Presentation on theme: "Bladder Cancer Immunotherapy: Progress and Current Limitations"— Presentation transcript:
1 Bladder Cancer Immunotherapy: Progress and Current Limitations Donald L. Lamm, MD, FACSBladder Cancer, Genitourinary OncologyPhoenix, AZHebrew University of JerusalemYissum Technology TransferTel Aviv, September 27, 2005
2 Bladder Cancer Statistics, 2005 New Cases: 63,210Men: 47,010; #4 Women: 16,200 #8Estimated Deaths: 13,180Men: 8,970; #9 Women: 4,210Incidence/Mortality: 20.8%Men: 19% Women: 26%Prevalence: More than 600,000 in US
3 Bladder Cancer, 2005 Peak Onset: 6th to 8th decades Men/women: 3 to 1 Twice as common in white men compared with African American menGenetic mutations: genes on chromosome 9 including p16. Invasion p53, Rb, p21. H19: 84%Screening: hematuria detection reduces mortality
4 Diagnosis 85% present with gross of microscopic hematuria Cystoscopy is key: papillary tumors are easily seen. High grade, solid, flat or in situ tumors may not be seenUrinary Cytology: 80% + sensitivity in high grade tumors with 95% specificity. Insensitive with low grade. Sensitivity improved with FISHIVP, CT scan for upper tract evaluation
8 Bladder Cancer Immunotherapy is Primarily BCG Immunotherapy GoalsBrief History of BCGBCG Controlled Trials: vs TUR alone, vs ChemoImproving BCG Therapy: Maintenance, BCG + IfnLimitations of BCGProspects for New Agents
9 BCG History 1921- Calmette & Guerin successfully tame M. bovis 1929- Pearl reports TB reduces incidence of CA1930- Lubeck incident brings erroneous scandal1935- Holmgren reports BCG success in 28 cancer pts1936- Rosenthal reports BCG’s profound RE stimulation1950’s- Animal studies confirm efficacy1972- Rosenthal reports leukemia with vaccination1970’s- Multiple uncontrolled reports of clinical efficacy
10 BCG History- Bladder Cancer 1976- Morales reports 12 fold reduction in recurrence in 9 patients treated with BCG1973- Lamm begins controlled animal studies in TCC1978-NCI controlled trials begin based on Morales’ work1980- Lamm reports first successful controlled trial1982- Current: Brosman, Netto, Martinez-Pineiro and many others report BCG to be superior to Chemotherapy
18 BCG Versus Doxorubicin: Time to Treatment Failure 10080604020n year RFSBCG CIS %BCG Ta, T %Doxorubicin Ta, T %Doxorubicin CIS %Percentage of patientsTime after registration, monthsLamm DL: N Engl J Med. 1991;325:1205
19 Diet, Lifestyle and Environmental Factors Diet: low vitamin A, low serum carotene increase risk; increased fat increases risk; soy, garlic, selenium, NSAIDS, and green tea may reduce riskVitamins may be protective: A (differentiating agent); B6; C (antioxidant); E (antioxidant), and possibly folic acid and D
20 Kaplan Meier Estimate of 5 Year Tumor Free Rate In 65 Patients Receiving Vitamin Supplement and BCG Therapy For Bladder CarcinomaLamm D. J Urol 151(1): 21-26, 199410090807060504030201040,000u Vitamin A, 100mg B6, 2gm C, 400mg E: "Oncovite"Percent Tumor Freep=0.0014RDAVitamins Oncovite(N=30) (N=35)RDA Vitamins51015202530354045505560Months After Registration
21 Oncovite (Vitamins A, B6, C &E) in Bladder Cancer Overall recurrence reduced from 80% to 40% (P=0.0011)42% reduction in recurrence in Ta, T1 TCC53% reduction in low grade (G1, G2) TCCAssociated with statistically significant increase in long-term NK cell activity in BCG treated patients
22 Controlled BCG Trials Author no. NoRx BCG Ben. P Lamm ' % 20% 32% <.001Herr ' % 42% 53% <.001Herr (CIS) ' % 35% 65% <.001Yamamoto' % 17% 50% <0.05Pagano ' % 26% 57% <.001Mekelos ' % 32% 27% <0.02Krege' % 29% 24% <0.05Kolodziej ‘ % 19% 36% <.001Total: % 27% 43%In contrast, controlled comparisons of surgery alone versus surgery plus intravesical BCG immunotherapy has consistently shown BCG to be superior. The reduction in tumor recurrence ranges from 24 to 65%, and 40% or more reduction in recurrence can be expected.
