Lori Wood MD MSc FRCPC Medical Oncologist Queen Elizabeth II Health Sciences Centre Professor of Medicine Dalhousie University Halifax NS Canada Nepal November 2017 Objectives Review basic epidemiology staging pathology ID: 1041346
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1. Bladder Cancer:An Overview of TreatmentLori Wood, MD, MSc, FRCPCMedical Oncologist, Queen Elizabeth II Health Sciences CentreProfessor of Medicine, Dalhousie UniversityHalifax, NSCanadaNepalNovember 2017
2. ObjectivesReview basic epidemiology, staging, pathologyDescribe treatment options for advanced muscle invasive UCCSummarize treatment options for curative muscle inclusive bladder cancerAdjuvantNeoadjuvantFocus on practical tips with chemotherapy
3. Bladder CancerCanadian Incidence and Mortality, 2017Men4th most common cancer6.5% of all new cancers (6700 men)5th most common cause of death1,700 deathsWomen12th most common cancer2.1% of all new cancers (2,000 women)11th most common cause of death680 deaths
4. Risk FactorsSmoking: 3X increased riskChemicalsPrior RadiationChronic Irritation e.g. Indwelling catheter, infectionsEsp squamous cellSchistosomiasis? Lifestyle e.g. Sedentary, overweight
5. Risk Factors: ChemicalsAromatic aminesBenzidine, naphthylamine – chemical, dye, rubber industries as well as fungicides, plastics, exhaustPolycystic Aromatic Hydrocarbons –crude oil, combustion industries, firefighters4,4 methylenebis(2-chloroaniline) – synthetic, polyurethane partsPesticides – OR= 1.65
6. Urothelial CancersCan involve theBladderUpper tract – ureter, renal pelvisUrothelial cancer = transitional cell cancerCan be flat or papillaryNon invasive or invasive
7.
8. PathologyISUP/WHO classification system – 2016UrothelialClassicWith other features (e.g. micropapillary, nested)SquamousAdenocarcinomaUrachal (25-35% of bladder adenocarcinomas)Dome
9.
10. TNM Staging – 7th editionTa: Noninvasive papillary carcinomaTis: Carcinoma in situT1: Tumor invades subepithelial connective tissue (i.e. lamina propria)T2: Tumor invades muscleT2a: tumor invades superficial muscle (inner half)T2b: tumor invades deep muscle (outer half)T3: Tumor invades perivesical tissueT3a: microscopicallyT3b: macroscopicallyT4: Invades prostate, uterus, vagina, pelvic wall, abdominal wall
11.
12. Non-muscle Invasive Bladder CancerPrimarily managed by the urologistsRepeat cystoscopiesIf recurrence or high grade – BCG intravesical therapyIf recurrences during or shortly after BCG - cystectomy
13. TNM StagingN0: No regional lymph node metastasesN1: Metastases in one lymph node < 2 cm N2: Metastases in a single lymph node > 2 cm but < 5 cm or multiple nodes none > 5 cmN3: Metastases in a lymph node > 5 cm
14. TNM StagingStage I: T1 N0 M0Stage II: T2a-b N0 M0Stage III: T3a-b, T4a N0 M0Stage IV: T4b N0 or any T and N1, N2, N3 or any M1
15. Muscle Invasive Bladder Cancer OutcomesStageOutcomepT1a – T2 N075-85% long-term survivalpT3a or 3b N0pT4a N040-55% long-term survivalAny pT N1-325-35% long-term survivalMetastaticMedian Survival 12-14 m
16. Metastatic Disease
17. Metastatic Disease: HistoryNo therapy – median survival: 3-6mSingle agent Cisplatin – median survival: 4-6mCombination chemotherapy phase II studiesMVAC – 1985, RR 72% (CR 36%)CMV – 1985, RR 56% (CR 28%)CISCA, MVComparative studiesMVAC vs. Cisplatin 1992 (12.5m vs. 8.2m)MVAC vs. CISCA, 1990 (48.3w vs. 36.1w)CMV vs. MV 1998 (7m vs. 4.5m)MVAC vs. FAP 2002
18. MVACMethotrexate 30 mg/m2 d1, 15, 22Vinblastine 3 mg/m2 d2Adriamycin 30 mg/m2 d2Cisplatin 70 mg/m2 d2Every 28 days
19. Metastatic DiseasePhase III RCTGemcitabine/Cisplatin (GC) vs. MVACn=405T4b, N2, N3 or M1 TCCPlanned StatisticsNon inferiority study 33% difference in survivalp=0.05p=0.20von der Masse et al. J Clin Oncol 2000, pp3068-3077.
