Appreciating the Natural History of Prostate Cancer in 2005: The Art of Medicine

Transcription

1 Appreciating the Natural History of Prostate Cancer in 2: The Art of Medicine Larry Goldenberg, MD, FRCSC, FACS The Prostate Centre at VGH, University of British Columbia, Vancouver, Canada Prostate Cancer: Not an Insignificant Problem 26,9 new cases (NA) per year!! 3, deaths 1 in 6 lifetime probability (16%) 33% of all new male cancer cases (most common) 1% of all male cancer deaths (2nd, behind lung) 3-4% of all deaths in men Enormous use of resources Undefinable degree of morbidity Huge personal loss to patients and their loved ones Natural History Histologic model of progression from normal prostate to cancer Histologic development Clinical Progression Biological significance Clinical relevance WSU Autopsy Study: Prevalence of cancer and PIN by decade n= n= n=3-9 n= n= n=8 Cancer PIN Courtesy W. Sakr

2 Growth of the 6+ Population By Age Group, 19 to 2 Natural History Number in Millions (bars) % Percent 6+ (line) Histologic development Clinical Progression Biological significance Clinical relevance US Bureau of the Census: 19 to 2 Prostate Cancer: Clinical Disease States Natural History Cancer suspected (PSA, DRE) Localized cancer Rising PSA Indolent Salvage Rx Metastases Post-castrate mets Histologic development Clinical Progression Biological significance Clinical relevance Death, other cause Death,, cancer Modified from Scher et al Urology 2 Biologically Significant vs. Clinically Relevant Biologically significant = destined to cause significant morbidity or mortality Clinically relevant = causes anxiety or leads to treatment with the potential for treatment related morbidity

3 Cancer of the prostate: SEER incidence and mortality, PrePSA Era PostPSA Era - April 23 The Changing Face of Prostate Cancer Fishing for Prostate Cancer in the Pre-PSA Era PSA-based improvements in diagnosis and increased diagnostic activity has resulted in: Declining age at diagnosis Shifts to earlier stages QuickTime and a TIFF (LZW) decompressor are needed to see this picture. Decreased tumor volumes Increased treatment rates Fishing for Prostate Cancer in the PSA Era Estimated new cancer cases and deaths in men: United States A Disconnect QuickTime and a TIFF (LZW) decompressor are needed to see this picture. Jemal et al, CA Cancer J Clin 24; 4: 8

4 Cancer of the prostate: SEER incidence and mortality, Canada - 24 PrePSA Era PostPSA Era New Cases Deaths Deaths/Cases Prostate 2, Breast 21,4,3.2 A B Colorectal 19,1 8,3.44 Lung 11,9 8,2.87 A: UNDERDIAGNOSIS B: OVERDIAGNOSIS - April 23 Prostate cancer dilemma An Oncologic Dilemma Is the profound difference between incidence and mortality rates due to the beneficial effects of treatment or the benign natural history of the disease? Is cure of prostate cancer possible when it is necessary? Is cure necessary when it is possible? Willet Whitmore, Jr., MD Possible solutions Possible solutions Decrease overdiagnosis?? Decrease overtreatment?? Decrease overdiagnosis?? Decrease overtreatment?? Other??

5 What happened as a result of the U.S. experiment with PSA? The most compelling data: Results of the U.S. experiment with PSA? PSA screening began in earnest in then. Stage Migration Improved local therapies Dramatic fall in metastatic disease Death rates falling in multiple health settings PSA screening began in earnest in then. Stage Migration Improved local therapies Dramatic fall in metastatic disease Death rates falling in multiple health settings Stage Migration, DoD CPDR Prostate Cancer Stage at Diagnosis CaPSURE National Database %T1a+b %T1c %T2a+b %T3 + T4 %D % Year T1 T2 T3/4 Trends in stage over time, n=794, radical prostatectomy series, 6 US and European centers But what else happened as a result of the U.S. experiment with PSA? 1% 8% 6% 4% 2% % T3 T2c T2b T2a T1c T1b T1a Clinical stage Pathological stage /92 93/94 9/96 97/ /92 93/94 9/96 97/ LN+ SVI From Ohori M, Eastham JA, Scardino PT, Bochner B, Rabbani F, ECE Kattan WM, Kupelian P, Klein EA, Skinner DG, Graefen M, Confined Huland H, Slawin K, Shariat S, Wheeler TM, 21. PSA screening began in earnest in then. Stage Migration Improved local therapies Dramatic fall in metastatic disease Death rates falling in multiple health settings