23 Meta-Analysis of BCG vs. TUR Alone Shelly et al Meta-Analysis of BCG vs. TUR Alone Shelly et al. Cochrane Group BJU Int 2001, 88:20926 publications reviewed6 acceptable trials with 585 patientsMean log hazard ratio for recurrence -.83, P<0.00156% reduction in hazard attributable to BCGManageable toxicity: cystitis 67%, hematuria 23%, fever 25%, frequency 71%Conclusion: BCG provides significantly better prophylaxis of tumor recurrence in Ta, T1 TCC
25 Randomized BCG vs. MMC Studies Rec.MMC BCGP valueAuthor/year42861476446435124383213%%%vs34628042435666295426%%%+30+34+19-5-21-3+9+15+5+24+22+13<.01<.001NSPagano '87Finnblad '89Lee '92Witjes '94Vegt '95 '95SWOG '96Malmstr. '96Krege '96Ayed '98Milan '00Nogueira '01In contrast, direct randomized comparisons of BCG and Mitomycin C have not consistently shown BCG to be better. 7 of 11 studies found BCG to be significantly better than MMC. This may relate to the failure to use maintenance BCG schedules. All 6 studies that used maintenance BCG were statistically significant, compared with only one of 5 that did not use maintenance BCG.36.7% of 781 vs 53.8% of 771 (+17%) in maintenance BCG studies.6/6 maintenance BCG studies significant vs 1/5 non-maint.
26 BCG Versus Mitomycin-C (SWOG 8795) Lamm DL: Urol Oncol 1: , 1995100908070605040302010Percent RecurrenceMedianin MonthsAt. RiskFailBCGMMC1901874464Not Reached2061218243036Time To RecurrenceN
27 Intravesical BCG is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. Shelley et al. (2004) BJU Int. 93:485-90“This is the highest level of evidence-based medicine and the results presented here suggest that intravesical BCG is superior to mitomcycin C.”“A subgroup analysis of 3 trials that included only high-risk Ta and T1 patients indicated no heterogeneity (P-0.25) and a LHR for recurrence of (0.012). With MMC used as the control in the meta-analysis, a negative ratio is in favour of BCG and, in this case, was highly significant (P<0.001).”
28 Complete Response in CIS Intravesical Chemotherapy Agent N CR% RangeThiotepa % (20-50%)Adriamycin % (0-88%)Mitomycin C % (0-100%)Epirubicin %Epi + MMC %
29 Progression in CIS Prior to BCG Immunotherapy CIS patients are perhaps the most suited for BCG. Prior to BCG 54% of patients with CIS developed progression to muscle invasion.
30 Comparison of BCG Preparations in the Treatment of CIS CR %Range CRConnaughtTokyoPasteurTiceEvansA FrappierS AfricanDanishRomanianRIVM45011123027718014513421579%77%74%71%65%60%69%67%64%70% - 92%63% - 84%40% - 80%56% - 88%53% - 88%39% - 100%Total:1496 (72%)In contrast, 72% of patients in BCG series are reported to have complete response.
31 BCG vs Chemo For CIS: Meta-Analysis Sylvester: J Urol. 174:86, 2005 9 randomized trials including 700 pts. With CISChemo: MMC, Epi, Adria, or sequential MMC/AdriaBCG: 68% CR vs Chemo CR: 52%; P=0.00023.6 year follow: 47% BCG vs 26% Chemo NED26% reduction in disease progression with BCG“BCG reduces the risk of short and long-term treatment failure compared with chemotherapy… agent of choice in the treatment of CIS.”
