Prostate Cancer Lecture: Diagnosis, Staging & Treatment - PDF

Nephrology and Urology Prof. Buffi – Urology – Lesson 02 Prostate cancer 29/10/2024 – group #40 (Maria Zozzaro-Carmela Ierardi) Clinical case discussion: 1. The patient is 60 years old, he's not a s...

Nephrology and Urology Prof. Buffi – Urology – Lesson 02 Prostate cancer 29/10/2024 – group #40 (Maria Zozzaro-Carmela Ierardi) Clinical case discussion: 1. The patient is 60 years old, he's not a smoker, he doesn't have significant comorbidities. At the digital rectal examination, no suspicious nodules were detected (tells the t staging of tumor). He doesn’t have familiarity with prostate cancer. It has an intermediate-risk tumor because: How to proceed: - The first thing to do is to test PSA levels; in this case, it is 10.8 ng/ml. you would recommend it because he is older than 60 years old. - The second step would be imaging testing (image): a traditional US would not be accurate enough to detect prostate cancer, so a (multiparametric) mpMRI is recommended (discussed later). From the imaging results, the prostate seems a little enlarged (mpMRI: volume 44ml, PIRADS 4), and a suspicious lesion is detected. - Next a biopsy is needed for histological confirmation. Small specimens are collected, the pathologist assesses that it's a carcinoma of the prostate. The grade is 4+3, or 3 with the ISUP grading system. (discussed later) - Staging is next. We need to check if the cancer is in situ or if it has spreaded already. Clinical N (lymph nodes) and M (metastasis) staging is required. A CT scan of the abdomen and a bone scintigraphy is necessary; for our patient they both come out negative. - The recommended treatment in this case is radical prostatectomy and radiotherapy, as the patient is young and has no comorbidities. 2. The patient is 48 years old; he is not a smoker, he doesn’t have significant comorbidities. He has familiarity with prostate cancer (father), the DRE is negative, and you would recommend testing PSA based on the guidelines, so to start the screening of PCa. 1 Prostate cancer – epidemiology PCa is really common so it is important to have some knowledge. Prostate cancer is the second most common type of cancer in males (only) worldwide, most common malignancy of males. - Incidence -> number of people which get affected by the disease in a short period of time taken in consideration, usually one year, so they are the new cases. Its incidence is pretty high, around 29% - Prevalence -> in this exact moment how many cases you have, usually higher if it is uncurable or if you have a low mortality rate. In this case is lower because the cancer can be cured in a high number of cases. (in the graph: in blue incidence, in red mortality). In Europe, in the USA and in the Western world is the most common solid neoplasm. On the other hand, especially in Asia, is not the first ontological concern, others are more common. That's why worldwide it is the second most commonly diagnosed cancer in males. It’s a good case study meaning you have a large temporal window to see how it is changed across the years, also with the discovery of the PSA agent in the 90’. So, the incidence of PCa has changed a lot thanks to the increasing use of TURP and PSA screening. TURP: is a type of endoscopic surgery to remove the inner part of the prostate, and it's a common treatment for benign prostatic hyperplasia. PSA testing: PSA is a protein that is prostate-specific. After this, there was then an issue of overdiagnosis of this disease. Doctors preferred to diagnose only patients with symptoms or metastasis. For this reason, PSA testing is not done on every patient. So, when you have markers you have to be careful in order to use them to make the right diagnosis. Prostate cancer has a low mortality rate, usually is an indolent cancer so is not really aggressive, and it doesn’t affect the life expectancy of the patient. Mortality burden is still high, but mortality rate is lower. 2  The survival rate of this disease is very high, it is at 89% from 5 to 10 years, if the disease is localized the mortality is almost 0. As we already said, incidence rises with PSA screening. Mortality went up as well, but this is probably because patients who died for other causes and tested positive for prostate cancer were included in the study. With surgical therapy and chemotherapy mortality decreased. In the last decades the mortality went down a lot thanks to improvements in terms of treatments. Prostate cancer - Risk factors The most important risk factors for prostate cancer are: - Age -> older than 60, while around 50 is a bit weird so we would need to check - Familiarity-> if you have one first line relatives has prostate cancer, the risk of having the cancer is double, if two or more first-line relatives are affected, the risk increases by 5-11- fold - Ethnic origin->African descendants in particular, extremely well studied in the US populations of African descendants. Genetic mutations: Mutations in particular in BRCA (breast cancer gene) and ATM genes are associated with a higher chance of contracting the disease and also with a more aggressive cancer. This is important for early diagnosis, for treatments. As a general rule, diet and lifestyle are not real risk factors due to not having enough data to prove this. So, lots of low-level evidence. Take home messages: - Incidence: high incidence, most incident tumors in males in our years in Europe and in the US. - Mortality: rate is pretty low while mortality burden is high cause we have lots of cases. - Risk factors: age, ethnicity and family history. Prostate cancer – early detection and screening Prostate- specific antigen (PSA) PSA is a protein, an antigen specific for prostate and is a tumor marker for this tumor. 