MANAGEMENT OF CARCINOMA URINARY

BLADDERBy: Dr Satyajeet Rath

Moderator: Prof Kamal Sahni

Date: 15.03.17

Aim of Management of Bladder cancers- Stage wise•Superficial bladder cancer- prevent recurrent and progression to muscle invasive cancer.•Muscle invasive bladder cancer- patient selection for cystectomy and for bladder preservation protocol and for integrated systemic chemotherapeutic approach.•Metastatic bladder cancer- palliation and quality of life.

Urinary Bladder Cancer

NMIBC (75%) Muscle Invasive cancer - MIBC(20%)

Metastatic cancer (<5%)

Petrovich JCO 2001

TREATMENT OPTIONS• Surgery• Chemotherapy• Immunotherapy• Radiotherapy

Non-muscle-Invasive Bladder Cancer - NMIBC

• 70-80% of patients with bladder cancer present with NMIBC

• Tis, Ta, and T1

• 50-70% will recur; 10-20% will progress to MIBC

• Low grade (G1,2) and lower stage (Ta) – 50% recurrence rate• Higher grade (G3, T1 with CIS, multifocal) – 70% recurrence rate

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

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 absent (50% vs 15%) [Herr JU 1999] 1/4 will have upstage [Herr JU1999] 1/3 will have to change management [Herr JU 1999]

European Association of Urology Guidelines 2015

Predicting recurrence and progression of NMIBC EORTC bladder cancer calculator CUETO risk calculator

EORTC - predict recurrence and progression in patient with stage Ta, T1 bladder cancer• number of tumors• size,• prior recurrence rate• T category• grade• presence of CIS

CUETO - predicts risks of recurrence and progression for BCG-treated patients

• sex• age• prior recurrence status• number of tumours• T category• associated CIS;• tumour grade

CUETO risk calculator is available at: http://www.aeu.es/Cueto.html

 European Organisation for Research and Treatment of Cancer. Bladder cancer calculator.  http://www.eortc.be/tools/bladdercalculator/.

Treatment recommendations in Ta, T1 tumours and CIS according to risk stratification – EAU Guidelines

European Association of Urology Guidelines 2015.

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.

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

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

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.

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 yrs• 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.

*European Association of Urology Guidelines 2015.

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.

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.

• Goals of treatment : • Cure patient• Optimize survival• Prevention of Pelvic failure and Distant metastasis• Functional Urinary reservoir and High Quality Of Life

MUSCLE INVASIVE BLADDER CANCER

RADICAL CYSTECTOMY

WITH URINARY RECONSTRUCTION

BLADDER CONSERVATION PROTOCOLS

RELAPSE or PROGRESSION

• Conservative Surgery• Partial Cystectomy

• Radical EBRT ± Brachytherapy boost• Combined modality treatment

• Chemotherapy +TURBT/Partial cystectomy• Trimodality Therapy: maximal TURBT,

chemotherapy & radiotherapy

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Surgery: Radical cystectomy• Indication:

• Muscle invasive or locally advanced disease T2-T4a

• 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• 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• decrease in OS, RFS, CSS

Hautmann RE, et al. Does the option of the ileal neobladder stimulate patient and physician decision toward earlier cystectomy?. J Urol 1998;159(6):1845-50Chang 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

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

Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006

ILEAL CONDUIT(incontinent diversion to

skin)

CONTINENT CUTANEOUS RESERVOIR

(continent diversion to skin)

ORTHOTOPIC NEOBLADDER

(continent diversion to urethra)

Types of Urinary Diversion

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.

Standard PLND Proximal: Bifurcation of common iliac artery Distal: Circumflex iliac vein Lateral :Gentitofemoral nerve Medial: Bladder wall Pelvic floor and hypogastric vessels

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,

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.

The Bladder Cancer Collaborative Group recommends 10-14 lymph nodes should be removed at time cystectomy

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

No trials have till date directly compared Cystectomy and Bladder-preservation

• 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

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 - 19% of patients with primary, MIBC are potential candidates• Local recurrence rates : 38-78%• Half of the recurrences appear in the first year and two thirds by 2 years

Bladder Preservation Approaches1. Radical radiotherapy.2. Concurrent chemoradiotherapy.( European approach)3. Induction chemoradiotherapy f/b consolidation chemoradiotherapy.