32 Meta-analysis of BCG versus Chemotherapy in CIS Sylvester RJ: J Urol Jul;174(1):86-91
33 Carcinoma in situ: SWOG 8507 CIS: 269 Randomized114 Induction Evaluable Maintenance6 week BCG week BCG3 mo: 58% CR P= % CRObservation 3 week BCG6 mo: 69% CR P= % CR26% of CIS failures at 3 mo NED at 6 without further treatment; 64% with 3wk BCGThis 72% average CR can be significantly increased- to 84%- by the addition of 3 weekly BCG instillations at 3 months.Note that 26% of patients with residual disease at 3 months will have CR by 6 months without any further BCG.64% of patients with residual CIS will go on to CR at 6 months if 3 additional instillations are given at 3 months. Note, the 6 week delay in giving the 3 weekly instillations is critical. Continued instillation beyond 6 weeks typically suppresses the immune response. Also, a second 6 week instillation should be avoided since stimulation with the second round peaks at 3 weeks.
35 BCG Maintenance: Not Created Equal 10050M BCGI BCG100908070605040302010% Tumor FreeN=42 pts. 1q 3mo.3211215183324273069M. Ta, T1M. CISMonths901007080604050302010I. CISPercent Tumor RecurrenceM BCGI BCG% Disease FreeI. Ta, T1N=93 pts. 1q 1mo.N=385, 3q 3-6mo.36918273 weekly instillations appear to provide adequate immune stimulation without inducing immune suppression. Monthly instillation has no immunologic rationale and repeated 6 week instillations is immunosuppressive in most patients. Quarterly single instillations similarly is found to not significantly reduce recurrence.MonthsM, TaT1, 3wk maintenance BCGM, CIS, 3wk maintenance BCGI, CIS, 6wk induction BCGI, TaT1, 6wk induction BCG220.127.116.11.18.104.22.168.22.214.171.124Global recurrenceN=126, 6q 6mo.123456789***MaintenanceYearsCompletion of Therapy*Apparent Increase in Rate of RecurrenceOne Year After Completion of Maintenance**Control122436486072Time in months
36 3 Weekly Maintenance BCG Schedule: Lamm 2005 Induction Mo: Yr:Full x6 1/3x3: * * * * * * * * * * * *Full strength BCG is given weekly for 6 weeks during induction (reduced if needed for increased side effects)1/3 BCG, reduced to 1/10, 1/30, 1/100th if needed due to increased side effects, given at 3,6,12,18,24, and 36 months, then years 4, 5, 6, 8, 10 and 12 years in G3/CIS
37 Dose-Response Curve to BCG (in mice) Individual responses and preparations vary, buttoo little or too much BCG reduces effect604020-20PasteurTiceGlaxoOver allIncreased survival vs control %In our murine bladder cancer studies the optimal dose of BCG was 10 million CFU. Antitumor response as measured by increased survival decreased as dose approached 100 million units.105106107108BCG ·colony forming unitsLamm DL, et al. J Urol. 1982; 128:
38 Progression: Maintenance BCG Patients No BCG BCG ORNo Maint % 10.8%Maintenance % 9.5%Test for heterogeneity: P = 0.008BCG was only effective in trials with maintenance, where it reduced the risk of progression by 37%p =In studies using maintenance BCG progression was reduced by 37%, a highly significant difference.Sylvester RJ: J Urol Nov;168(5):Meta Analysis of 24 Randomized Trials
39 All Studies With Maintenance /650.41.2ProgressionAll Studies With Maintenance1996Rintala (Finnbl 2)390921.51995440228-0.51.3Lamm (SW8795)2418615191-4.88.81999Malmstrom (Sw-N)22125-3.57.92001Nogueira (CUETO)812710247-1.93.91991Rintala (Finnbl 1)58510.7de Reijke (EORTC)1884-45.9vd Meijden (EORTC)19279558-4.79.11982Brosman (UCLA)271990Martinez-Pineiro109167-0.9Witjes (Eur Bropir)25-0.61997Jimenez-Cruz76162.91994Kalbe3532-10.51721-1.11993Melekos (Patras)9962-1.5Study Publ YearAuthor and GroupEvents / PatientsNo BCGBCGStatistics(O-E)Var.OR & CI:(BCGNo BCG)|1-OR|% ± SDProgressionAll Studies With Maintenance1991Pagano (Padova)11/63370-4.43.11987Badalament (MSKCC)64647-0.12.62000Lamm (SW8507)10219287-7.524.12001Palou261ProgressionAll Studies With MaintenanceForrest plot illustrates the significant advantage of maintenance BCG vs control.1988Ibrahiem (Egypt)12/305/17-1.12.6Total257/1749196/2065-36.880.937% ±9(14.7 %)(9.5 %)reduction0.00.51.01.52.0Test for heterogeneityBCGNo BCGc2=9.73, df=18: p=0.9betterbetterTreatment effect: p=
