Oncology 11

Localised Prostate CancerLouise Olson

Paul CleavelandArie Parnham

Mr Mokete

22nd December 2014

Objectives

• Natural history Prostate Cancer• Treatments• Complications of Treatment• Brachytherapy & External Beam XRT• VIVAs

Natural History - Incidence• Most common cancer diagnosis in UK (2011)• Accounts for nearly 25% of all new male

cancers• Huge rise in CaP incidence past 20yrs

- increase in T1c tumours- increase in PSA screen-detected tumours

• Increase in incidence not reflected in mortality rates

Office of National Statistics 2013

UK CaP incidence statistics

Cancer Research UK

In 2010, in the UK, the lifetime risk of developing prostate cancer is 1 in 8

CaP Incidence by Age

Cancer Research UK

Trends over Time

• Substantial increases in incidence have been reported in recent years for many countries– TURP– PSA testing

1. Hsing AW, Tsao L, Devesa SS. International Journal of Cancer (Pred.Oncol) 2000; 85:60-67.2. Bray F, Lortet-Tieulent J, Ferlay J, et al. Eur J Cancer 2010; 46:3040-52.3. Quinn M, Babb P. BJU Int 2002; 90:162-73.

Post-Mortem Studies• Half of men in their fifties will have histological

evidence of CaP on post-mortem• This rises to almost 80% of men in their

eighties1

• BUT only 1 in 26 men die from CaP• In other words, men are more likely to die with

prostate cancer than from it – an important fact when considering population screening of asymptomatic men2

1. Sakr WA et al. Eur Urol. 1996; 30(2): 138-442. Frankel S et al. Lancet. 2003; 361(9363): 1122-8

Geographic Variation in CaP Incidence

115.2

98.2

88.9

5.29

UK Mortality Statistics CaP

Cancer Research UK

Geographic Variation in CaP Mortality

Prostate Cancer Mortality By Age

Mortality Trends in CaP

Age-specific mortality trends in CaP

Prostate Cancer Risk Factors

• No modifiable RF has been identified on which to base a prevention strategy

• Accepted RFs include:- Age- Family history- Ethnicity

• Other RFs have been studied but evidence inconclusive

Age and Prostate Cancer Risk

• Age strongest known RF for CaP• Very low incidence in men under 50 yrs• Incidence in men aged 85+ is five times that

of men aged 55-59• Post-mortem studies

PSA• Loeb et al. UROLOGY 67: 316–320, 2006• 1991-2001• 13,943 men <60 years• Median PSA level was 0.7 aged 40-49 & 0.9 aged 50 to 59• Men <60, baseline PSA value between the age-specific median

and 2.5 ng/mL was a significant predictor of later CaP and was associated with a significantly greater PSA velocity

• A young man’s baseline PSA value was a stronger predictor of CaP than family history, race, or suspicious DRE findings. A greater baseline PSA level was associated with significantly more adverse pathologic features and biochemical progression

Family History and CaP Risk• A family history of prostate cancer is one of the

strongest known risk factors for this disease

• 5–9% of all CaP cases

• Risk 2.1-2.4 for men with a father has/had CaP, risk 2.9-3.3 brother, 1.9 2nd degree relative1-3

• Familial CaP higher in men aged under 65

1. Bruner DW, Moore D, Parlanti A, et al. Int J Cancer 2003;107:797-803.2. Johns LE, Houlston RS. BJU Int 2003;91:789-94.3. Kicinski M, Vangronsveld J, Nawrot TS. PLoS One 2011;6:e27130.

Family History and CaP• 19-24% higher in men whose mother

has/had breast cancer (not associated with risk in sister)1,2

• 5 times higher in men with BRCA2 mutation3

• May be higher in men with BRCA1 – evidence unclear4-6

1. Hemminki K, Chen B. Prostate 2005;65:188-94.2. Chen YC, Page JH, Chen R, et al. Prostate 2008;68:1582-91.3. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999;91:1310-6.4. Thompson D, Easton DF. J Natl Cancer Inst 2002;94:1358-65.5. Fachal L, Gomez-Caamano A, Celeiro-Munoz C, et al. Prostate 2011;71:1768-79.6. Leongamornlert D, Mahmud N, Tymrakiewicz M, et al. Br J Cancer. 2012;106(10):1697-701.

Ethnicity and CaP

• In the UK, black Caribbean and black African men have 2 - 3 x the risk of being Δ or dying from CaP than white men1

• Asian men have a lower risk than the national average2

1. Ben-Shlomo Y et al. Eur Urol. 2008; 53(1): 99-105 2. Jack RH et al. Int J Androl. 2007; 30(4): 215-20

Diet and CaP

The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) are the gold standard in cancer epidemiology.

Alcohol and Smoking and CaP

• EtOH – 2 meta-analyses: The largest showed no increased risk whilst the other demonstrated modest risk increases1,2

• Smoking inconclusive as a risk factor3,4

1.Bagnardi V et al. Br J Cancer. 2001; 85(11): 1700-5 2. Dennis L.K. Prostate. 2000; 42(1): 56-66

3. Gong Z et al. Cancer Causes Control. 2008; 19(1): 25-31 4. Doll R et al. Br J Cancer. 2005; 92(3): 426-9

Other Risk Factors

• IGF-1 38-83% risk1-2

• Vasectomy risk by 10%3 but meta-analysis inconsistent4-5

• Prostatitis 60-80% risk6,7

• High BMI & metabolic syndrome (30% risk)8

1. Renehan AG, Zwahlen M, Minder C, et al. Lancet 2004;363:1346-53.2. Roddam AW, Allen NE, Appleby P, et al. Ann Intern Med 2008;149:461-71, W83-8.

