PROSTATE CANCER (PCa) - PDF Free Download

PROSTATE CANCER (PCa) Tomasz Drewa Department of Urology, Collegium Medicum, UMK

? PCa = 11/6/16 PCa

Urology, 1995 11/6/16

PSA increase Natural history of prostate cancer patient Testosterone Deprywacja deprivation androgenowa Chemoterapy Chemioterapia Terapia Local miejscowa treatment Diagnosis Asymptomatic Nonmetastatic Low T Sensitive (T deprivation) Symptomatic Metastatic Resistant for Low T Death Śmierć

At the moment of dignosis prostate cancer represents different stages of tumor growth and oncological potential

According to the EBM only two local treatment are able to cure prostate cancer patient: 1) Radical Prostatectomy (RP) (prostate and local lymph nodes excision) or 2) External Beam Radiation Therapy (EBRT) combined with chemical castration (androgen deprivation)

2015

A B C D The curves represent biochemical relapses after RP and EBRT for all patients (A), low risk patients (B), intermediate risk (C) and high risk patinets (D).

A B C D The curves represent survival after RP and EBRT for all patients (A), low risk patients (B), intermediate risk (C) and high risk patinets (D).

Natural history of prostate cancer patient PSA increase Biochemical Relapse Testosterone Deprywacja deprivation androgenowa Survival Chemoterapy Chemioterapia Terapia Local miejscowa treatment Diagnosis Asymptomatic Nonmetastatic Low T Sensitive (T deprivation) Symptomatic Metastatic Resistant for Low T Death Śmierć

2014

2014 Radical Prostatectomy External beam radiation therapy The curves represent cancer dependent mortality for radical prostatectomy and external beam radiation therapy (34 515 patients).

2014 Benefit of Radiotherapy Benefit of Surgery Hazard ratio for cancer dependent mortality in patinets risk subgroups treated with Radiotherapy or Surgery subdivided in age and Charlsona comorbidity index groups (34 515 patients)

Overall survival for patients treated with Radical Prostatectomy (RP) Intensive Modulated Radiation Therapy (IMRT)

Mortality from other causes according to the treatment Radical Prostatectomy (RP) Intensive Modulated Radiation Therapy (IMRT)

Cancer specific survival to 7 years according to risk grups Radical Prostatectomy (RP) Intensive Modulated Radiation Therapy (IMRT)

Biochemical Disease free survival at 3 years according to risk grups Radical Prostatectomy (RP) Intensive Modulated Radiation Therapy (IMRT)

Hazard ratio for overall mortality in patinets treated with Radiotherapy or Surgery

Hazard ratio for cancer specific mortality in patinets treated with Radiotherapy or Surgery

Radical prostatectomy should be the first choice treatment in young patients suffering from prostate cancer, but why? 1) Aspect of prostate biopsy 2) Aspect of circulating cancer cells 3) Aspect of possible multimodal treatment

Prostate biopsy has limited and reduced possibilities in discovering the total nature of prostate cancer

Metastatic lesions orygin from circulating tumor (cancer) cells CTC. This first source of CTC is the prostate and then metastatses realase CTC. Prostate with Cancer EMT Metastatic leasion MET Viens and lymphatic vessels 11/6/16 EMT

Cancer cell can represent epithalial or mesechymal morphology. CTC are mesenchymal-like looking cells 11/6/16

Counting the CTCs is the keypoint to understand of prostate cancer dissemination and therapy failure

Prostate cancer CTCs

Number of CTCs correlated with prostate cancer agressivness and number of micrometastases

Prostate cancer patients survival curves correlate to CTCs number and PSA level Danila D C et al. Clin Cancer Res 2011;17:3903-3912

Aspect of possible multimodal treatment: 1) Radiation therapy can be offered after radical prostatectomy 2) Radical prostatectomy after radical radiation is very risky procedure (incontinence, fistulas, bowel complications) 3) Chemical castration is always added to radiotherapy (mental disordes - depression, osteoporosis, obesity) 4) Chemical catration eliminates PSA as a relible marker, PSA decrease after surgery is observed after 1 month to the level of 0,01 and lower, but after radiation therpy PSA is decreasing during the first two years, so it is difficult to plan additional treatment during this period of time

Does prostate cancer patient deserve systematic treatment? Hormonal therapy only? Chemotherapy? Chemotherapy combined with hormonal therapy?

Androgen (receptor for Testosterone) receptor (AR) is not only receptor but it is transcriptional factor, as well! The production of PSA is a proof that AR works, even in low Testosterone environment! T T T PSA T? T AR-P 11/6/16 PSA

Castration (decreasing the Testosterone level) inhbits Androgen Receptor activity, which resulted in PSA progression < 20ng/ml 20-50ng/ml > 50ng/ml 11/6/16 Lepor i Shore 2012

Castartion sensetises AR and increase its expression, which resulted in undependence of castration levels of Testosterone. Cancer cells start to divide very quickly and without additional chemotherapy patient will die in a short period of time. 11/6/16 Green i wsp. 2012 Koochekpour, 2010

Prostate cancer is a hormone dependent tumor, but it is composed of cells showing different sensitivity to testosterone

Prostate cancer is a hormone dependent tumor, but it is composed of cells showing different sensitivity to testosterone Matured epithelium Stem cell layer Basal membrane Fibroblasts, Myoblasts Matured epithelium sensitive to Testosterone, possible hormonal treatment and manipulations Stem cell layer unsensitive to Testosterone, unpossible hormonal treatment Fibroblasts, Myoblasts sensitive to Testosterone but unpossible hormonal treatment and manipulations 11/6/16 Wang i wsp, 2006, Wu i wsp., 2011

Prostate cancer is a hormone dependent tumor, but it is composed of cells showing different sensitivity to testosterone 1 2 AR 11/6/16

CTCs which express lower sensitivity to Testosterone are responsible for prostate cancer dissemination, so in many circumstances hormonal therapy shoud combined with chemotherapy.

Take home messages 1. Overall survival and survival related to cancer is better for patients treated with surgery than radiation therapy. This trend is exreamly strong for high risk patients. 2. Radical prostatectomy should be offered younger patients, specialy dedicated to patients with expected survival longer then 10 years. 3. Local clinical relapse after radical prostatectomy should be treated with additional radiation therapy for the prostatic bed. 4. Distant metstases (systemic relapse) should be treated with hormonal therapy (castration) combined with chemotherapy in selected patients.