6 Cure After Radical Prostatectomy Radical Prostatectomy Biochemical Outcome based on Risk Stratification 1 Biochemical Relapse-Free Survival P < Time (months) D Amico et al, multiple publications Example of Fall in Complication Rate: Radical Prostatectomy The most compelling data: Results of the U.S. experiment with PSA? % Other Complications % Impotence PSA screening began in earnest in then. Stage Migration Improved local therapies Dramatic fall in metastatic disease Death rates falling in multiple health settings Study Year Study Focus Severe incontinence Stress incontinence Impotence Pulmonary embolism Death DOD Prostate Cancer 1-Year Trends in M+ Disease The most compelling data: Results of the U.S. experiment with PSA? 2. Metastases/ 1K Population No PSA Screening Age Adjusted Mets PSA Screening PSA screening began in earnest in then. Stage Migration Improved local therapies Dramatic fall in metastatic disease Death rates falling in multiple health settings Year Optenberg SA, Thompson IM.(personal communications)

7 Fall in Mortality SEER total fall in Prostate Cancer mortality Documented: SEER Olmsted County Canada/Quebec Department of Defense (U.S.) Tyrol, Austria - -1 % Decline in Mortality -1-2 Decline from peak year (1991) Stephenson, R. 22 Prostate Cancer Conference, USVI, July 2, 22. Source of Data - SEER US Prostate Cancer Mortality: US Prostate Cancer Mortality: Years of possible increase in attribution bias ( ) Possible mortality curve without attribution bias effect Early Diagnosis Is Associated With a Fall in Mortality Prostate Cancer mortality in Mexico Fall in mortality now seen: SEER Olmsted County Canada/Quebec Department of Defense (U.S.) Tyrol, Austria Mortality fall not seen where PSA not readily available or widely used. e.g., Mexico no PSA screening Year Adjusted Crude Tovar-Guzman. The Prostate 39:23, 1999

8 So, Overdiagnosis?: To Find It, You Have To Look For It! Possible solutions Decrease overdiagnosis?? Decrease overtreatment?? Why is there overtreatment happening? In the absence of randomized trials, physicians cannot determine the true efficacy of treatment interventions The inability to accurately predict the biological behavior leads to a hesitation in recommending expectant management As a result physicians tend to recommend aggressive therapy If the disease progresses, they have done everything possible If the disease does not progress, they have cured the patient Today's metastasis was once organ-confined cancer However, prostate cancer is not the only cause of death in men The Greatest Challenge of Treating Prostate Cancer Today To find the biologically significant cases and to intervene to prevent serious morbidity and mortality, even if years away, or to avoid the morbidity of treatment whenever possible. In the absence of a crystal ball = The Art of Medicine

9 Individualize Selecting Appropriate Therapy Stage grade PSA health status pt. Preference QOL Match Surgery Conformal XRT Brachy Cryo NHT WW Investigational Conservative Approach Aggressive Approach Undertreat those who need to be treated Spare those who do not need to be treated Overtreat those who will die of other causes and not be bothered by prostate cancer Futile treatment of those whose cancer is beyond the therapeutic scope of modern therapy Life Expectancy Outcome factor: Patient age at diagnosis 3 8% 2 6% Years 2 1 Percent 4% 2% 1992, n=13, , n=7,633 1 % < >64 Age at diagnosis Mettlin, CJ., Cancer, Age Nearly one-third of newly diagnosed patients are < 64 years of age Outcome factor: Patient age at diagnosis Outcome factor: comorbidity Loss of potential life years At age : Grade 1 Grade 3 2 years >11 years At age 7: Grade 1 Grade 3 <1 years 2 years Albertsen et al, (JAMA, 199): 1. comorbidity may pose an even higher risk of death than the cancer itself Young men lose many more potential life years to cancer than older men with disease of comparable grade and have a correspondingly higher risk of dying from, as opposed to with, their cancer. 2. life expectancy loss because of cancer is lower in men who have coexisting illnesses Albertsen demonstrated that comorbidity was as powerful a predictor of overall survival as tumour grade

10 Percent Outcome factor: patient preferences 4% 29% N=78 US TOO pts Age-6; phone survey 13% Preserve Q of L Extend life Delay disease progression Younger patients are placing a higher premium on QOL issues making the treatment decision process more challenging and more complex Key Studies: Clinical Outcome: Tumor Grade VACURG - Gleason Johannson - Lancet 1987, JAMA 1989, JAMA 1997 Chodak - N Eng J Med 1994 Lu-Yao - Lancet 1997 Albertsen - JAMA 199, 1998 Johansson - JAMA, 24 Crawford ED, Urology,1997 Mortality Rates by Gleason Score 1 Year disease-specific survival of Johannson s patients (localized disease) Deaths/patient year Gleason Score Cancer deaths All deaths Percent Well (n=148) Moderate (n=66) Histology Grade Poor (n=9) Percent alive Percent alive without metastases Johansson et al, JAMA,24:291, 2713 Johansson et al, JAMA,24:291, 2713