40 Survival Death Patients No BCG BCG Total OR All % 23.2% % 0.89Bladder % 5.6% % 0.81The reductions in the odds of death, 11% overall and19% bladder cancer, are not statistically significant,as might be expected with 2.5 year mean follow upSylvester RJ: J Urol Nov;168(5):Meta Analysis of 24 Randomized Trials
41 Limitations of BCG Immunotherapy: 50 to 80% Eventually Fail Early failure to respondExcess or remote tumorsRapidly dividing/growing tumorLow grade, “non-antigenic” tumorsUnresponsive hostLate recurrence: immunosuppression, resistanceToxicity
42 Treatment of BCG Failure Chemotherapy for BCG failures provides poor response rates 19% for MMC post BCGMalmstrom, J Urol, 2001Low Dose BCG after one cycle BCG failure provides 60% durable CR (same as BCG naive)
47 Early Comparison KLH Trials Treatment R/100 pt mo N Rec %MMC %KLH 10mg %Epodyl %KLH 20 mg %Jurincic, 1988; Flamm, 1990
48 Purified vs Crude KLH vs BCG Treatment Incidence Volume SurvivalPure KLH 4/ mm 5Crude KLH 0/10** 230 ** 10 **BCG 2/10* 71 ** 9 *Saline 8/* P<0.012; ** P<0.002
49 Complete Response to KLH by Disease Category Stage CR (N) CR (%)CIS %Ta, T1, CIS %Ta, T %Total %
50 ConclusionsBladder Cancer is immunoresponsive and an excellent model for drug development.BCG immunotherapy is superior to chemotherapy and reduces progression, but 50-80% fail.Maintenance schedules, vitamins, and interferon may improve response.New agents such as KLH and others hold promise for reduced toxicity, and new approaches such as DNA-based therapy are greatly needed!
52 H19 Expression in Bladder Cancer 84% of TCC express H19Levels are nearly undetectablein surrounding normal urotheliumG2 TCC with H19 StainCIS H19 ISH Color Intensity
53 What is the Best Induction Schedule ? Six weekly instillations: excellent but clearlysuboptimalImmune stimulation peaks at 6 weeksContinued treatment beyond 6 weeks cansuppress the immune responseWith retreatment, stimulation peaks at 3wksControlled trial of "6" vs "6+3" in CIS shows< CR from 69% to 84% (P<0.01)
54 Why Not Give Monthly BCG Maintenance ? Historical and controlled studies show noadvantage over 6 week inductionToxicity is increased over inductionThere is no biological or immunologicalrationale for the monthly scheduleImmune suppression may occur
55 Percutaneous BCG ? Two studies failed to demonstrate benefit 40-60% of patients convert PPD skin test afterintravesical BCGMore than 90% convert with I.D. BCGLamm '85 and Torrence '88:17/55 (31%) recurrence with PPD conversion, 51/82(62%) recurrence with no conversion P=0.0225CR in CIS increased from 49% to 77% with PPDconversion (SWOG, P<0.001)
56 Optimal BCG Retreatment "6+6" should be avoided, unless the intervalsince last treatment has been long (many years)and little or no side effects occurredIf a second six week course is given one cannotdistinguish decreased sensitivity to BCG fromiatrogenic immunosuppressionFor repeat BCG, think "3 plus 3"
57 Toxicity of Maintenance BCG Log dose reductions (1/3, 1/10, 1/30, 1/100th) or stopping maintenance BCG appears to prevent toxicitySide effects are not required to receive thebenefit of maintenance BCG
58 Treatment of BCG Sepsis Isoniazid 300mg, rifampin 600mg, and ethambutol 1200mg daily plus a fluoroquinolone or an aminoglycosidePrednisone 40mg daily (higher doses sometimes are required)Taper steroid slowly when patient improvesResume steroids if symptoms recur after taperContinue triple antibiotics for 3-6 monthsNo more BCG