Chemotherapy in ca urinary bladder dr prasanta dash

DR. PRASANTA KUMAR DASHModerator Dr. S K GUPTA

1.5-2% of all malignant neoplasms in males in India

Second commonest urologic malignancy after prostate cancer in india.

More common in urban than rural areas

Clinical spertrum

SURVIVAL

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

Neoadjuvant chemotherapy-CMV EORTC/MRC trial (European) –Using CMV

976 patients randomized to CMV vs no chemotherapy

Definitive management of primary either cystectomy or RT

No subgroup analysis done to compare cystectomy and RT groups

With a median follow-up of eight years, neoadjuvant CMV was associated with a reduction in the risk of death compared to local treatment alone (HR 0.84, 95% CI0.72-0.99) . This corresponds to an absolute improvement in OS at 10 years of six percent (30 to 36 percent).

Lancet 354 (9178): 533-40, 1999

Neoadjuvant Chemotherapy

INT-0800(American) study-MVAC Confirmed results of MRC study

317 patients with T2 to T4a disease Randomized to 3 cycles of neoadjuvant

MVAC prior to cystectomy or cystectomy alone

Improved median survival by almost 3 years (77 months vs 46 months)

Decreased risk of bladder cancer specific death by 25%

Improved OS by 5% (p=0.06)

Grossman et al, N Engl J Med 349 (9): 859-66, 2003

Results of INT-0800(American) study-MVAC

NACT+ surgery

Surgery only

Path CR 38% 15%

Median survival

77mths

(55-104)

46mths

(25-60)

5yr acturial survival

57% 43% P=0.06


INT-0080 continued Of long term survivors 85% had a

complete pathologic response at the time of cystectomy

cPR rates 38% in MVAC group 15% in surgery alone group (post TURBT) p=0.001

Patients with T3 and T4 disease achieved the greatest survival benefit

Gem /Cis as NACT

Hussein Khaled and his colleagues at the Egyptian Bladder Cancer Cooperative in Cairo, Egypt-gemcitabine/cisplatin regimen as neoadjuvant chemotherapy for invasive bladder cancer

phase 3 trial, 114 patients were randomized to receive either cystectomy alone (56 patients), or to 3 cycles of gemcitabine/cisplatin preoperatively (58 patients).

Patients with a complete response received 3 additional cycles followed by radiation treatment (68 Gy/7 weeks). Patients who were subsequently downstaged to T2-T3 went on to surgery and received an additional 3 cycles of the regimen postoperatively. Patients with stable disease or disease progression following chemotherapy went on to surgery immediately

reported an overall response of 56% (30% complete response [CR] and 25% partial response [PR]), and bladder preservation was possible in 22% of those patients who had a CR.

They also noted a trend toward increased 1-year survival in the chemotherapy patients relative to cystectomy-alone patients (69% vs 54%, P = .9)

GC Vs MVAC as NACT GC and MVAC have only been compared in

retrospective studies

These studies suggest it results in similar rates of pCR and survival outcomes .

Despite the lack of prospective data, GC is administered in this setting based on data from studies performed in patients with metastatic urothelial carcinoma, which show six cycles of GC result in a better toxicity profile compared to MVAC without a major difference in OS.

Yeshchina O, et al. Relative efficacy of perioperative GC Vs MVAC in the management of locally advanced urothelial carcinoma of the bladder. Urology 2012; 79:384.

Neoadjuvant Chemotherapy-Meta-analysis(3)

Meta-analyses (1) Advanced Cancer Meta-analysis

Collaboration Included 2688 patients from 10

randomized trials (did not include INT-0080)

Showed increased overall survival benefit of 5% at 5 yrs p=0.016 when neoadjuvant platinum based combination chemotherapy used

Not significant if only single agent cisplatin trials were included Advanced Bladder Cancer Meta-analysis Collaboration.: Neoadjuvant

chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361 (9373): 1927-34, 2003


Canadian Meta-analysis(2) Winquist et al

2605 patients in 11 trials with stage II or stage III disease

2-4 cycles of neoadjuvant chemo Improved OS by 6.5% p=0.006 Mortality due to chemotherapy 1.1%

Winquist E, et al, J Urol. 2004 Feb;171(2 Pt 1):561-9


Advanced Bladder Cancer Meta-analysis collaboration(3) Included 11 trials with 3005 patients Included 98% of all known patients in

randomized trials using cisplatin based combination chemotherapy

Improved OS by 5%; p=0.003 Decreased risk of death by 14%

Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.Eur Urol. 2005 Aug;48(2):202-5

Cochrane review --2008

Platinum based combination chemotherapy

showed a significant benefit on overall survival

with a combined hazard ratio (HR) 0.86 (95% CI

0.77 to 0.95, P =0.003);

14% reduction in the risk of death;

5% absolute benefit at 5 years (95% CI 1% to 7%);

overall survival increased from 45% to 50%.

