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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.
Recommended