3 It is a member of the kallikrein-related peptidase family and is secreted by the epithelial cells of the prostate gland. PSA is produced by the ejaculate, where it liquefies semen in the seminal coagulum and allows the sperm to swim freely. Is an organ-specific marker but it is not disease-specific, not tumor-specific. It can be increased physiologically because of enlargement of the prostate during the patient's life (this is why it's important the PSA density, to relate PSA levels to the prostate’s size) or also because of trauma, prostatitis, or inflammation. The specificity of the PSA is not high because the tumor is not the only reason why the PSA can be high. Generally, the normal threshold for PSA levels is 4 ng/mL. We can have some types of tumors, named high-grade differentiated tumor, which can present with low level of PSA, but they are quite rare. In order to improve the diagnosis, we have other markers that we can use: Free and Total PSA. PSA RATIO: The ratio between the 2 values which can be of some help. If the total PSA level is between 4 and 10 ng/ml, also free PSA needs to be tested. If the PSA ratio is higher or around 30%, it's probably the case of a benign condition, such as enlargement or inflammation. If the value is lower than 10%, it might be the case of a tumor. Between 10 and 20% the test is not conclusive. This is due to the fact that an enlarged but overall healthy prostate produces more free PSA then normal, while tumors produce PSA in an irregular manner and in higher quantities both bounded and free as the basal membrane is disrupted. Keep in mind that the reliability of this test is pretty low. PSA density: ratio between the total PSA and the volume of the prostate. It is useful in cases in which imaging testing as MRI came out not very conclusive. If the PSA density value is high, this would indicate a small gland with high PSA. The higher the density, the higher the possibility of the tumor, because if the density value is low, it means the gland is big and that is why it is producing more PSA. About the additional tests mentioned, in the scheme below, FDA approved only two of these tests, while in Europe they are not commonly used. They are not fully approved so are not used routinely. 4 ERSPC Study: This study showed the importance of PSA screening in a randomized fashion in European males across 60 years. With increased PSA screening, the mortality decreased. A standard screening for PSA is not recommended for detecting PCa: using a standard screening shows higher diagnosis of the tumor but no benefits of the overall survival. That's why PSA screening is not implemented in the health care system. Randomized screening of PSA is associated with increased diagnosis (incidence) of PCa. This is not in the guidelines yet, as some studies show controversial results. The mortality specific to the disease and overall survival does not seem to decrease radically. To sum up the ERSPC Study findings: - Screening is associated with an increased diagnosis of PCa (Incidence ratio [IR]: 1.23 95% CI: 1.03–1.48). - Screening is associated with detection of more localized disease (RR: 1.39, [1.09–1.79]) and less advanced PCa (T3–4, N1, M1; RR: 0.85 [0.72–0.99]). - No PCa-specific survival benefit was observed (IR: 0.96 [0.85–1.08]). This was the main endpoint in all trials. No benefit found in terms of survival so the standard screening for cancer was not approved. - No overall survival (OS) benefit was observed (IR: 0.99, 95% CI: 0.98–1.01). None of the trials were designed/powered for this endpoint. So PCa screening remains one of the most controversial topics. 5 Early detection and screening: Important things to remember: - In patients with no risk factors, PSA levels are tested in men older than 50. - Avoid an excessive testing of PSA - If there are familiarity or ethnicity-related risk factors, PSA testing starts at 45. - With BRCA mutations, testing should start at 40 years of age. - If the levels are normal, the test is to be repeated up to 8 years after the first one. - In asymptomatic patients that have a life expectancy of less than 10 years there is no need for PSA levels screening. The reason for this is that this type of cancer is quite indolent, and these patients would not die because of it. Prostate cancer - Diagnosis and staging: - Localized prostate cancer -> most common, usually asymptomatic - Metastatic prostate cancer -> less common, more likely to have