20. Gemcitabine/CisplatinCisplatin 70 mg/m2 d1Gemcitabine 1000 mg/m2 d1, 8, 15Every 28 days
21. ResultsGC(n=203)MVAC(n=202)p ValueRR49 %46 %p=0.51Median TTP7.4m7.4mp=0.66Median OS13.8m14.8mp=0.75Median OS*14.015.2p=0.66*Roberts et al. Ann Oncol 2006, p118-122.
22. Prognostic Factors in Metastatic Bladder CancerMSKCC Database (n=203)#KPS 80%No visceral metastasesGC vs. MVAC Trial (n=405)KPS 80 Low/normal alkaline phosphataseNo visceral mets# Bajorin et al. J Clin Oncol 1999, pp3173-3181.
23. Prognostic Factors: MSKCC # of Risk FactorsMedian Survival033m(18.4-42.2)113.4m(11.9-17.6)29.3m(8.0-10.7)
24. Gemcitabine/Cisplatin vs. MVAC ToxicityGemcitabine/CisplatinMVACGrade 3Grade 4Grade 3Grade 4Anemia23.5%3.5%15.5%2.1% Platelets28.5%28.5%7.7%12.9% ANC41.2%29.9%17.1%65.2%Neutropenic Fever2%14%Neutropenic Sepsis1%12%Mucositis1.0%17.7%4.2%
25. Gemcitabine/Cisplatin in Every Day UseCisplatin 70 mg/m2 d1 Gemcitabine 1000 mg/m2 d1, 8, 15 q28 daysCisplatin 70 mg/m2 d1 Gemcitabine 1250 mg/m2 d1, 8 q21 daysApproximately 2 months of chemotherapy – repeat CT scanUsually 4-6 cycles of therapyWill depend on patient tolerance, creatinineNo data to say that 6 is better than 5 is better than 4 cyclesIn the study GC median 6 cycles, MVAC median of 4 cycles
26. CisplatinNeed adequate renal functionDebate about creatinine clearance? 60, 50 or 40 ml/minDefinitely not if 40 ml/minIf between 40-60 ml/minConsider 35 mg/m2 d1 and d2 or d1 and d8Ensure well hydrate and no obstructionLots of hydration, Mannitol, check lytes, Mg++
27. GemcitabineWatch for thrombocytopeniaGrade 3 – 28.5%Grade 4 – 28.5%If platelets drop within first cycle – probably need to dose reduce early
28. What To Do For The Frail? Age, PS, Creatinine ClearanceCarboplatin has been studiedCarboplatin/TaxolCarboplatin/GemcitabineCarboplatin/Gemcitabine (35% RR)More myelosuppressionCan only use an AUC 4.5 (vs. lung cancer 6.0)21 day cycle (d1,8)Gemcitabine alone (10-15% RR)
29. Is There Anything New in the First-line Setting Since 2006?Gem/Cis (GC) vs. Taxol/Gem/Cis (PCG)n=627RP (57 vs. 46%) with PCGMedian survival 15.7m vs. 12.8m - NSSurvival HR=0.896 (95% CI 0.72-1.03)Dose Dense MVACn=263 RR (63% vs. 50%) with HDMVACSurvival 15.5m vs. 14.1m – NSBut…
30. Second-line pre 2016No great studiesMVACTaxol/CarboplatinTaxane single agentVincasPhase III trial of vinflunine vs BSCApproved in EuropeBest supportive careClinical trialsTaxane vs Abraxane
31. Second-line since 2016Immune Checkpoint InhibitorsPD-1: pembro, nivoPDL-1: atezo, durvalumab, avelumabFDA approved these 5 based on phase II dataHealth Canada approvedAtezo – March 2017 – phase IIPembro – Sept 2017 – phase IIIDurv –November 2017 – phase II
32. Phase III RCTAtezo vs Chemo (Taxane or Vinflunine)N=931RR: 14.8% vs ? (26% if PDL-1 >5%)OS: Pembro vs ChemoN=542RR: 21.2% vs 11.4% (R 7% vs 3.3%)OS: 10.7 vs 7.4 m, HR 0.73, p=0.0022
33. RCT: Moving Immunotherapy to First-lineCisplatin eligibleIO vs cisplatin based chemoCombination IO (Ipi/Nivo) vs chemoCombination IO and chemo vs chemoCisplatin ineligibleIO vs carboCombination IO and chemo vs chemo
34. Localized Disease
35. Localized Muscle Invasive Bladder Cancer: Curative Treatment OptionsSurgeryNeoadjuvant chemotherapy and surgerySurgery and adjuvant chemotherapyConcurrent chemotherapy/radiation
36. Role of Lymphadenectomy at time of CystectomyStagingpT2 disease – 10-30% chance of N+> pT3 disease – 30-65% chance of N+Therapeutic? Role of extended LNDIf N+, number of LN (or LN density) removed has been shown to be of prognostic value≤ 15 LN - 25% 10 RFS> 15 LN – 36% 10 RFSControversialMany believe it makes a difference
37. Neoadjuvant/Adjuvant ChemotherapyProsConsNeoadjuvant:Treats micro-metastatic diseaseDelays potentially curable surgeryDownstages and makes surgery easierNever know the true pathologyMay be easier to give pre-opNo patient selectionAssess response to primary tumorAdjuvant:Can base decisions on pathologyDelays treatment of micro-metastasesDoes not defer curative surgeryMay be difficult to give post-opCannot assess chemotherapy responsiveness
38. Neoadjuvant Chemotherapy
39. Neoadjuvant ChemotherapyMeta-analysisLancet 2003;361:1927-1934SWOG studyGrossman et al, NEJM 2003;349:859-866Cochrane ReviewCD005246First published 2004, updated Oct 2008
40. Neoadjuvant Therapy: Meta-analysis10 randomized studies analyzedn=2688Cisplatin-based therapy showed OS benefitHR=0.87 (0.78-0.98); p=0.01613% reduction in risk of death5% absolute benefit at 5 years (45% 50%)Lancet 2003, p1927-1934.
