Kittinut Kijvikai, MD, FACS Associate Professor

Ramathibodi Hospital, Mahidol University

Radical Prostatectomy for High Risk and Advanced

Prostate Cancer

Treatment Options for Prostate Cancer continued

S14 VOL. 9 SUPPL. 2 2007 REVIEWS IN UROLOGY

state of the disease continuum. Thesepatients may in fact have a very dif-ferent disease course. Oefelein andcolleagues2 recently demonstratedthat this reported range of survivalwas not consistent with current clini-cal presentations. They reported thatthe median survival after the develop-ment of hormone-refractory diseasewas approximately 40 months in thepatients with evidence of skeletalmetastasis and 68 months in thosewithout skeletal metastasis.2 In spite ofintensive research efforts, the molecu-lar mechanisms by which prostate can-cer cells become resistant to hormonetherapy remain poorly characterized.3,4

Actually classifying these patientscan be confusing. Patients who havecastrate levels of testosterone andare no longer responsive to hor-monal manipulations are by defini-tion “androgen independent.” Manycurrent clinical trials for patientswith advanced prostate cancer, how-ever, include patients who do nothave any additional hormonal ma-nipulations. In the broadest sense,patients with hormone-refractorycancer include all those with PSAand/or clinical progression while onhormonal therapy and with castratelevels of testosterone.

Owing to the diversity of thisgroup, this review attempts to aid theurologist who treats the spectrum ofthese patients from advanced, symp-

tomatic metastatic disease to theasymptomatic patient on hormonaltherapy with a newly discovered in-creasing PSA. This review outlines aprogression of treatment choices thatinclude specific hormonal manipula-tions, chemotherapeutic options, andadjunctive therapies (Table 1). Theclinician must individualize care, asprior therapies, current rate of diseaseprogression, symptoms, and evidenceof clinical/radiographic metastaticdisease are just a few of the issuesthat must be considered. Importantly,these patients should have the benefitof multimodality therapy (Figure 1).

Hormonal ManipulationsToday, a significant number of pa-tients demonstrate progression whileon androgen deprivation therapy withonly a PSA increase. Although theoptimal timing of therapy has notbeen established, after ensuring a cas-trate state in these patients, some typeof hormonal therapy represents a rea-sonable course. Historically it hasbeen recommended to continue an-drogen deprivation despite diseaseprogression based on the evidencethat administration of exogenoustestosterone has been shown toworsen patient symptoms.5 It is im-portant at the first evidence of treat-ment failure that serum testosteronelevels be checked to confirm castratelevels (! 50 ng/dL).

Initially, if maximum androgenblockade has not been used, addingan antiandrogen may be helpful. Al-though several randomized controlledtrials have shown that maximum an-drogen blockade (leuteinizing hor-mone releasing hormone [LHRH] ago-nist combined with an antiandrogen)offers a modest survival advantageover LHRH agonist therapy alone,many physicians and patients chooseLHRH therapy alone because of cost,side effects, and minimal survivalbenefit from maximum androgenblockade.6-10

For those patients treated withmaximum androgen blockade with anantiandrogen and LHRH agonist, thefirst therapeutic maneuver can be an-tiandrogen withdrawal. PSA declinesare well recognized, and occasionalclinically significant responses suchas radiographic changes can be seen.11

The response time of PSA decline willactually depend on the type of an-tiandrogen used. For example, flu-tamide has a relatively short half-lifeof 6 hours, and the response is usually

Figure 1. The current multidisciplinary treat-ment algorithm for patients with hormone-refractory prostate cancer.

Table 1Treatment Options for Hormone-

Refractory Prostate Cancer

ObservationMaximum androgen blockadeWithdrawal of antiandrogen Varying specific antiandrogens (eg, bicalutamide, flutamide, nilutamide)Estrogen compounds (diethylstilbestrol)Adrenal suppressants (ketoconazole)Clinical trials/investigational therapiesSpecific therapies for symptomatic disease (eg, bisphosphonates, external beam radiation, bone-targeted radiopharmaceuticals)Chemotherapy (docetaxel)Pain management

RIUS0003(Sanofi)_04-30.qxd 5/1/07 10:53 AM Page S14

Diagnostic Radiologist

Hormonal therapy works better than the best when combined with surgery of LAPC

High risk diseases

• No standard treatment (locally advanced disease)• BCR > 50 % in 5 years• cStaging may differ from pStaging.• Morbidity of surgery • Need MDT

Advanced diseases

• Advanced disease; disease has entered the systemic circulation so local treatment has potential for harm without clear benefits???