11 1 year disease-specific survival for Chodak s patients 1 Year disease-specific survival for Lu-Yao s patients Percent Well Moderate Poor Histology Grade Percent alive Percent alive without metastases Percent Well (n=984) Moderate Poor (n=2236) (n=6198) Histology Grade Percent alive Albertsen Study Gleason Score Age at Diagnosis Gleason score Prostate cancer mortality at 1 years % 6-11% % % % 1X Competing risk analysis of men age -74 at diagnosis managed conservatively for localized prostate cancer Albertsen PC, JAMA 1998;28:97-98 Mortality (grey band) Prostate cancer mortality (red upper band) Years Following Diagnosis The active surveillance hypothesis: Delayed curative therapy can be offered effectively to the subset of patients with rapid progression, while the majority of favorable risk patients can be managed with observation, resulting in improved QOL, at least for a number of years. Critical Assumption: PSA DT, tumour grade and DRE are useful means to separate indolent from biologically aggressive malignancy

12 Clinically detected cancer Indolent cancer Nomenclature Map of whole mount radical prostatectomy specimen Each Gleason pattern of cancer is color coded and mapped. Watchful waiting Expectant management Active Surveillance Conservative management Judicious observation you can observe a lot just by watchin Yogi Berra Active Surveillance Studies CapSURE Toronto Vancouver MSKCC DoD, CPDR Boston Salt Lake City Hopkins UCSF Montreal Patient Preference in the US Based upon Medicare data, 1999 Patterns of Care Study and CaPSURE data: - 3% of patients undergo RP (3% w/ NHT) - % of patients undergo XRT 18% brachy alone (32% w/adt) 18% brachy + EBRT (.4% w/adt) 14% EBRT alone (3% w/ ADT) - 1% watchful waiting - % hormonal therapy alone Profile of surveillance patients 329 of 448 (8.2%) selected surveillance Age 7 years (1% vs 16%, p<.1) Caucasian race (93% vs 8%, p<.1) Lower initial PSA (p<.1) Clinically oc (97% vs 88%, p<.1) Gleason score <7 (97% vs 88%, p<.1) CA: Cancer J Clin 3: -26, 23 Lee WR et al. Cancer 98: 1987, 23 Penson DF et al. Urology 7: 499, 21 CaPSURE database analysis Koppie et al, AUA,2

13 Likelihood of secondary treatment Distribution of PSA doubling times (%) in 299 patients. 329 of 448 (8.2%) selected surveillance Likelihood of secondary treatment within years = 2% Predictors of secondary therapy: age <6 and increased initial PSA Median PSA DT 7. years Median F/U 62 months Median # measurements: 8 (3-19) 22% had PSA DT < 3 years 42% had PSA DT > 1 years CaPSURE database analysis Koppie et al, AUA,2 < >1 PSA Doubling time Klotz et al Actuarial Probability of Being Progression-Free Prostate cancer specific survival (N=299) 96% at 1year 79% at 2 years 6% at years Prostate cancer survival 99% at 8 years 2 prostate cancer deaths, each at years after study entry Both had PSA DT X 2 years Active Surveillance at VGH Total number of patients: 64 (1987 to 2) Lost to Followup: 1 Mean Age 69 years (49-87) Mean follow up 66 months (12-17) PSA Doubling Time 32 % of the patients that are still on WW have a PSA doubling time > 1 years and 44 % a decreasing PSA. 23% of all patients had a PSA doubling time <48 months decr psa >48 nonths WW RRPx RT HORM

14 Change in Treatment Expectant Management (N = 88) Probability of progression and of treatment 1. 7 (11%) 6 (9%) 8 (13%) 43 (67%) WW RRPx RT HORM Probabilty free of progression/treatment Progression Treatment Progression Free Probability 3 year 71% year 64% Treatment Free Probability 3 year 9% year 6% MONTHS MSKCC: Patel et al, AUA, 22 Patient Characteristics During Follow Up PSA Doubling Time Predictors of Progression From Patel et al, AUA, 22 Percentage of patients Median: 68.6 months (4.-74) Negative Doubling Time (months) Univariate analysis Positive second biopsy PSA (baseline) PSAD (baseline) Clinical Stage >T1a Predicted year PFP (baseline) Gleason score (baseline) PSA doubling time Clinical stage (baseline) No. of positive cores (1 st biopsy) Proportion of cores positive (1 st biopsy) p-value Freedom from progression: 2 nd biopsy result (n=7) DoD CPDR Database Study 1. Freedom From Progression Log Rank Test p=.2 Negative (n=33) Positive (n=37) Temporary Deferred Therapy(TDT) (Watchful Waiting) in Low/Intermediate-Risk Localized Prostate Cancer in the PSA-Era: Selective Study N= Months From Patel et al, AUA, 22 Moul, personal correspondence

