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นพ.พชัิย จันทร์ศรีวงศ์

นพ.วเิชียร ศริิธนะพล

ผศ.นพ.พทิยา ด่านกุลชัย

Multimodality approach in

bladder cancer management

Outline

MDT in MIBC

Cystectomy

Neoadjuvant and adjuvant chemotherapy

Adjuvant RT

Bladder preservation and CCRT

M1 disease

• 74-year-old male smoker with hypertension who presents with painless gross hematuria.

• He has no known drug allergies and current medications include hydrochlorothiazide.

• He has no known family history of cancer • Physical examination is normal/unremarkable. • Work up :

– Cystoscopy – CT scans – Urine cytology.

Pathology

• TURBT : High grade TCC, invade Muscular layer, no perineural invasion, no lymphovascular invasion.

Lab

• CBC : Hct 33 WBC 7300/mm3 ( N 55%) Plt 220,000 • BUN 19 mg/dl Cr 1.25 mg/dl • LFT : normal • Albumun 39.4 g/L

CT scans chest and whole abdomen

• Lung clear, Liver: no mass • Bladder; multiple enhancing polypoid lesions at poeterior wall of urina

ry bladder abutting bilateral UVJ. • Lesions at left side posterior wall measure 16.5 x 13.4 mm. T3 lesions,

No hydronephrosis. • Lymph node : no enlargement, Bone : no lesions • Staging T3N0M0

29/7/2017

AJCC cancer staging

What are appropriate options for muscle invasive bladder

A. Radical cystectomy (RC) then adjuvant chemotherapy B. Neoadjuvant chemotherapy then cystectomy C. Trimodality therapy : bladder sparing D. CCRT , not done RC E. Partial cystectomy

Cystectomy or adding neo-adjuvant chemotherapy

• Cystectomy

Neoadjuvant treatment

Peri-operative chemotherapy : Rationale

• Deaths from TCC are generally not local events • Patients die as a result of metastatic disease • Local interventions will not deal with micro-metastatic disease • Systemic therapy neoadjuvant or adjuvant must be given to improve

cure rates

Neoadjuvant

NEOADJUVANT CHEMOTHERAPY

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

MVAC

CMV

Tolerability of cisplatin-based neo-adjuvant

chemotherapy and effect on radical cystectomy

• MVAC regimen: The mortality rate in patients assigned to chemo 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

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

#ASCO 2014 - Neoadjuvant dose-dense gemcitabine and cisplatin (DDGC)

in (MIBC): Final results of a multicenter phase II study

• Patients had cT2-T4a, were node negative, and had GFR > 50. • Dose-dense GC was administered as follows:

– gemcitabine 1200 mg/m2 – cisplatin 70 mg/m2 on day one – with pegfilgrastim 6 mg on day 2 or 3.

• This cycle was repeated q 2 weeks, x 3 cycles.

#ASCO2014 –

Neoadjuvant DDGC in (MIBC): Final results

• 31 evaluable patients • 30 underwent radical cystectomy, 32% had a pCR, and 13% were downstaged

to non-muscle invasive disease. • pCR rates are similar to those achieved with accelerated MVAC

• Significantly greater toxicity, particularly vascular toxicity including

DVT, stroke, MI, and PE.

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 neoadjuvant treatment ( not eligible for cisplatin based chemotherapy)

Carboplatin in Neoadjuvant

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

Key points on Neo-adjuvant chemotherapy

• MDT case conference for invasive TCC patients • Patient selection is critical : Not all patients are appropriate • Patients who are offered neo-adjuvant treatment:

– Tend to be younger (<65) – Better PS (ECOG 0-1) – Good renal function (GFR >40)

Adjuvant treatment

• Chemotherapy

• Radiotherapy

Role of Adjuvant chemotherapy

Adjuvant treatment

Value of Adjuvant chemotherapy

Immediate vs Defer

HR 0.77

Adjuvant in T2N0

• pT2 or less and have no nodal involvement or LVI : not recommended to receive adjuvant chemotherapy

Cystectomy is life changing

Resection : en bloc removal of ant pelvic organ, including bladder, prostate in men, TAH+ BSO+ vaginal cuff in women, pelvic LN dissection

Urinary diversion: Intestinal conduit draining into: A. an external collecting bag B. neobladder

Cystectomy is life changing

Morbidity: Memorial Sloan Kettering experience of 1142 cases High volume surgeons:

No cystectomy

• Bladder preservation ( stills need operation ) • CCRT ( say no for operation: palliative aims)

– Chemo alone – Rt alone – Only TURBT

Role of adjuvant RT and

Bladder preservation

Bladder preservation: Med

Does TMT compare with RC?