Current practice

•CRPC: Abiraterone, Enzalutamide and a lot of new comings

•Chemotherapy in hormonal sensitive disease

•New radiology intervention

•Urologist ?????

Arthur Schopenhauer All truth passes through three stages.

First, it is ridiculed. Second, it is violently opposed.

Third, it is accepted as being self evident.

Euro Urol 2014;65:1067-68

As physicians, we have a duty to provide treatment to the ailing person.

This duty is a part of who we are, what we do …many of us have dedicated our life to our

profession.

Euro Urol 2014;65:1067-68

To feel powerless is not in our nature, so we attempt to push forward the limits

to improve outcomes.

Euro Urol 2014;65:1067-68

High risk diseases

•Localized disease•PSA > 20 ng / mL•or GS > 7•or cT2c———————————————————•Locally advanced disease•any PSA •any GS, cT3-4 or cN+

•64 years old Prof. of Ecology/Business man

•Healthy, high PSA 18, Biopsy Gleason 3+4 bilateral lobe.

•MRI: SV invasion

•Treatment ? ADT + RT?

Case 1

•Robot prostatectomy: Continence: no pad, but ED (bleeding 200 ml)

•Gleason 3+4, SV invasion (T3b), LN negative

•PSA 0.003 (36 months f/u)

•Refuse for adjuvant RT

•OS, CSS

•Local symptoms ?

•Accurate staging ?

High risk disease (G8-10)

• The incidence of organ-confined disease is 26-31% in Gleason 8-10 lesions.

• These pts can be cured from surgery.

•RP plus ADT/RT

• PFS (BPFS) at 5- and 10-years follow-up ranged between 35-51% and 24-39%, respectively.

• The CSS at 5, 10 and 15-years follow-up was 96%, 84-88% and 66%, respectively.

EAU guideline 2016

PSA > 20

• The largest multicenter surgical series to date, including 712 patients with PSA > 20 ng/mL

• CSS of 90% and 85% at 10 and 15 years follow-up, respectively.

Eur Urol, 2010. 58: 1

Locally advanced disease

• No gold standard treatment.

• Patients have an increased risk of positive surgical margins and lymph node metastases and/or distant relapse.

• Observe alone, LA progresses systemically and locally over a 36-month period in 100% and 87% of cases, respectively.

• RP alone: 843 cases, local recurrence-free survival 76%, metastasis-free survival 72% and CSS 81% at 20 years. Mitchell CR. BJU Int 2012;110:1709-13

Locally advanced disease (Surgery vs RT)

•A cohort study > 2300 cases, on their multivariate analysis, RP was found to be associated with reduced risk of developing metastatic disease in comparison to EBRT, especially in high-risk patients (HR 0.35; p<0.001).

Zelefsky MJ. J Clin Oncol 2010;28:1508-13

Locally advanced disease (Surgery vs RT)

•Deoxyribonucleic acid damage to a cancer cell from RT could lead to radio resistant tumors.

•Cases who fail RT are very rarely operated, in contrast to cases who underwent salvage RT.

Locally advanced disease

•PSA follow-up is usually more straightforward.

•Morbidity and mortality are similar between localized and locally advanced diseases.

•Extended lymphadenectomy is recommended.

•Neoadjuvant systemic therapy randomized trials are under evaluation. (Abi + RP v RP & Enza + RP v RP).

Locally advanced disease

•Retrospective studies of RP

•Cancer-specific survival at 5-, 10- and 15-years ranged between 90-99%, 85-92% and 62-84%, respectively.

• Five- and 10-year OS ranged between 90-96% and 76-77%, respectively.

EAU guideline 2016

Locally advanced disease

•Cohort; cT3b-cT4

•CSS was 88-92% at 5 years and 87-92% at 10 years, while the OS was 73-88% at 5 years and 65-71% at 10 years.

Scand J Urol Nephrol, 2012. 46: 164.Cancer, 2006. 106: 2603.

Prostate Cancer Prostatic Dis, 2015. 18: 31

Locally advanced disease (LN +)

• The combination of RP and early adjuvant HT in pN+ PCa has been shown to achieve a 10-year CSS rate of 80%.

• Two retrospective observational studies have shown a dramatic improvement in CSS and OS in favor of completed RP vs. abandoned RP in patients who were found to be N+ at the time of surgery.

