Optimal sequencing in treatment muscle invasive bladder cancer : oncologists. Phichai Chansriwong, MD Ramathibodi Hospital, Mahidol University

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1 Optimal sequencing in treatment muscle invasive bladder cancer : oncologists Phichai Chansriwong, MD Ramathibodi Hospital, Mahidol University

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4 Slide 2 Presented By Andrea Apolo at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

5 Slide 18 Presented By Jeffrey Holzbeierlein at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

6 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%

7 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?

8 NEOADJUVANT CHEMOTHERAPY THE JOURNAL OF UROLOGY, Vol. 177, , February 2007

9 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

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11 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)

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13 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)

14 NT0800 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 arm 20% sepsis No death

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16 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

17 NAC does NOT increase the risk of perioperative morbidity Presented By Maria De Santis at 2017 Genitourinary Cancers Symposium

18 Split dose Cis/Gem real life data Presented By Maria De Santis at 2017 Genitourinary Cancers Symposium

19 Carboplatin in Neoadjuvant Not recommendation in using carboplatin in neoadjuvant treatment ( not eligible for cisplatin based chemotherapy)

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22 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:

23 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

24 HD MVAC toxicity Toxicity Grade MVAC (n=129) (%) HD MVAC (n=134) (%) p Neutropenia < Neutropenic fever < case of toxic death in each arm Less WBC toxicity in HD MVAC likely secondary to GCSF Toxicities otherwise similar Sternberg Eur Urol 2006

25 Carboplatin in Neoadjuvant Not recommendation in using carboplatin in neoadjuvant treatment

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30 Value of Adjuvant chemotherapy

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33 Adjuvant in T2N0 pt2 or less and have no nodal involvement or LVI not recommended to receive adjuvant chemotherapy

34 Slide 13 Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

35 AUA/ASCO/ASTRO/SUO Guidelines: Key Findings Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

36 AUA/ASCO/ASTRO/SUO Guidelines: Key Findings Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

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39 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

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41 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

42 5yr overall survival range 39% - 74% Bladder preservation 31% - 60%

43 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

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46 Hilighted studies

47 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

48 Slide 2 Presented By John Coen at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

49 Slide 3 Presented By John Coen at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

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51 Slide 7 Presented By John Coen at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

52 Slide 9 Presented By John Coen at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

53 Slide 10 Presented By John Coen at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

54 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

55 Slide 38 Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

56 Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: What is This About? Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

57 Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: What is This About? Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

58 Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Key Findings-- LRFS Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

59 Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Key Findings-- DFS Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

60 Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Key Findings Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

61 Adjuv Chemo + XRT vs Adjuv Chemo Alone After Cystectomy: Importance Presented By Sam Chang at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

62 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