This effect was observed irrespective of the type

of local treatment and did not vary between

subgroups of patients.

Cochrane review –2008-Contd The HR for all trials, including those that used

single-agent cisplatin, tended to favour neoadjuvant

chemotherapy (HR= 0.89, 95% CI 0.81 to 0.98, P =

0.022).

Although platinum based combination

chemotherapy was beneficial, there was no clear

evidence to support the use of single-agent

platinum, indeed there was significant difference in

the effect between these groups of trials (P = 0.029)

Conclusions-NACT

Neoadjuvant chemotherapy — For patients undergoing neoadjuvant chemotherapy, cisplatin-based combination regimens should be used.

However, the ideal neoadjuvant chemotherapy regimen is not known.

Commonly employed regimens administered in the neoadjuvant settinginclude:MVAC,CMV,GC

Doses

MVAC — Methotrexate (30 mg/m2 on days 1, 15, and 22), vinblastine (3mg/m2 on days 2, 15, and 22), doxorubicin (30 mg/m2 on day 2), and cisplatin (70 mg/m2 on day 2) administered every 28 days for three cycles .

CMV — Methotrexate (30 mg/m2) and vinblastine (4 mg/m2) on days 1 and 8 plus cisplatin (100 mg/m2 on day 2), with folinic acid (15 mg every six hours for four doses) on days 2 and 9, repeated every 28 days forthree cycles .

GC — Gemcitabine (1000 mg/m2 on days 1, 8, 15) plus cisplatin (70mg/m2 on day 2) every 28 days for a maximum of six cycles .

Adjuvant Chemotherapy -RATIONALE For patients with muscle invasive bladder

cancer, cystectomy alone is associated with a 50 to 65 percent overall survival rate, which may be as high as 80 percent in patients who have pT2 disease .

However, patients with locally advanced disease

are at risk for worse outcomes. The five-year survival rate in patients with invasion beyond the bladder muscle is approximately 40 percent, while the survival for patients with lymph node involvement does not exceed 10 percent.

Given the benefit of chemotherapy in the neoadjuvant setting and the poor prognosis of patients following surgical resection, adjuvant chemotherapy is often used in patients with high-risk bladder cancer.

Although this rationale provides the justification for the use of adjuvant chemotherapy, the available data from randomized trials provide little conclusive evidence that adjuvant therapy improves survival outcomes.

In addition, approximately 30 percent of patients experience complications following radical cystectomy that preclude them from receiving adjuvant chemotherapy .

Spanish Oncology GU Group Trial 99/01 The Spanish Oncology Genitourinary Group

trial 99/01 planned to randomly assign 340 patients with T3-T4 or node positive disease to treatment using four cycles of paclitaxel, gemcitabine, and cisplatin (PGC) or observation .

However, the trial was terminated in 2007 because of poor accrual after only 142 patients were enrolled.

The preliminary results of this trial were presented at the 2010 American Society of Clinical Oncology (ASCO) meeting. At a median follow-up of 51 months, adjuvant PGC resulted in a significant increase in overall survival (OS) at five years compared to no chemotherapy (60 versus 30 percent, hazard ratio [HR] 0.44). Paz-Ares LG, Randomized phase III trial comparing adjuvant PGC to observation in patients with

resected invasive bladder cancer: J Clin Oncol 2010; 28:18s

Adj CT-Italian trial-Using GC Gemcitabine plus cisplatin (GC) -194 patients

with pT2 (grade 3) or pT3-4, N0-2 urothelial bladder carcinoma were randomly assigned to four cycles of GC or observation.

Patients on the GC arm were also randomly assigned receive gemcitabine 1000 mg/m2 days 1, 8 and 15 and cisplatin 70 mg/m2 day 2 or gemcitabine as above plus cisplatin 70 mg/m2 day 15, every 28 days .

For patients on observation, GC was administered at the time of disease progression.