Engel, J., et al. Eur Urol, 2010. 57: 754 938 LN-positive patients (688 with RP and 250 without RP)Steuber, T., et al. BJU Int, 2011. 107: 1755.158 consecutive patients

Locally advanced disease (LN +)

• Recent studies described survival outcomes after surgery in pN1 PCa, with 5-, 10- and 15-year CSS ranging from 84-95%, 51-86% and 45%, respectively.

• The OS at 5, 10 and 15 years ranged from 79-85%, 36-69% and 42%, respectively.

EAU guideline 2016

T 4 disease

• 87 cases T4 who underwent RP from Mayo clinic

• Follow up 9.8 years

• 10 Y BCR free survival, SP free survival and OS was 37%, 64% and 70%, respectively.

Int Braz J Urol. 2016; 42: 1091-8

Case 2

•60 years old, PSA 18, adenocarcinoma 3+4 bilateral with LUTS.

•Bone scan (-), MRI T3b

•Mild HT

• Robotic prostatectomy, G 3+4 T3b, LN negative

• Continence

• Bleeding 400 ml

• PSA post operation 2 months = 31 ng/ml

•RCC, Colon & Ovary cancer, surgery is worthwhile.

Direct Evidence in support cytoreduction

OS; 67.4% v 52.6% v 22.5%DSS; 75.8% v 61.3% v 48.7%

Culp SH. Eur Urol 2014;65:1058-66

SEER-base study(2004-2010)

• SEER study of 8,185 cases showed higher 5 y overall and cancer specific survival rates for the surgery and brachytherapy than ADT.

Munich cancer registry(1998-2010)

OS = 55% vs 21%Gratzke C. Eur Urol 2014;66:602-3

J UROL 2015;193:832-38

1st case control study 23 cases (CRP+ADT 2y) v 38 casesADT

Time to CRPC Median CSS

PFS 36.8 vs 26.5 m

CSS 95.6% VS 84.2%

Time to CRPC; 40 m vs 29 m

Local symptoms

• 28.9% required surgical or percutaneous interventions due to local pro- gression of PCa (n = 38).

• 10.4% required transfusion of 3 to 6 units of red blood cells.

• In comparison, the RP group (n = 23) required lymphocele drainage in 2 patients(8.7%),

• lymphocele marsupialization in 1 patient (4.3%),

• 3 (13.0%) patients developed a deep vein thrombosis and1 patient (4.3%) experienced a pulmonary emboli

J UROL 2015;193:832-38

Possible Mechanisms

• Tumor self-seeding

• CTCs are the intermediaries between primary tumors and metastases, and that CTCs return to, and grow in, the primary tumor sites from their derived metastases

• Tumor microenvironment which has been suggested to be a source of continued androgen production potentially driving the tumor

Shaw YH. Eur Urol 2014;65;693-700.Negri-Cesi P. J Steroid Biochem Mol Biol 1994;51:89-96.

Morbidity of Surgery

Faiena I. Int J Onco 2014;45;2193-98

Surgery in T3 a-b provided the same outcomes as in the more localized diseases.

Advanced disease

106 casesRetrospective study

EUR UROL 2015

106 cases

Functional outcomes were a significant consideration with 64% pad free and18.6% requiring > 2 pads at1year.

Current data Robotic prostatectomy

•Bleeding 200-300 mL (Robot)

•Recovery 48-72 hours

•Continence > 95%

•ED 60-70 %

•Stricture: rare

Ongoing Randomized Trials

•UK based trial (TRoMbone) randomised oligometastasis disease to RP and look for OS.

•Multicenter study

•ADT + RP v ADTTesting RP in men with prostate cancer and OM to the bone1-3 skeletal, 6 months measurement.

•Impact of RP as primary Tx in CAP pt with limited bone metastasis (g-RAMPP)

•1-5 bone metastasis of CAP

•ADT + RP or ADT alone

•Outcome: CSS at 5 years (end 2025)

US study (MD Anderson randomized trial)

Bayne CE. EUR UROL 2015;XXX

Conclusions

It has been significant changes in the treatment of PCa over the past 10 years.

We dismiss local therapy in advanced disease but now we pursue surgical therapy in locally advanced disease.

Conclusions

We should realise the potential effect of local treatment in metastatic disease.

We should further expand the urologist’s role in the multidisciplinary treatment of locally advanced and advanced prostate cancer.

Thank You for Your Attention