cystectomy which is the standard of care for T2 lesions, however, was on frozen section, was found to have metastatic lymphadenopathy ( T2N1M0 – Stage IV TCC). The patient was started on palliative chemotherapy with Gemcitabine. </li></ul>

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Investigations and Treatment decisions <ul><li>Alkaline phosphatase was elevated at 174 but bone scan revealed Paget’s disease with out any bony metastases ( 4/2009). </li></ul><ul><li>Repeat CT scan in 4/2009 revealed increasing retroperitoneal lymphadenopathy. Chemotherapy was continued. </li></ul><ul><li>Restaging CT scan performed in 8/2009 revealed sclerotic bony lesions in the lumbar vertebrae and osteolytic lesion in right acetabulum, pulmonary nodules, Right groin and para-aortic lymphadenopathy indicating a diffuse metastatic disease  recommended orthopedic stabilization of the hip / hip replacement  patient refused and hence given Zolendronic acid + palliative RT. Possible palliativer chemotherapy to be started as well. </li></ul>

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Bladder Cancer Polychronotropic Recurring in time and space any where along the urothelial tract ( from renal pelvis to proximal two-thirds of urethra)

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Epidemiology <ul><li>5th male, 9th female cancer </li></ul><ul><li>Incidence ( M:F = 3:1) </li></ul><ul><ul><li>142/100 000 in Men </li></ul></ul><ul><ul><li>33/100 000 in Women </li></ul></ul><ul><li>Pathology usually Transitional Cell Carcinoma (95%) also </li></ul><ul><ul><li>Squamous cell, adenocarcinoma, small cell, lymphoma, sarcoma, carcinosarcoma </li></ul></ul>

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Screening <ul><li>Routine screening in all patients for bladder cancer with either urinalysis or cytology is not recommended </li></ul><ul><li>Screening for bladder cancer in high risk individuals ( those exposed to dyes/ leather, smokers) is controversial  no clear recommendations. </li></ul><ul><li>Incidentally discovered hematuria should not be neglected. </li></ul>

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Etiology <ul><li>Smoking ( accounts for 2/3 of bladder cancer cases) </li></ul><ul><li>Other risk factors </li></ul><ul><ul><li>Age, male sex </li></ul></ul><ul><ul><li>Chronic bladder inflammation, schistosomiasis </li></ul></ul><ul><ul><li>External beam radiation </li></ul></ul><ul><ul><li>Previous exposure to cyclophosphamide ( Carcinogenicity attributed to it’s metabolite “Acrolein”) </li></ul></ul><ul><li>At risk occupations (carcinogens, aniline dyes, diesel) </li></ul><ul><ul><li>Hairdressers, machinists, printers, painters </li></ul></ul><ul><ul><li>Rubber, chemical, textile, metal, leather industries </li></ul></ul>

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Staging

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Stage grouping Stage 0a Ta N0 M0 Stage 0is Tis N0 M0 Stage I T1 N0 M0 Stage II T2a N0 M0 T2b N0 M0 Stage III T3a N0 M0 T3b N0 M0 T4a N0 M0 Stage IV T4b N0 M0 Any T N1 M0 Any T N2 M0 Any T N3 M0 Any T Any N M1

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Symptoms <ul><li>Hematuria (80%) </li></ul><ul><ul><li>Painless Microscopic Hematuria </li></ul></ul><ul><li>‘ Cystitis’ and sterile pyuria </li></ul><ul><li>Bladder irritability </li></ul><ul><li>Anemia </li></ul><ul><li>Urinary tract infection </li></ul><ul><li>Pain (advanced disease) </li></ul><ul><li>Ureteric orifice obstruction </li></ul><ul><ul><li>hydronephrosis, kidney failure </li></ul></ul>

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Investigations <ul><li>Cystoscopy </li></ul><ul><ul><li>EUA ( Examination Under Anesthesia) </li></ul></ul><ul><ul><li>Transurethral Resection of the Bladder Tumors ( TURBT) </li></ul></ul><ul><ul><li>Biopsies </li></ul></ul><ul><li>Ultrasound kidneys/abdomen </li></ul><ul><li>CT scan/MRI scan </li></ul><ul><ul><li>Differential diagnosis </li></ul></ul><ul><ul><li>Staging ( In muscle invasive disease, CT abdomen must always be performed for staging prior to making treatment decisions) </li></ul></ul><ul><li>Bone scan if symptomatic or raised alkaline phosphatase </li></ul>