41. Neoadjuvant StudiesAuthorAccrualNumber StageChemotherapyWallace (1991)1984-88159T2-T4, NXCIS x 3 *Mardinez (1995)1984-89122T2-T4a, NX-N2CIS x 3Abol-Enein (1997)1984-96196T2-T4a, NXCARBO MV x 2Raghavan (1991)1985-8896T2-T4, NXCIS x 2 *Malmstrom (1996)1985-89325T2-T4a, NXCIS/ADRIA x 2 *Cortesi (not published)1988-92171T2-T4, N0MVEC x 3Bossi (1999)1989-96206T2-T4, N0MVAC x 4International Collaborators (1999)1989-95976T3, T4a, NXCMV x 3 *Sengelov (2002)1989-95153T2, T4b, NXCM x 3Sherif (2001)1990-97317T2-T4a, NXCM x 3
42.
43. Survival Curve
44. Neoadjuvant Therapy: SWOG Trial1987-1998n=317; T2-T4a; N0M0MVAC x3/cystectomy vs. cystectomyGrossman et al. NEJM 2003, p859-866.
45. SWOG Trial ResultsChemo/SurgerySurgeryp Valuen153154p0 Rate38%15%p0.001Median Survival77m46mp=0.065Y OS57%43%p=0.06
46. Survival According to Treatment Group and Whether Patients Had Superficial Muscle Involvement (Stage T2 Disease) or More Advanced Disease (Stage T3 or T4a)
47. Cochrane Review11 RCT, n=3005Similar conclusions to Lancet meta-analysisHR=0.86 (0.77-0.95)5% absolute survival improvement (45 to 50%)p=0.03
48. Other ReviewsAdvanced Bladder Cancer (ABC) Meta-analysis Group on Neoadjuvant ChemotherapyEuropean Urology 48:202-206, 2005Meta-analysisWinquist et al, J Urol 171: 561-569, 20048 RCT with cisplatin based combination chemotherapy6.5% improvement in 5Y OS from 50% to 56.5%HR=0.87
49. Neoadjuvant ChemotherapyNote: all these studies were with Cisplatin-based chemotherapyMVACCMVWe have extrapolated to use Gem/Cis in this settingCarboplatin would presumably give worse resultsSo if we can’t give Cisplatin – we tend not to giveNone of the studies included upper tract TCC
50. Adjuvant Chemotherapy
51. Adjuvant ChemotherapyUnderstudied areaVery poorly conducted studies
52. Adjuvant ChemotherapyMeta-analysisEuropean Urology 48: 189-201, 2005Italian RCTCognetti, Ann Oncol March 2012 23;695-700EORTC RCTEarly vs Delayed Chemotherapy
53. Adjuvant TherapyAdjuvant randomized bladder trials pre 2005:SeriesChemoSurvival BenefitnStockleMVA(E)CYes49SkinnerCAPYes91FreihaCMVNo55StuderCisplatinNo77Richards FU/DoxNo129TOTAL401
54. Adjuvant Therapy: Meta-analysisMedical Research Council Meta-analysis groupn=491 from six trialsAuthors state that the power of this analysis is limited given small number of patientsTherefore this meta-analysis should NOT be considered Level I evidenceEuropean Urology 48: 189-201, 2005
55.