symptoms. Its definitive diagnosis depends on the histopathologic verification of adenocarcinoma in prostate biopsy cores or operative specimens. Symptoms are very rare. If present: - local or bone pain - bleeding - hematuria - kidney injury - erectile disfunction - lower limbs edema - lower unitary tract symptoms (LUTS) - obstruction: for example, due to enlargement of the gland around the urethra -even if usually cancer grows in the peripheral zone, so outside the prostate, so it doesn't usually give 6  obstructive symptoms, unless in a very advanced stage. On the other end, benign hyperplasia usually develops in the inner part around the urethra, causing obstruction. These symptoms usually are present in locally advanced or metastatic prostate cancer. The typical patient: test with PSA, you do the screening, is asymptomatic. If a patient presents with back pain and a PSA of 100 is probably metastatic. Digital rectal examination is the first step in diagnosis -primary diagnosis/major marker in urology, as it's very simple and inexpensive. The accuracy of this exam is low and limited, both in matter of sensitivity and specificity (definitions: specificity refers to the number of patients that with a negative digital rectal examination are not actually affected by the disease, sensitivity meaning how many true positive diagnoses are done with this test being positive). Also, with this test you evaluate just one surface of the prostate, the posterior peripheral zone (in contact with the rectum, surrounding the whole gland). This is the main area where the tumor develop, then in the transition zone which cannot bet sensed through the DRE and then in the central zone. The first portion of urethra is in the middle of the prostate. It shouldn't be painful, but it can cause discomfort, if you feel pain it may be due to inflammation. It tells the size, the consistency and uniformity (regular or not) of the prostate, and look for nodules. In 18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level. The DRE is considered insensitive for detecting extracapsular tumor extension. At least 40% of patients with cancers judged to be clinically confined by DRE are found to have extraprostatic extension at surgery. If you feel that the tumor is extra capsular and feel it with the fingers, it is extremely specific and say that there is extra capsular extended. Prostate cancer - Imaging techniques - Traditional transrectal US (TRUS) -> inaccurate, low sensitivity, non specific and cannot be used for diagnosis of PCa but it is used for US guided biopsy. It gives information about the side of the prostate. It helps to find the margin of prostate but not the nodules. The ability of TRUS to predict ECE varies from 37 to 83% and is limited by relatively low spatial resolution. TRUS is equal to DRE in assigning a T stage. - Standard Extended Sextant Randomized biopsy -> randomly sample the area of the prostate and by doing that you hope you can find the tumor. This technique is preferred (also called systematic) but not common nowadays. 7  - mpMRI imaging and High-resolution-micro-ultrasound (microUS)-> more accurate. They have been implemented in the last few years. mpMRI is used with different parameters and with it the percentage of tumor in the prostate can be assessed and is recommended to all the patients before the biopsy, in order to have an image of the tumor. For the prostate having a good imaging was always very hard so now the MRI allow to have a better vision of the pathology. It was providing advantages in tumor detection, so we do MRI before the biopsy. mpMRI can be used both for initial risk assessment and to improve detection rates through targeted biopsy. It has many functions: 1. T2-Weighted MRI: High sensitivity; tumor as hypointense area. 2. Diffusion-weighted Imaging (DWI): Measures water movement (reduced in cancers). 3. Dynamic Contrast-Enhanced Imaging: Measures neoplastic angiogenesis. With MRI they compare and combine all the different images in order to have a likelihood of the presence of the tumor, using PI-rads systems (prostate imaging-reporting and data system). Overall, the number of cases of prostate cancer that are not visible, not even with this type of imaging, is quite high. That's why even if a lesion is visible on the MRI a systematic biopsy (usually 12 samples) of the whole gland is needed, not one of the lesions only -targeted. 8  If the patient is biopsy-naive, meaning he was never tested with a biopsy, a systematic biopsy is done in any case. In case of a prior negative biopsy, if the practitioner still suspects PCa, a targeted biopsy can be done. - Micro-ultrasound –> relatively new, resolution is much higher (29 MHz compared to the 6- 9 MHz of the ultrasound), and consequently, the prostate can be investigated much better, so it can provide high quality images. PRI-MUS score is similar to the PI-RADS of the MRI as they validate a 5-point risk scale according to the likelyhood of having a prostate cancer. PSA density testing Especially in cases of PI-RADS (Prostate Imaging–Reporting and Data System) 3 or 4 (see table), so when the presence of the tumor is in doubt, PSA density (PSA-D, total amount of PSA on the volume of the prostate) is tested. As said before, if its value is high, then it's probably the case of a tumor. The PSA-D score is a continuous value as its a ratio. A prostate-specific antigen density (PSAd) cutoff of 0.15 ng/ml/cc is a commonly recommended threshold to identify patients with negative prostate magnetic resonance imaging (MRI) who should proceed to a prostate biopsy. Depending on the results, a biopsy can be taken into consideration. Summary: -PSA levels are not checked if the patient presents no risk factors. 