Cognetti F, Adjuvant chemotherapy with GCversus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol 2012; 23:695

The trial was prematurely closed due to poor accrual.

At a median follow-up of 35 months, there was no difference in either overall survival (HR 1.29, 95% CI 0.84-2.00) or disease-free survival (HR 1.08, 95% CI 0.73-1.59) compared to observation

However, the study was underpowered to show the impact of treatment on either endpoint.

Adj CT - EORTC Trial

EORTC Trial — A very different phase III study which aimed to randomly assign 660 patients to observation or treatment with adjuvant chemotherapy (either methotrexate, vincristine, doxorubicin, cyclophosphamide [M-VAC] or High Dose M-VAC [HD-MVAC] or GC at the discretion of the treating physician).

After enrollment of 248 patients, the trial was closed due to slow accrual (though this surpasses the accrual of patients in other contemporary trials).

Other adj trials

Summary of these trials

Multiple trials Small patient numbers ranging from 49-102 Two trials suggest survival benefit Skinner et al. J Urol 1991

91 patients Included T3-4 or node positive patients Randomized to 4 cycles of cis/doxo/cyclo or

observation Median survival

4.3 yrs chemo p=0.006 2.4 yrs observation

Criticized - ? selection bias: 91 of 498 patients screened were eligible

Skinner DG et al, J Urol. 1991 Mar;145(3):459-64

Adjuvant chemotherapy-Meta-analysis

Meta analysis- Cochrane Collaboration 2006

491 pts. from 6 trials Power limited

Small numbers Impact of trials stopped early Patients not receiving allocated rx Patients not receiving salvage chemotherapy

Showed a relative decrease in death of 25% in favour of adjuvant chemotherapy (p=0.02)

Absolute survival benefit: 9%

Cochrane Database Syst Rev. 2006 Apr 19;(2):CD006018

Single agent

combination

Conclusion--Compare and Contrast

Neoadjuvant Deals with

micromets sooner Best evidence of

benefit Concern re: delay

in surgery ? 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?

METASTATIC BLADDER CANCER

Typically, bladder cancer recurs in the pelvic lymph nodes and distant sites

Despite the fact that bladder cancer is chemosensitive, the prognosis of patients with metastatic disease remains poor, with a median survival of 14 months and a 5-year survival rate of 15%

CHEMOTHERAPY IN METASTATIC BLADDER CANCER

• Cisplatin 28 % (26-32)• Carboplatin 15 % (11-19)• Methotrexate 29 % (23-35)• Ifosfamide 28 % (19-37)• Doxorubicin 17 % (13-22)• 5-Fluorouracil 17 % (11-25)• Vinblastine 16 % (4-28)• Mitomycin C 13 % (3-23)

single agents


• Cisplatin + Methotrexate

- CM• Cisplatin + Methotrexate + Vinblastine

- CMV• Methotrexate + Vinblastine + Adriamycin + Cisplatin

- MVAC

“Old” drug combinations

MVACIN METASTATIC BLADDER CANCER

• Sternberg et al., 1985, 1989

– overall response rate 72%– CR rate 25% + 11% (surgery)– median survival 13 months


• 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


Phase III studies

• Logothetis et al., 1990– MVAC > CISCA– MS 82 vs 40 weeks

• Loehrer et al., 1992– MVAC > Cisplatin– MS 12.6 vs 8.7 m

MVAC - ERAIN METASTATIC BLADDER CANCER

• MVAC is associated with substantial toxicities and a toxic death rate of 3-4%

• Thus, a need for alternative regimens with superior efficacy and/or decreased toxicity was identified


• Taxanes• Gemcitabine

Most promising new drugs

PACLITAXEL ALONE IN METASTATIC BLADDER CANCER

Study Prior CT

Patients (n)

OR% (CR%)

Survival (months)

Papamichael, 1997

Y 14 7% (0%) NR

Vaughn, 2002

Y 31 10% (0%) 7.2

Dreicer, 1996

Y/N 9 56% (0%) NR

Roth, 1994

N 26 42% (27%) 8.4

DOCETAXEL ALONE IN METASTATIC BLADDER CANCER

Study Prior CT

Patients (n)

OR% (CR%)

Survival (months)

McCaffrey, 1997

Y 30 13% (0%)

9

de Wit, 1998

N 29 31% (14%)

NR

Studies

(n)

Patients

(n)

OR rate

(%)

CR rate

(%)

Median survival

(months)