56. Italian Adjuvant RCT Trial Eligible patientsT2 (G3 only) or T3-4 (any G), N0-2, M0n=194 (largest to date in 2012)Target recruitment 610 patients to detect a 10% difference in 5 yr survivalAccrual: Sept 2001 – July 200745 Italian centresMedian follow-up – 27 months abstract and 35 months publicationCognetti et al, Ann Oncol March 2012 23;695-700
57. Italian Adjuvant RCT TrialControlGC Chemop ValueHR5Y DFS42.3%37.2%0.701.08 (0.73 – 1.59)5Y OS53.7%43.4%0.241.29 (0.84 – 1.99)N Negative73.2%64.5%N Positive27.6%25.8%Only 62% of patients received all 4 cycles of adjuvant therapy.Only 67% of patients received chemotherapy at time of metastatic disease.
58. EORTC RCT: Immediate vs. Delayed ChemotherapyInclusionpT3-T4 or N+ M0Cystectomy and PLND (minimum of 15 is recommended) Chemo within 90 days of surgery Immediate: GC or MVAC or HDMVAC x 4Deferred: Same chemo x 6 cycles Sternberg et al, Lancet Oncology 2015; 16:76-86
59. EORTC Accrual/StatisticsOriginally n=13445Y OS 42% vs. 35%80% power = 0.05; HR=0.826April 29, 2002 – August 14, 2008, n=2842005 Revised number n=660A lot of N+ patients, therefore more eventsHR=0.762014 n=284 so closed earlyHR=0.62 (5Y OS 65% vs. 50%)Median follow up – 7 years
60. EORTC: Patients IncludedImmediateDeferredn141143pT1-2 N+23%22%pT3-4 N-30%31%pT3-4 N+48%48%pN- 1518%19%pN- 1512%12%pN+ 1543%46%pN+ 1528%23%
61. EORTC ResultsImmediateDeferredp ValueHR95% CIMedian PFS3.11 yrs0.99 yrs 0.00010.540.4 – 0.735Y PFS47.6%31.8%Median OS6.74 yrs4.60 yrs0.130.780.56 – 1.085Y OS53.6%47.7%Bladder Cancer Mortality at 5Y38.6%43.5%0.220.800.56 – 1.15
62. EORTC ResultsImmediateDeferredn141143Received Treatment12867No Treatment1376(53 – No PD)(23 – Never)Gem/Cisplatin84%85%
63. EORTC Post hoc Subgroup AnalysisImmediateDeferredp ValueHR5Y OS LN-79.5%59.0%0.0120.37 (0.16 – 0.83)5Y OS LN+42.7%42.9%0.720.94 (0.65 – 1.34)Note – 60% of LN- patients had 15 lymph nodes
64. Combined TrialsEORTC, Italian, Spanish, plus other studiesBenefit with adjuvant HR=0.77 (0.65 – 0.91)p=0.002
65. Based on EvidenceWe try to give neoadjuvant chemo:More data to support neoadjuvantPatients that have a pathological CR do betterThey are in better shapeEspecially if upper tract disease (2 kidneys for Cis)If we do not see them preoperatively:We do offer adjuvantUCC variants (micropapillary, predominant squamous or adenocarcinoma)We offer upfront surgery
66. SummaryVery common cancerVery under-studied cancerOnly have one chance to cure themOften sick, older patients with co-morbiditiesNeed to emphasize supportive care/ palliative care involvement/radiation
67. Questions?
68. Case
69. Case 68-year-old maleChristmas 2009: 100% normalJan/10: Constipation (q5-6 days) Weight loss Periumbilical pain No heartburn; no dysphagia; no vomitingMar/10: Early satiety Anorexia
70. What Do You WantTo Do?
71. Case Feb. 10/10CT chest, abdomen and pelvis1.8 cm nodule near (L) UVJ worrisome for malignancyMultiple liver metastases(L) Iliac lymph nodes and mesenteric lymph nodes near head of pancreas 4 cmLung nodules up to 1 cmT8 and sacral sclerotic foci
72. What Do You WantTo Do?
73. Case Feb. 17/10: Referral to UrologyMar. 3/10: Bladder biopsyMar. 19/10: Seen by General SurgeryMar. 29/10: Bladder pathology back Referral to Medical OncologyApr. 12/10: Seen by Medical Oncology
74. Bladder Pathology Results
75. Case Apr. 12/10Bladder pathology: low grade T1 lesionHistory: 24 lb weight loss x 2 months; constipated – on MorphineO/E: liver by palpation – 12 cm MCL and 6 cm below xiphoidECOG PS = 3
76. What Do You WantTo Do?
77. Case Repeat CTGastroscopy
78. CaseGastroscopy:Obvious primary gastric cancerBiopsies prove itPatient deteriorated quickly:Best supportive care only