9 -MRI is not recommended as an initial screening tool as it is not accurate, it's expensive and time- consuming. When PCa is suspected, then MRI imaging is used. -According to the guidelines, since 2018, MRI comes before biopsy testing when PCa is suspected. Transrectal vs transperineal biopsy 1. Transrectal biopsy -> most common, needle is going through the rectal mucosa towards the prostate. We use an ultrasound probe as it’s important to observe the boundaries of the prostate. Then the needle is inserted in the rectum and inside the prostate (after localized anesthesia). The problem with this biopsy is that there is a higher risk of infections, but it is still very used even though, according to the guidelines, you should use the transperineal approach. 2. Transperineal biopsy -> you pass through the perineum (through the skin), and the main advantage is that it’s a cleaner way than the rectum in the transrectal biopsy. Thanks to mpMRI, you can do a targeted biopsy. You can perform it in many ways: one is cognitive fusion, and a more sophisticated way is the software that is going to overlap in real-time, the images of previous MRI with the real-time imaging from the ultrasound. Prostate cancer - Pathology - Adenocarcinoma of the prostate is the most common 95% - of course after biopsy we need a grading classification - Urothelial carcinoma (because we have urethra inside the prostate) 5% - Mesenchymal tumors 0.1-0.2%--> like rhabdomyosarcomas Tumor inside the prostate can originate by other cell types than the gland itself. Gleason score – scoring system of the prostate It is the methodology for grading prostate cancer and gives you 2 numbers: one is for the most represented/extensive pattern (dominant) and the second for the next most represented/frequente pattern. Each number can be from 3 to 5; less than 3 is not considered a tumor. The lowest grade is 3+3 which equals Gleason score 6. You may also have a 3+4 that it’s better than 4+3 which indicates a more aggressive tumor. 5 is the highest group, so for example, if we have 4+5, it means that we have a very high-grade disease/ risk. 10 Grading is a strong predictor of aggressiveness of the disease. Biopsy Gleason score correlates with the extent of the disease. One issue present with this grading can be that, for example, if you have Gleason 7, you may have 3+4 or 4+3 which are different, so it’s less informative regarding the type of the disease. That is why we now use the ISUP (International Society of Urologic Pathologists) grading system, which derives from the Gleason score and goes from 1 to 5 (for example, if you have 3+3 it’s grade 1). The grade of the tumor is strongly correlated with prognosis of prostate cancer, with significant outcomes, so the recurrent survival and cancer-specific deaths. This table shows how to convert the Gleason (a little confusion for the patient) score into the ISUP (different grading) In the last few years, there has been a discussion of whether ISUP grade 1 or GS 6 (3+3) should be called cancer or not. In all the report that you will see you will find both cause the Gleason score is really common, so it is hard to cut it off from practice. GS 6 is a low-grade tumor, indolent cancer, so it doesn't have any metastatic potential. However, they have the hallmarks of cancer, and pathologists agree that it is cancer. If we don't call it “cancer,” we can risk missing future possible signs of metastasis in patients. In the end, we still call it cancer, but it’s clear that we need to focus on the clinically significant cancers, which means to focus on cancers that are actually going to affect the patient. There is no univocal consensus on the definition of clinically significant cancer. The common definition used for this type of cancer is ISUP grade 2 and above. 11  This is the table where you can see the risks of having cancer according to age and PSA level. All the images are developed in terms of clinical use in order to identify from ISUP 2 and above and not the Gleason 6, so they are calibrated to find just those type of cancers. PSA doesn’t have a cut off value, so you have to consider the density, the age of the patient and everything, so the value depends on different things there is not a normal one for everyone. The highest the PSA, the highest the risk of having the tumor. Low risk tumor risk to undergo overtreatment. All the diagnostic pathways have been developed to find out the high-risk prostate cancer and not the lower risk tumor. Diagnosis pathway in PCa 1. Medical history and physical examination 2. PSA testing (it is recommended to test for UTI with the dipstick test, given that a high PSA could also mean an infection of the urinary tract) 3. Imaging: MRI and ultrasound (also additional test and stratification tolls in order to better stratify the patient and the risk of the patient to have a prostate cancer) 4. Biopsy (find a confirmation to what has appeared previously with the imaging) 5. Tumor (histological) diagnosis and grade Staging The stage generally takes into account the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes it has spread to (if any), and whether it has appeared in more distant locations (metastasized). 