Survival After Curative therapy

Cox Regression Analysis of OS

Candidates for preservation

• Solitary tumor <5 cm

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

• No CIS

• No hydronephrosis

• No evidence of LN or distant mets

• Normally functioning bladder

Team and Co-operation

Does Age Matter? • Pooled RTOG MIBC studies : DSS for age < 75 vs Age ≥ 75

Improving CR over time

Concurrent Chemotherapy is important to the success

Doublet

BC2001: Phase 3 of CCRT vs RT in MIBC

RTOG 0233: randomized phase 2

OS : RTOG 0233

QoL after TMT

MGH Urodynamics and QoL study

MGH/UNC : long term QoL

• Six validated QoL questionnaires, scored out of 100

MGH/UNC : long term QoL

CCRT

Role of pre-op CCRT: Phase 3 trials of neoadjuvant chemotherapy

Study group Neoadjuvant arm Standard arm Patients (n) Survival

Australia/United

Kingdom DDP/RT RT 255 No difference

Canada/NCIC DDP/RT or preop RT + Cyst RT/preop RT + Cyst 99 No difference

Spain (CUETO) DDP/Cyst Cyst 121 No difference

EORTC/MRC CMV/RT or Cyst RT or Cyst 976 5.5% difference in favor of CMV

SWOG M-VAC/Cyst Cyst 307 Trend in survival benefit with M-

VAC (p=0.06)

Italy (GUONE) M-VAC/Cyst Cyst 206 No difference

Italy (GISTV) M-VEC/Cyst Cyst 171 No difference

Genoa DDP/5FU/RT/Cyst Cyst 104 No difference

Nordic 1 ADM/DDP/RT/Cyst RT/Cyst 311 No difference, 15% benefit with

ADM + DDP in T3-T4a

Nordic 2 MTX/DDP/Cyst Cyst 317 No difference

Abol-Enein CarboMV/Cyst Cyst 194 Benefit with CarboMV

From Calabro Eur Urol 2009

• T2-T4a NXMO • 2 cycles comprising cisplatin 70 mg/m2 and doxorubicin 30 mg/m2, Q 3-week

• Locally irradiated with 4 Gy daily for 5 consecutive days. • 5-year OS improvement of 15% only for T3–T4 disease compared with RT or Sx

alone (P = 0.03)

• while no survival benefit was found for early stage disease (T1–T2). • Not compare for RT+chemo vs chemo

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 T3–T4a,

especially in who are not candidates for or decline cystectomy

M1 treatment

Overall response rate ( 55% vs 43%, P.0031)

OS 15.8 vs 12.7 Mo (HR 0.85, P .075 NS)

Second-line chemotherapy for muscle

invasive bladder cancer:

• There are no definitive recommendations for second-line

therapy

• Chemotherapy options may include drugs such as

cisplatin, gemcitabine, pemetrexed, carboplatin,

vinblastine, and bleomycin.

• In May 2016, the FDA approval of 1st OI: atezolizumab

vi

vinflunine

OS 6.9 vs 4.6 months

Vinflunine vs BSC

• Chemotherapy in M1 prolongation OS to 12-13

mo VS 3-4 mo in BSC

• 3-year survival: 15-20%

Immuno-Oncology Developments

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

Updated Efficacy From IMvigor210: <br />Atezolizumab in Platinum-Treated Locally Advanced/Metastatic Urothelial Carcinoma (mUC)

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

IMvigor210 Cohort 2: Study Design<br />Basis for Accelerated Approval

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

KEYNOTE-045: Open-Label, Phase 3 Study of Pembrolizumab vs Investigator’s Choice of Paclitaxel, Docetaxel, or Vinflunine for Previously Treated Advanced Urothelial Cancer

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

KEYNOTE-045 Study Design (NCT02256436)

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

Overall Survival: Total

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

Atezolizumab Duvalumab

Nivolumab

Confirmed Objective Response Rate

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

combined positive score (CPS) ≥10% for

PD-L1 expression.

10.3

Atezolizumab as 1L Therapy in Cisplatin-Ineligible Locally Advanced/Metastatic Urothelial Carcinoma: IMvigor210 Cohort 1

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

1st line in cisplatin ineligible

Unfit for Cisplatin

IC 0 ( < 1%), IC1 (≥ 1%- ≤ 5%), IC2/3 (≥ 5%)

OS 14.8 months

14.8

15.3

12.3

Mutation load associated with ORR

Frontline Therapy for UC: Cis-Ineligible

Presented By Matthew Milowsky at 2017 Genitourinary Cancers Symposium

2nd line

IC2/3 (≥ 5%)

11.1 vs 10.6

Systemic Therapy for Bladder Cancer Now

Presented By Elizabeth Plimack at 2016 ASCO Annual Meeting

LBA4 RANGE

• Phase III Docetaxel +/- Ramucirumab in platinum-refractory TCC

• ➢ Positive trial for PFS but difference is modest, OS data are awaited • ➢ Current standard for 2nd-line metastatic urothelial cancer is

checkpoint inhibition

• ➢ Uncertain benefit in the 3rd line setting (after first-line platinum, second-line checkpoint inhibition)

Take home massage • Bladder cancer is genomically complex

• Neoadjuvant produces 5% absolute benefit in survival, need for

MDT in care.

• Trimodality increase Qol, but need MDT and case selection

• 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

• Ongoing need to improve treatment in bladder cancer, Checkpoint

inhibitor emerges the high efficacy in mTCC.