3 104 60% 19% 10.6 - 13.0

PACLITAXEL + CISPLATIN IN METASTATIC BLADDER CANCER

Studies

(n)

Patients

(n)

OR rate

(%)

CR rate

(%)

Median survival

(months)

3 129 55% 17% 8.0 - 13.6

DOCETAXEL + CISPLATIN IN METASTATIC BLADDER CANCER

DOCETAXEL + CISPLATIN vs MVAC IN METASTATIC BLADDER CANCER

Drug regimen Overall response Median survival

D + C 37% 9.3 months

MVAC 54% 14.2 months

N=220

Bamias et al., 2004

Studies

(n)

Patients

(n)

OR rate

(%)

CR rate

(%)

7 192 25% 9%

GEMCITABINE ALONEIN METASTATIC BLADDER CANCER

1st and 2nd line

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 STUDYIN METASTATIC BLADDER CANCER

T4BN2, N3M1

GC (203 patients)

MVAC (202 patients)

Study initiated Nov. 1996 - recruitment completed Sept. 1998

Response GC (n=164)

MVAC (n=151)

CR

12% 12%

PR

37% 34%

Response rate

49% 46%

GC versus MVACResponse

GC versus MVACTime 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

Proportion surviving

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Pts at risk 202 203

6

120 128

12

64 55

18

22 24

24

8 8

30

3 1

36

0 0

months

MVAC GC

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 MVACOverall 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

Proportion surviving

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Pts at risk 202 203

6

161 167

12

124 120

18

54 52

24

18 18

30

4 1

36

0 0

months

MVAC GC

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%15%

Mucositis (grade 3-4) 1% 22%22%

Diarrhea (grade 3-4) 3% 8%8%

Alopecia (grade 3) 11% 55%55%

Anemia (grade 3-4) 27%27% 18%

Thrombocytopenia (grade 4) 29%29% 13%

Neutropenia (grade 4) 30% 65%65%

Neutropenic fever 2% 14%14%

Neutropenic sepsis 1% 12%12%

Toxic deaths 1% 3%3%

• GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC

Conclusion

von der Maase et al.

J Clin Oncol 18:3068-3077, 2000

Second-line Chemotherapy

No standard second-line chemotherapy exists for patients with bladder cancer who progress on the standard first-line platinum-based treatment with MVAC or GC

Various single agents, including paclitaxel, docetaxel, gemcitabine, ifosfamide, oxaliplatin, and vinflunine, have been studied in this setting with modest response rates of less than 20%.

Pemetrexed, a multitargeted antifolate, is also an active agent in the second-line setting

The Hoosier Oncology Group37 study demonstrated a response rate of 28% and a median survival of 9.6 months

Albumin-bound paclitaxel is another agent that has shown promising activity in a phase II study in 48 patients progressing on platinumbased chemotherapy

Eribulin has demonstrated response rates of 40% as a single agent in bladder cancer

it is not renally excreted and is being studied in patients with renal dysfunction

Novel Agents in Bladder Cancer Trastuzumab Tyrosine kinase inhibitor (TKI)

Gefitinib , Erlotinib VEGF TKI Sunitinib, Pazopanib Dovitinib is an oral inhibitor of VEGFR

and FGFR and is being evaluated in combination with GC or carboplatin in bladder cancer

Conclusions

Bladder cancer is a chemosensitive disease, and systemic chemotherapy plays a role in its management

Cisplatin-based combination chemotherapy prolongs survival in the metastatic setting, and methotrexate,vinblastine, doxorubicin, and cisplatin or combination gemcitabine/cisplatin is the current standard of care

carboplatin should not be substituted for cisplatin in fit patients, it may be considered in those who are ineligible for cisplatin

No approved second-line chemotherapy for metastatic bladder cancer exists, and response rates with available agents are variable

The role of neoadjuvant cisplatin-based combination chemotherapy has been extensively evaluated and is associated with a modest but significant survival benefit

The achievement of pathological complete response (pT0) with neoadjuvant chemotherapy has strong prognostic significance and may represent an alternate clinical end point for clinical trials

Although robust data are lacking for the use of chemotherapy in the adjuvant setting after cystectomy, it may be considered in patients who are at high risk for relapse

Unlike other solid tumors, targeted therapy is not well established in bladder cancer, and a critical need exists to develop novel agents that complement or are an alternative to conventional chemotherapies

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Chemotherapy in ca urinary bladder dr prasanta dash