(RTOG/MGH protocol)4. Neoadjuvant chemotherapy f/b chemoradiotherapy.5. Chemoradiotherapy f/b adjuvant chemotherapy.

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.

Radiotherapy• Traditionally RT alone was given only for unfit/older pts• Definitive radiotherapy gives consistent and reproducible effects• It’s a viable option for bladder preservation• Results are better in younger, fitter and in those without extravesical disease• Poor prognostic factors in Radical cystectomy hold true for radical radiotherapy series also

Ideal candidate for definitive Radiotherapy• Disease confined to the bladder• With good bladder function• cT2 tumor• No associated CIS• Willingness for prolonged course of therapy & regular follow up

Contraindications of pelvic Radiotherapy• Pt with active inflammatory bowel disease • Previous pelvic irradiation• Pts with extensive bladder CIS are at high risk for tumor recurrence after RT so cystectomy

should be done

Cozzarini IJROBP 1999

• 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

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

Bladder protocol to account for organ motion in conformal planning

• Patient is asked to void the urine and empty the bladder as much as possible. • Patient is asked to drink 500 ml of water and time is recorded. • After 60 minutes of drinking water, CT simulation without contrast is performed

suggestive of full bladder• Thereafter, patient is asked to void urine and empty the bladder as much as

possible and CT Simulation with contrast enhancement is performed suggestive of empty bladder

• Both images (with full bladder and empty bladder) are 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.

Conventional radiotherapy volumes2 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/#

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 bladder+tumor with a 2-cm margin to a total dose of 66 Gy

ContouringGross Tumor Volume (GTV): macroscopic tumor visible on radiological imaging/ cystoscopy findings provided by the urologist during TURBT

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 is given a 1-1.5 isotropic margin to create the PTV_Primary.• PTV_LN: 1 cm isotropic margin is given to CTV_LN.• PTV_Primary booleaned (added) with PTV_LN to produce a PTV_Total in order to facilitate treatment

planning. 

• Both images (with full bladder and empty bladder) are 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 form the primary image for GTV and CTV delineations.

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 a way 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.

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

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

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.• Caution: However morbidity of post operative radiation is high due to small

bowel toxicity that occupies pelvis after cystectomy.

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

• Five-year local control rates for selected patients 70% -90% • High rates of bladder preservation

• Doses : • 40 Gy in 2 Gy daily fractions is followed by a brachytherapy dose of 25–30Gy EQD2• When brachytherapy is combined with a partial cystectomy the brachytherapy dose can be

reduced to 15–20 Gy EQD2

Pieters BR et al. GEC-ESTRO/ACROP recommendations for performing bladder-sparing treatment with brachytherapy for MIBC. Radiother Oncol (2016)

Trimodality TherapyCombination 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

• 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

Ideal candidates:

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

Pioneering single institution studies of Trimodality treatment

± NACT:MCV

Multi-modality Treatment Evolution In RTOG trials

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

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

CTRT with 5-FU and mitomycin C chemotherapy.

• Median FU - 70 months

CT-RT RT alone

P value

DFS 67% 54% 0.03

OS 48% 35% 0.16

Conclusion about agent of choice for CT-RT 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.

• 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

Role of systemic chemotherapy

• Neoadjuvant• Adjuvant• Palliative

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

Randomized Phase III Trials of Neoadjuvant Chemotherapy

(Overall Survival)

Single agent

Advanced Bladder Cancer (ABC) Meta-analysisAnalysis 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

Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Vale, C The Lancet , Volume 361 , Issue 9373 , 1927 – 1933, 2003

Metaanalysis

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

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 more2. Node positive

• 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

Metastatic Bladder Cancer

• The prognosis of metastatic bladder cancer, is poor, with a median survival on the order of only 12 months.

• 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 is short, with a median of 4 to 6 months, • Therefore, the impact of chemotherapy on survival has been disappointing

• 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

Summary

Thank you