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Management <ul><li>Non-Muscle Invasive Bladder Cancer </li></ul><ul><li>Muscle-Invasive Bladder Cancer </li></ul><ul><li>T4 Disease </li></ul><ul><li>Metastatic Bladder Cancer </li></ul>

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Superficial Bladder Cancer <ul><li>70%, Ta, T1, Tis {CIS} </li></ul><ul><li>Presence of Tis in the mucosa adjacent to a Ta or T1 tumor  increases the risk for muscle invasive disease </li></ul><ul><li>Recurs at primary site or elsewhere in UT. </li></ul><ul><li>22% cause death </li></ul><ul><li>May be lifelong disease </li></ul><ul><li>Diagnose by cystoscopy </li></ul><ul><li>TURBT then adjuvant intravesical therapy for high risk ( BCG is most commonly used and superior intravesical agent. Mitomycin C single shot - (17% decrease in early recurrence rate) </li></ul><ul><li>Further management depending on pathology and risk stratification ( risk for recurrence or progression) (see next slide): </li></ul>

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Grading <ul><li>In addition to tumor stage (Tis, Ta, or T1), histologic grade also influences </li></ul><ul><ul><ul><ul><li>rate of recurrence </li></ul></ul></ul></ul><ul><ul><ul><ul><li>survival </li></ul></ul></ul></ul><ul><li>Grading : </li></ul><ul><ul><li>Grade I : Well differentiated </li></ul></ul><ul><ul><li>Grade II : Moderately differentiated </li></ul></ul><ul><ul><li>Grade III : Poorly differentiated </li></ul></ul><ul><li>In one study, grade was the most significant tumor variable in superficial bladder cancer predicting for the development of invasive carcinoma. ( Superficial bladder cancer: the primacy of grade in the development of invasive disease. AU Torti FM; Lum BL; Aston D; MacKenzie N; Faysel M; Shortliffe LD; Freiha F SO J Clin Oncol 1987 Jan;5(1):125-30) </li></ul>

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Other Prognostic Variables <ul><li>Multicentricity </li></ul><ul><ul><li>Patients with multiple papillary tumors at the time of presentation have higher rates of recurrence of both non-muscle invasive and invasive cancer. </li></ul></ul><ul><li>Molecular markers </li></ul><ul><ul><li>May provide an additional way to identify non-muscle invasive bladder cancers that are likely to progress to muscle invasive or high-grade disease eg: abnormalities in p53 may be associated with a less favorable prognosis where as, the presence of mutations in fibroblast growth factor receptor 3 (FGFR3) may indicate favorable prognosis </li></ul></ul>

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Superficial Bladder Cancer

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Superficial Bladder Cancer

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Muscle invasive disease <ul><li>T2-T3 disease (40-60% 5 year survival) </li></ul><ul><li>Options are </li></ul><ul><ul><li>cystectomy (+/- reconstruction) with neoadjuvant chemotherapy or </li></ul></ul><ul><ul><li>radiotherapy +/- chemotherapy </li></ul></ul><ul><li>Radical cystectomy (2-3% mortality rate) </li></ul><ul><ul><li>Main treatment modality for muscle invasive bladder cancer for patients who are not candidates for bladder preservation approaches. </li></ul></ul><ul><ul><li>Involves lymph node dissection and removal of bladder and prostate and seminal vesicles or anterior vaginal wall, uterus, fallopian tubes and ovaries </li></ul></ul><ul><ul><li>Side effects include loss of native bladder and impotence. </li></ul></ul><ul><li>Bladder preservation strategies </li></ul><ul><ul><li>Elderly, those with significant comorbidities, poor performance status, those who desire to preserve their bladder. </li></ul></ul>

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Bladder Preservation Strategies <ul><ul><li>Tumor characteristics that are optimal for bladder preservation : </li></ul></ul><ul><ul><ul><ul><li>Solitary, muscle invasive tumor clinically confined to the bladder. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No associated CIS </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No evidence of hydronephrosis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No prostatic urethral involvement </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No prior history of recurrent bladder or upper tract urothelial tumors. </li></ul></ul></ul></ul><ul><li>Strategies : </li></ul><ul><ul><ul><li>Partial Cystectomy </li></ul></ul></ul><ul><ul><ul><li>Radical Transurethral Resection ( TURBT) </li></ul></ul></ul><ul><ul><ul><li>TURBT followed by chemotherapy alone </li></ul></ul></ul><ul><ul><ul><li>Chemoradiation </li></ul></ul></ul>