12 Types of staging Clinical: assessment of disease extent using pretreatment parameters (DRE, PSA, needle biopsy findings, and radiologic imaging). Pathological: determined after prostate removal and involves histologic analysis of the prostate, seminal vesicles, and pelvic lymph nodes if lymphadenectomy is performed. Therfore, clinical staging is done before having a histological confirmation (also for the metastasis). For example, if you do the imaging and you have a suspicion of involvement of the lymph nodes, you can say that the patient is clinically N positive, meaning that you tested them before surgery. You can have the staging for the primary tumor (T), regional pelvic lymph nodes (N) and distant metastasis (M). The staging changes for every type of tumor; the overall staging of the tumor is the combination of T, N and M stagings. Metastatic condition is associated to the highest staging grade. T-staging T-staging is clinical because it is done with clinical tools. In fact, the T-staging of PCa is based on DRE (digital rectal examination), which is not accurated a lot but is still widely used, and prebiopsy imaging, such as MRI and microUS. Ț1 tumor: no palpable tumor, but still findable on biopsy. If it is found by needle biopsy it is a T1c, while if it is found by chance is a T1a or T1 b depending on the extension. T2 tumor: palpable tumor which is confined within the prostate. T3 tumor: tumor extends palpably through the prostatic capsule. If it has an extracapsular extension (unilateral or bilateral) is a T3a tumore, while if the tumor invades seminal vesicles is T3b tumor. T4 tumor: tumor is fixed or invades adjacent structures other than seminal vescicles, such as the external spinchter, the rectum, the levator muscles and/or the pelvic wall. 13 N-staging N-staging is the staging of the lymphonodes. We may have a pathological and clinical N (PN and CN). NX tumor: regional (pelvic) lymph nodes cannot be assessed. N0 tumor: no regional lymph node metastasis. N1 tumor: regional lymph node metastasis. Clinical N-staging MRI to assess lymph nodes Abdominal CT scan PET-CT a) Choline PET/CT scan has some limitations in the usage: its sensitivity singes between 0 and 100% and it is limited by an intrinsic spatial resolution of about 5 mm and for this reason it might miss potential micro-metastases. It was quite popular in Italy for a couple of years, but we no longer use it. It was used for assessing both visceral and bone metastasis. b) PET PSMA, which is a membrane antigen of the prostate overexpressed by the tumor, is a new approach used in PCa imaging. Standard exams are CT and bone scans nowadays, but lots of studies show that PSMA is a more specific marker thanks to its nuclear imaging methodology, more accurate than conventional imaging and can show us more often distal small metastasis and nodes. If the patient has a recurrence, the PSMA is more accurate and specific in finding the recurrence. o PSA < 0,5 ng/mL: multidisciplinary discussion o PSA = 0,5 – 2 ng/mL: 68Ga-PSMA o PSA > 2 ng/mL and negative 11C-18F-choline PET/CT: 68Ga-PSMA The most accurate method for staging the lymph nodes involvement is lymphadenectomy (removal of the lymphonodes), which is also called ePLND (extended pelvic lymph nodes dissection). 14 If you can assess the presence of the PCa ePLND0 it means that there is no metastasis, on the other hand ePLND1 suggests that lymph nodes are involved. ePLND includes the removal of the external iliac, internal iliac and obturator lymph nodes, you can also reach the common and perisacral lymph nodes. M-staging M0 tumor: no distant metastasis. M1 tumor: distant metastasis. a) M1a: non regional lymph node(s) b) M1b: bone(s) c) M1c: other site(s) Clinical M-staging Bone scintigraphy: sensitive (79%) and specific (82%) method for the detection of bone metastases. The axial skeleton is involved in 85% of patients with mPCa. PSMA PET/CT: most accurate method for staging. For both the N and the M staging the traditional staging goes through bone scan (distant metastases) and abdominopelvic CT (lymph nodes); the current staging goes through PSMA PET/CT. You can use the PSMA to investigate the tumor, so it is investigational. You can use it, for example, in an intermediate-high risk patient, with a tumor thought to be localized. Unfortunately, we don’t have the data on the impact of the PSMA on the clinical outcome, for now we don’t know how to use this information well, so we need to use it carefully. In most of the tumors, you combine TNM information, while for prostate and testis, you take in consideration other things, such as the PSA level (before biopsy) and the grade group and then you can have low-risk, intermediate-risk and high-risk tumors. If you have a low-risk tumor you should not do anything else in terms of staging. Summary of the European guidelines about what should be done in terms of staging. 