15 Kaplan-Meier free from secondary treatment curve in 313 Low/Intermediate Risk WW patients CONSERVATIVE MANAGEMENT : Zeitman, 21 Secondary treatment - free survival rate (%) yr=27% A retrospective review of 199 men with T1-2 prostate cancer and PSA <2ng/ml. Median follow up 3.4 years Overall survival at and 7 years was 77% and 63%, disease-specific survival 99% and 99%. Alive and untreated: 43% at years and 26% at 7 years (median PSA rise from diagnosis to last f/u was.9ng/ml) Time (years) UCSF Series, 24 3 to year rates of intervention n= 163 mean Age = 64±8 mean PSA = 6.3 mean GS =.9 (median 6) U.S. sites: 31% to 73% Canadian sites: 28% to 3% 3/163 (18%) progressed mean time to progression: 3.7 yrs 48% grade progression 39% TRUS progression 13% PSA progression (velocity > 6 mos) The uncertainty: and in any given individual one must remember that.. Does PSA doubling time change over time (PSA acceleration)? How often, and over what time period, does this occur? Does this preceed, or follow, clinical progression? Does PSA always reflect tumor biology? How accurate are the biopsy techniques used? Today's metastasis was once organ-confined cancer

16 wait for that wisest of all counsellors.time Upcoming important trial A broad-based CALGB/NCIC/SWOG trial to compare immediate intervention with active surveillance and selective delayed therapy ( START trial) Pericles The Challenge We met the challenge with stage T1a prostate cancer Patients hear Cancer and want definitive treatment The word Cancer evokes a response which is disproportionate to the natural history of minimal volume, low grade, good risk prostate cancer It is a communication challenge to overcome this These patients often used to be treated radically Data from many centres demonstrated the benign natural history of this entity (1% progression at 1 years) There is a consensus that T1a prostate cancer is best managed with surveillance We need to recognize T1C-a prostate cancer T1a Incidental post TURP % of chips No Gleason pattern 4 or T1C-a Based on systematic biopsy ( 12 cores) < 1/3 of cores involved 1% of total surface area No Gleason pattern 4 or PSA 1 Management: Long term follow up with PSA, DRE, biopsy Treat if rapid rise in PSA (PSA DT < 3 years) or grade progression Summary: Can we decrease Overtreatment? In a screened population, many patients have a long window of curability Prostate cancer is usually slow growing, and may not be life threatening, even when diagnosed in young patients Men with poorly differentiated disease (Gleason 7-1) have a 1- fold higher risk of dying from prostate cancer and are not candidates for expectant management How much aggressive management alters outcomes remains to be determined

17 Summary: Can we decrease Overtreatment? Patient participation or buy-in is critical in a watchful waiting protocol. With respect to outcome, patient preferences are equally important to age, co-morbidity, tumor stage and grade Traditional prognostic factors of PSA, Gleason score, and clinical Stage, reflect the biological characteristics of malignancy at a single point in its long natural history These prognostic factors are often inaccurate reflections of the natural history in a given patient Summary: Can we decrease Overtreatment? Periodic prostate biopsies are an essential part of any follow-up protocol, especially in patients with stable PSA growth patterns One must monitor all potential indicators of progression in the followup of men treated with watchful waiting. Watchful waiting in the PSA era often represents delayed curative therapy The impact of treatment on prostate cancer is uncertain and is best assessed by randomized trials ( START ) Predict Outcome??? Clinically detected cancer Indolent cancer Map of whole mount radical prostatectomy specimen Each Gleason pattern of cancer is color coded and mapped.

18 Molecular Diagnosis Profile of the Patient and the Tumor Gene Microarray Slide adapted from Dr. E. Kohn, NCI Signal Network Profile MUC1 protein expression predicts recurrence Microdissection Biopsy Protein Microarray Personalized Medicine Risk Assessment and Earlier Detection Enhanced Diagnosis Individualized Intervention The R 7 Paradigm Will Revolutionize Health Care In 21 we will provide: to the Right patient and tumor the Right intervention for the Right reason at the Right location at the Right time with the Right outcome monitored in Real time 1 Men 1. Apply genetic or other tests 2. Identify the men who will develop prostate cancer. 3. Identify those for whom treatment will be necessary 4. Identify those whose cancer can be prevented with diet. Identify those for whom a medication will prevent prostate cancer. A Von Eschenbach, NCI USA The Future of Prostate Cancer WS AUA: July 3 - August 4, 2 Westin Bayshore