Optimal sequencing in treatment muscle invasive bladder ... · • About a third (36%) died with...

Optimal sequencing in treatment muscle invasive bladder cancer

: oncologists

Phichai Chansriwong, MD

Ramathibodi Hospital, Mahidol University

Presented By Andrea Apolo at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Presented By Jeffrey Holzbeierlein at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Cystectomy Alone

• “Standard of care” approach (with PLND)

• Disadvantages include:- loss of organ function

• 50% recurrence rate with-in 2 years

• Broadly--5-year survival rates:-• pT2:60-80%;

• pT4:0-20%;

• Unsuspected N1:60%

• N2/3 : 0-23%

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?

NEOADJUVANT CHEMOTHERAPY

THE JOURNAL OF UROLOGY, Vol. 177, 437-443, February 2007

Neoadjuvant Chemotherapy

• MRC and EORTC May 2002 : MCV

• MTX(30 mg/m2 d 1),

• vinblastine (4 mg/m2 d 1)

• cisplatin (100 mg/m2 d 2).

• T2-4a n0-x m0 TCC

MRC and EORTC Neoadjuvant Chemotherapy• OS was superior chemotherapy

• at 3 years (55% vs. 50%),

• 5 years (50% vs. 44%),

• and 8 years (43% vs. 37%)

• median follow-up of 7 years.

• improved disease-free survival (P = .012)

• local-regional progress-free survival (P = .003)

• Survival rate 55% vs 50% (not sig)

Neoadjuvant Chemotherapy

• INT-0800(American) study» 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–Results:

• 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)

INT0800

ARM Med Survival Alive at 5 yrs P-value

Surgey 46 Mos 42% .044 (HR .74)

MVAC 77 Mos 57%

33 % grade 3/4 toxicity in the chemo arm20% sepsisNo death

Tolerability of cisplatin-based neoadjuvant chemotherapy and effect on radical cystectomy

• MVAC regimen: The mortality rate in patients assigned to chemotherapy was 1%, but drug delivery was excellent with only 20%.

• In the USA, gemcitabine and cisplatin (GC), but there is no level 1 evidence. drug delivery exceeding 90%.

No RCT in using GC in neo-adjuvant

NAC does NOT increase the risk of perioperative morbidity

Presented By Maria De Santis at 2017 Genitourinary Cancers Symposium

Split dose Cis/Gem – real life data

Presented By Maria De Santis at 2017 Genitourinary Cancers Symposium

Carboplatin in Neoadjuvant

• Not recommendation in using carboplatin in neoadjuvanttreatment ( not eligible for cisplatin based chemotherapy)

Can we avoid radical cystectomy in patients who appear to have “responded” to neoadjuvant chemotherapy?

• The answer is no.

• SWOG phase II study. Of the 34 who achieved cT0, 10 had immediate cystectomy. Six of the ten (60%!) were found to have pT2–4.

• Herr HW : reviews outcome of 63 patients receiving pCR post 4 cycles of cisplatin-based chemotherapy and no surgery:

• About a third (36%) died with bladder cancer. The risk of death was high (75%) in patients experiencing recurrent invasive bladder cancer.

Herr HW. Outcome of patients who refuse cystectomy after

receiving neoadjuvant chemotherapy for muscle-invasive bladder

cancer. Eur Urol 2008;54:126 –32.

• 3 cycles of DD-MVAC every 2 weeks

• (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70mg/m2) on day 1 with G-CSF support

HD MVAC toxicity

Toxicity Grade

MVAC (n=129)

(%)

HD MVAC

(n=134)

(%) p

Neutropenia 3 46 12 <0.001

4 16 8

Neutropenic fever 26 10 <0.001

1 case of toxic death in each arm

Less WBC toxicity in HD MVAC likely

secondary to GCSF

Toxicities otherwise similar

Sternberg Eur Urol 2006

Carboplatin in Neoadjuvant

• Not recommendation in using carboplatin in neoadjuvant treatment

Value of Adjuvant chemotherapy

Adjuvant in T2N0

•pT2 or less and have no nodal involvement or LVI notrecommended to receive adjuvant chemotherapy

Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

AUA/ASCO/ASTRO/SUO Guidelines: Key Findings


Bladder preservation

“The aim of bladder preservation is to

achieve cancer survival with equivalence to

radical cystectomy while retaining an

anatomically normal functioning bladder”

- T2-3 ( some case of T4a) and

- node negative

Candidates for preservation

• Solitary tumor <5 cm

• Clinical stage T2-T3a ( not properly indicate for T4)

• No CIS

• No hydronephrosis

• No evidence of LN or distant mets

• Normally functioning bladder

• 5yr overall survival range 39% - 74%

• Bladder preservation 31% - 60%

Chemoradiation toxicity

Toxicity %

Grade 4

Salvage cystectomy due to contracted bladder 2

Bowel obstruction requiring surgery 1.5

Grade 3

Bladder capacity < 200cc 3

Grade 2

Frequency/urgency 10

Dysuria 8

Diarrhea 5

Proctitis 2

Rodel 2002 JCO

Hilighted studies

Selective Bladder Preservation with Twice-Daily Radiation plus 5-Flourouracil/Cisplatin or Daily Radiation plus Gemcitabine for Patients with Muscle Invasive Bladder Cancer – Primary

Results of NRG/RTOG 0712: A Randomized Phase 2 Multicenter Trial

Presented By John Coen at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Presented By John Coen at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Preop-CCRT

• Canadian randomized study

• Concurrent CDDP improved pelvic disease

control with preoperative CCRT compared with

RT alone (P = 0.038).

• Preoperative CCRT or RT may be an option

treatment for T ≥4 cm and T3–T4a, especially in

in patients who are not candidates for or decline

cystectomy

Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: What is This About?


Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Key Findings-- LRFS


Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Key Findings-- DFS


Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Key Findings


Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Importance


Take home massage

• Bladder cancer is genomically complex

• Neoadjuvant produces 5% absolute benefit in survival,

need for MDT in care.

• Combination chemo can prolong symptoms free and OS

in advanced bladder cancer, but, high levels of toxicity.

• Select treatments for patients: fit or unfit patients

• Bladder preservation should be an option of treatment

Optimal sequencing in treatment muscle invasive bladder ... · • About a third (36%) died with...

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