15 Risk group EAU risk groups for biochemical recurrence of localised and locally advanced prostate cancer. Treatment Two types of tumors to be treated: 1. Clinically localized PCa (the most common) 2. Metastatic PCa If you find a tumor in a patient whose life expectancy is less than 10 years, you should not do anything. If the patient develops symptoms of metastasis, he should be treated with systemic therapy, usually anti-androgen therapy. In patients older than 80 you are not going to do anything if they do not have symptoms. 1. CLINICALLY LOCALIZED PCa The therapeutic options for a patient are: Active surveillance Radical prostatectomy External beam radiotherapy/brachytherapy Focal therapy 16 The first 3 are gold standard options in different categories, while the last one is more investigational. Low-risk patients: active surveillance is required, if the patients have a life expectancy of at least 10 years. Active surveillance aims to avoid unnecessary treatment in men with clinically localized prostate cancer who do not require immediate treatment. It implies a follow-up of the patient, check of the PSA, MRI and biopsy every year. If the patient is well followed by the doctor, active surveillance has a very good outcome. Be sure you’re going to find an early development of the tumor if the tumor is progressive. Watchful waiting is, instead, a conservative management for patients deemed unsuitable for curative treatment right from the outset. In the ProtecT study, after 15 years of follow-up, prostate cancer–specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. Tumor is indolent (it grows slowly) so you have to do a follow-up of the patient, because it may develop in a higher-grade tumor. Intermediate-risk patients: radical prostatectomy and external beam radiotherapy/brachytherapy are 2 gold standard treatments in terms of oncological outcomes. Some patients with intermediate-low risk grade can be managed just with active surveillance, but most of them are going to be treated with RP and EBR. In some cases, also whole gland or focal ablative therapy can be done. High-risk patients with localized tumor: patients with extended lymph dissection but have no evidence of positive nodes. Radical prostatectomy and ePLND are racommended, together with a radiotherapeutic treatment. High-risk patients with advanced tumor: radical prostatectomy and ePLND are racommended, together with a radiotherapeutic treatment. In this case, radiotherapy should be used more than 17 surgery and always in a multimodal setting. The outcomes of survival are pretty good; in intermediate high-risk patients there is a survival of 90%, in locally advanced disease is a little bit lower. Radical prostatectomy The aim is the removal of the whole gland and seminal vesicles, while preserving the pelvic organ function: urinary continence and potency. Indeed, the prostate is in an area important for continence and potency (erectile function) so we need to be as delicate as possible with surrounding structures to provide better outcomes which can be oncological, functional and pathological (no positive surgical margin). If the risk of lymph invasion is higher than 5-7% you should also do a lymphadenectomy (external and internal iliac, obturator nodes) mainly though robotic intervention. Extended LND includes the removal of the nodes overlying the external iliac artery and vein, the nodes within the obturator fossa located cranially and caudally to the obturator nerve, and the nodes medial and lateral to the internal iliac artery. You have a pathologic state of the nodes. With this template, 94% of patients are correctly staged. Summary In radical prostatectomy the most impactful outcomes are medium-long term. We have 3 surgical approaches: open, conventional laparoscopy and robot-assisted laparoscopy In conventional laparoscopy, you do small cuts instead of a big one and you have a camera that can show you what is happening inside the patient. In robotic laparoscopy, the surgeon controls the robot that operates on the patient and can even be far away from the patient. Nowadays most prostatectomies are done with robots. 