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Chemoradiation <ul><li>Combines radical TURBT followed by external-beam radiation therapy with concurrent cisplatin as a radiation sensitizing agent ( 5-FU or Paclitaxal also used) </li></ul><ul><li>The most important predictor of outcome in patients undergoing chemoradiation is the completeness of transurethral resection (TUR) prior to RT. </li></ul><ul><li>Repeat Cystoscopy to evaluate the response </li></ul><ul><li>60 to 75% will achieve a complete response to chemoradiation and preserve their bladders </li></ul><ul><li>25 to 40 percent of non-responders will need immediate salvage cystectomy. </li></ul>

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Muscle Invasive Bladder Cancer - Radiotherapy

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Radiotherapy <ul><li>Linear accelerator </li></ul><ul><li>55 Gy in 20 fractions over 4 weeks </li></ul><ul><li>3 or 4 fields </li></ul><ul><li>CT planned treatment </li></ul><ul><li>Verification on set </li></ul>

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Muscle Invasive <ul><li>Side effects of RT include </li></ul><ul><ul><ul><li>Acute - tiredness, cystitis, diarrhea, loss of local hair, skin reddening </li></ul></ul></ul><ul><ul><ul><li>Late - bladder telangiectasia (5%), fibrosis and shrinkage, altered bowel habit (<50%), proctitis (5%), vaginal adhesions/stenosis, impotence (20-30%) incontinence (1%) </li></ul></ul></ul>

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Muscle Invasive <ul><li>Neo Adjuvant Chemotherapy should be added to surgery ( cystectomy). </li></ul><ul><li>Improves survival - 5% survival benefit at 5 years for neoadjuvant chemotherapy </li></ul><ul><li>Preferred regimen – Cisplatin based combination therapy </li></ul><ul><ul><li>Gemcitabine + Cisplatin preferred regimen due to less toxicity when compared to MVAC. </li></ul></ul><ul><ul><li>MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) with G-CSF support – toxicity limits its use. </li></ul></ul><ul><ul><li>Gemcitabine/ Paclitaxel or Gemcitabine/ Docetaxal are alternative regimens that are effective but have not been compared with above standard regimens </li></ul></ul>

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Muscle Invasive <ul><li>Adjuvant Chemotherapy </li></ul><ul><li>No clear consensus. </li></ul><ul><li>Following cystectomy, in patients who did not receive neoadjuvant chemotherapy, adjuvant chemotherapy with a cisplatin-based regimen can be considered for </li></ul><ul><ul><li>patients who have perivesical tumor extension (stage T3 or higher) or </li></ul></ul><ul><ul><li>regional lymph node involvement. </li></ul></ul><ul><ul><li>( Ongoing Phase III trials to provide more insight in to this.) </li></ul></ul>

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Stage T4 Disease <ul><li>T4a -prostate, uterus, vagina involved </li></ul><ul><li>T4b - pelvic side wall or abdominal wall </li></ul><ul><li>10 % 5 year survival for T4a </li></ul><ul><li>- give chemotherapy if patient is fit ( good performance status) and then radiotherapy to pelvis. </li></ul><ul><li>- For those with good PS and adequate renal function, Cisplatin-based chemotherapy. Gemcitabine + Cisplatin is the preferred regimen based upon its decreased toxicity compared to MVAC </li></ul><ul><li>- For those with poor PS and impaired renal function, carboplatin based therapy </li></ul><ul><li>Palliative treatment for T4b </li></ul>

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Metastatic Disease <ul><li>Chemotherapy is the main treatment option </li></ul><ul><li>Gold standard was MVAC (methotrexate, vinblastine, adriamycin, cisplatin) but very toxic - needs good PS and renal function, best for nodal disease only. </li></ul><ul><li>Gemcitabine/cisplatin is as good as MVAC with less neutropenia and mucositis and is the first line therapy. </li></ul><ul><li>In patients with GFR < 60ml/min, carboplatin must be substituted for cisplatin in the above regimens </li></ul><ul><li>Newer drugs - Taxol, gemcitabine – combinations of these agents with lower toxicity profile can be used based on patient’s performance status, other comorbidities ( neuropathy etc), compromised liver or kidney function . </li></ul>

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Metastatic Disease <ul><li>Radiotherapy has role in metastatic disease to treat bone metastases, brain metastases, cutaneous metastases, etc. </li></ul>

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End Questions?