3. Siddiqui MM, Wilson KM, Epstein MM, et al. J Clin Oncol 2014.4. Tang LF, Jiang H, Shang XJ, et al. Zhonghua Nan Ke Xue 2009;15:545-50.

5. Dennis LK, Dawson DV, Resnick MI. Prostate Cancer Prostatic Dis 2002;5:193-203.6. Dennis LK, Lynch CF, Torner JC. Urology 2002;60:78-83.

7. Jiang J, Li J, Yunxia Z, et al. PLoS One. 2013;8(12):e85179.8. Esposito K, Chiodini P, Capuano A, et al. J Endocrinol Invest. 2013;36(2):132-9.

Molecular Biology and Genetics• 5–10% of all CaP may have a substantial inherited component • Searches for high-risk prostate cancer loci identified BRCA2 as

important susceptibility factor1 • Carriers of germline mutations in BRCA2 have 5x risk of CaP &

develop aggressive disease2 • However, BRCA2 mutations account for only 2% of all early-

onset cases (<55years) indicating that further susceptibility loci exist

• Mutations in the BRCA1 gene have a smaller effect, increasing a man’s risk of prostate cancer by less than two-fold3

• Many other loci implicated - Genetic profiling likely to be important in the future to provide prognostic information and guide treatment

1. Edwards SM et al. Am J Hum Genet. 2003; 72(1): 1-122. Mitra A et al. Br J Cancer. 2008; 98(2): 502-507 3. Thompson D et al. J Natl Cancer Inst. 2002; 94(18): 1358-65

Natural History of Localised CaP

• How can we distinguish between those men who are likely to die from CaP, from those with indolent disease?- In the absence of RCTs, understanding the

natural history of CaP can help decision-making process for treatment

Natural History of Localised CaP

• Insight into natural history inferred from a number of sources:

– Results of deferred treatment– Longitudinal studies of serum PSA

Results of Deferred Treatment

Individual series:- Popiolek M et al 1

Meta-analyses:- Chodak et al 2

Cohort:- Albertsen et al 3

1. Popiolek et al. Eur Urol. 2013 Mar;63(3):428-352. Chodak et al. NEJM. 1994; 330:2423. Albertsen et al. JAMA. 2005; 293:2095

Popiolek M et al 2013

• Eur Urol. 2013 Mar;63(3):428-35• Natural history of early, localised prostate cancer: a final

report from three decades of follow-up.

• 30yrs F/U• 223 pts• Sweden• Androgen deprivation therapy was administered when

symptomatic tumour occured

RESULTS: Popiolek M et al 2013• All but 1 man (1%) had died• 41.4% locally progressed• 18.4% distant metastatic disease• 17% men died of prostate cancer• 4% men with gleason 8-10 died within first 10yrs (55% from CaP)• Survival for men with well-differentiated, non palpable tumours

declined slowly over 20yrs & more rapidly between 20 & 25yrs (from 75% to 25%)

• Conclusion: Localised CaP often has an indolent course, local progression & distant metastasis can develop over the long term, even if considered low risk at diagnosis

Chodak et al. 1994

• Pooled analysis of 828 pts with localised CaP treated with WW

• 6 non-randomised studies• Results measured as cause-specific survival

(CSS) and metastasis-free survival at 5 & 10 yrs of f/u

• Mean age 70yrs

Chodak et al. 1994• Outcome of deferred treatment in localised CaP

in relation to tumour grade

Chodak et al. 1994

• Drawbacks of study:- F/U period insufficient- Highly selected series (60% of pts had Grade 1 disease)- Many pts received hormonal therapy at time of progression therefore delaying development of mets- Therefore probably overestimates CSS rates and under-estimates rate of progression

Chodak et al. 1994

• Discussion:- Prostate cancer a progressive disease when managed conservatively- Even though low grade tumours have good CSS rates at 10 yrs, progression rates are still substantial- If life expectancy <10yrs and low/mod grade disease, WW is acceptable

Albertsen et al. 2005

• Re-evaluated biopsy specimens using more widely accepted Gleason score

• 767 men aged 55-74 at diagnosis between Jan 1971 & Dec 1984

• Follow up reported at 5, 10, 15 & 20 yrs• Median F/U 24yrs

Albertsen et al. 2005

• Drawbacks:– Pre-PSA era, therefore it is likely that series

contains a number of men with extra-prostatic disease

– Therefore study probably underestimates actual survival rates

Albertsen et al. 2005

• Discussion:– Men with high grade (Gleason 8-10) have high chance

of dying from CaP within 10 yrs– Men with low grade disease have minimal chance of

dying from CaP within 20 yrs– PSA testing introduces lead time bias, so PSA-screened

men with CaP should have improved CSS in comparison to this cohort

Longitudinal Series of Serum PSA

• Retrospective evaluation of progression in men with CaP• Baltimore Longitudinal Study of Aging• 15 yrs before diagnosis, men with metastatic CaP had PSA

significantly higher than controls & BPH, and higher yearly rates of change (Carter et al 1992)

• Suggests death rates in first 10 yrs from diagnosis with screening do not measure efficacy of any form of treatment

• Lead time in diagnosis associated with PSA screening 4-5yrs (Gann et al 1995)

Natural History Localised CaPSummary

• Localised CaP is a progressive disease- Even low grade tumours with an indolent course in first 15 yrs eventually progress

• 15 years is the earliest time when CSS analysis has any significance

• Lead time in diagnosis associated with PSA testing needs to be factored in when analysing treatment

• Age at diagnosis important factor in determining CSS