18  In Humanitas we use the da Vinci. (no need to know all the different types). Prostatectomy outcomes Perioperative outcomes: how much is the blood loss, duration of the surgery, duration of the stay in hospital, how long the patient keeps the catheter. Pathological Oncological: removal of the tumor, most important, so oncological outcomes are excellent. Functional: potency and continence recovery. Robot-assisted surgeries showed to have a better outcome than laparoctomy, but there are no high- quality studies that suggest that the preservation of abdominal organs is better with robotic approach. Indeed, they reduce admission times, blood loss, have a lower perioperative morbidity, and a reduced risk of positive surgical margins compared with laparoscopic prostatectomy. You want to preserve the sphinchter and the neuromuscular bundles as much as possible. The final stage of the surgery consists in the connection between the urethra and the bladder. He said to read from slide 111 to 115. Persistent PSA after RP: after treatment you want PSA to be zero because you have removed the prostate. If the PSA is rising, we are talking about biochemical recurrence (have biochemical evidence by lab testing that there is a recurrence). You have clinical recurrence if the imaging confirms the recurrence and when the PSA is higher than 0.2. If the PSA remains higher than 0.1 after the surgery, you have a PSA persistence. External beam radiation therapy/brachytherapy – standard treatment Brachytherapy is a form of radiotherapy where you are going to permanently implant small radioactive seeds inside the prostate in order to do radiotherapy of the prostate using these seeds. 19 Side effects are mainly gastrointestinal and urinary side effects like dysuria and bowel problems, also radiation proctitis, secondary tumors etc. Low-dose rate brachytherapy uses radioactive seeds permanently implanted into the prostate. High-dose rate (HDR) brachytherapy uses a radioactive source temporarily introduced into the prostate to deliver radiation. Offer low-dose rate brachytherapy to patients with low-risk PCa, without a previous transurethral resection of the prostate, with a good International Prostatic Symptom Score and a prostate volume < 50 mL. Low-dose rate brachytherapy can be combined with EBRT in intermediate-/high-risk patients. Focal therapy Focal therapy treats only an area of the prostate and that is a problem because usually prostate cancer is multifocal. If the tumor is intermediate-low risk (do a surgery or radiotherapy is too much), you can just do focal therapy. Focal therapy regained lots of popularity in the last years thanks to the MRI (that shows the target, the index lesion) and so you can target the tumor more specifically. Targeted treatment of the index lesion alone may provide acceptable oncological outcomes in patients with low-intermediate risk PCa. Focal therapy relies on the concept that residual PCa in the untreated area does not compromise long- term disease control. 20 We can use cryoablation, high-intensity focused ultrasound, laser, ecc Before widespread clinical introduction, clear, predefined, clinically relevant objectives are needed, such as a negative biopsy, OS, disease- specific survival and toxicity, as well as optimal follow-up schedules. If long-term benefit is proved (functional and/or oncological), FT would represent significant progress in PCa care. However, thus far, FT must be considered an investigational modality only. 2. METASTATIC PCa Treatment is based on hormone therapy, an androgen deprivation therapy so you chemically castrate the patient to reduce testosterone and so try to stop the cancer growth. If the patient has a metastasis, treatment of the primary tumor is done only in case of symptoms as there is not really a treatment for the primary tumor, so the main aim is to relieve the symptoms. Main treatment is the anti-androgen therapy, because at the beginning the tumor is androgen sensitive so if you remove the “androgen driver” the tumor growth slows down. You cannot cure the patient, but you can prevent tumor progression. In the past they used to do surgical castration (remove testis), now we do pharmacological castration. LHRH Agonists LHRH Antagonists Anti-androgens Other treatments involve: Chemotherapy: docetaxel, cabazitaxel, (mitoxantrone) Targeted Therapy: PARP Inhibitors, Radium-223 Immunotherapy: sipuleucel-T, (checkpoint Inhibitors - under investigation) 21 Supportive care and bone-modifying agents are used as coadiuvant. Hormonal treatment in M+ patients recommendations Offer immediate systemic treatment with androgen deprivation therapy (ADT) to palliate symptoms and reduce the risk for potentially serious sequelae of advanced disease (spinal cord compression, pathological fractures, ureteral obstruction) to M1 symptomatic patients. Do not offer ADT monotherapy to patients whose first presentation is M1 disease if they have no contraindications for combination therapy and have a sufficient life expectancy to benefit from combination therapy (≥ 1 year) and are willing to accept the increased risk of side effects. Castration-resistant PCa Definition of Castration-resistant PCa. Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either: a) Biochemical progression: three consecutive rises in PSA at least one week apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL. b) Radiological progression: the appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumours). Symptomatic progression alone must be questioned and subject to further investigation. It is not sufficient to diagnose CRPC. 22