div class=”ChapterContextInformation”>
35. Management of Localized and Locally Advanced Prostate Cancer
Keywords
Prostate cancerRadical prostatectomyLocalizedTreatmentActive surveillanceFocal treatmentRadiation therapyIntroduction
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer type, and the second and third leading cause of cancer death, among men in the United States and in Europe, respectively [1]. Based on risk group, preference and patient factors such as age and comorbidities, different treatment options are available for newly diagnosed PCa, which include active surveillance, radical prostatectomy, radiation treatment and focal therapy. The current chapter provides an overview of current management strategies for localized and locally advanced PCa.
Management of Localized Prostate Cancer
Active Surveillance
Despite misgivings and concerns at the time of its initial introduction [2], active surveillance (AS) for very low-risk (VLR) and low-risk (LR) prostate cancer (PCa) has become a guideline accepted standard of care. In contrast to watchful waiting, AS is defined as conservative management with periodic monitoring and selective delayed intervention with curative intent. With regular monitoring, AS enables appropriate re-classification and better patient selection for definitive treatment, such as radical prostatectomy and radiation therapy.
Active surveillance protocols may vary by institution, but most share the following features: confirmatory biopsy following initial prostate biopsy, serum PSA every 6–12 months, digital rectal exam at the time of clinic visits, serial repeat prostate biopsies every 1–3 years. Following an initial biopsy, a confirmatory biopsy within 6–12 months is recommended prior to enrollment onto AS as 20–30% of men are upgraded on repeat biopsy [3, 4]. Multiparametric magnetic resonance imaging (mpMRI) has been increasingly incorporated into the diagnostic pathways for prostate cancer and is now recommended prior to confirmatory biopsy and subsequent serial prostate biopsies in men on AS, having demonstrated the ability to identify clinically significant prostate cancer missed by standard prostate biopsy sampling [5, 6].
There have been five large prospective series evaluating AS [7–11]. While the inclusion criteria for these were variable, the majority of men met the following criteria: Gleason Grade Group 1 disease, clinical stage T1–2, PSA ≤10 ng/mL, and minimal core involvement (<1/3 cores and <50% each positive core). These resulted in 60–85% 5-year treatment-free survival and <1–5% prostate cancer specific mortality [12]. While there are no prospective studies specifically assessing AS, data from three randomized clinical trials comparing immediate definitive therapy to conservative management (active monitoring and watchful waiting) suggest that conservative management is a safe option for men with low-risk PCa [13–15]. In addition, large retrospective surgical series identified rates of metastasis approaching zero in men with confirmed Gleason 6 prostate cancer, demonstrating the indolent natural history of this disease [16, 17].
Based on the strength of this evidence, current international guidelines designate AS as the “preferred” management and standard of care for VLR and LR prostate cancer [18]. Despite this, uptake of AS remains moderate, hovering around 40% in patients with LR disease [19, 20]. Ultimately, the decision to proceed with AS is a shared decision with the patient, and options of definitive therapy should be offered. In some men, anxiety associated with living with untreated cancer may inform their decision to undergo treatment early, but they should be counseled regarding the significant complications and quality of life implications of definitive therapy.
As final caveats, it should be noted that while current research into the use of biomarkers may help safely expand AS to a selective population of men with intermediate risk prostate cancer, AS is not recommended for men with IR prostate cancer at this time. Furthermore, the integration of mpMRI with AS remains in evolution. It is not known or established how often mpMRI should be performed or whether patients with a negative mpMRI can safely avoid surveillance biopsies, recognizing a small false negative rate exists.
Radical Prostatectomy
Radical prostatectomy (RP) remains a standard of care for management of localized prostate cancer. The surgery includes removal of the entire prostate with its capsule and seminal vesicles. In contrast to other treatment options, RP offers pathologic evaluation of the true tumor grade and enables staging by pelvic lymph node dissection.
Outcomes of Radical Prostatectomy in Localized Prostate Cancer
In the Scandinavian Prostatic Cancer Group Study Number-4 (SPCG-4) 695 patients with clinically detected PCa were randomized to watchful waiting (WW) versus RP between 1989 and 1999 prior to the PSA era [21]. Long-term data (29 year follow-up) have just been reported and showed that at 23 years, a mean of 2.9 extra years of life were gained with RP compared with WW.
In the Prostate Cancer Intervention versus Observation Trial (PIVOT) 731 patients have been randomized to RP versus WW between 1994 and 2002 [15]. In contrast to the SPCG-4 trial, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation within a median follow-up of 12.7 years. A significant overall survival benefit for RP was only seen in patients with serum PSA > 10 ng/mL or high risk PCa (reduction in mortality of 33% and 31%, respectively). Main limitation of this study is the high overall mortality in the WW group (almost 50% at a median of 10 years).
To date, one randomized study, the Prostate Testing for Cancer and Treatment (ProtecT) trial, exists, which compared oncological outcomes of active monitoring, RP and radiation treatment after a median follow-up of 10 years [14]. Prostate cancer specific survival was at least 98.8% in all groups, and there were no significant differences in the three randomized groups (p = 0.48). Men in the group of active monitoring (approximately 40% with intermediate-risk PCa) had an increased risk of developing metastases. However, it has to be noted that active monitoring in the study was different from active surveillance. Active monitoring was based mainly on PSA alone without use of multiparametric MRI or regularly scheduled repeat biopsies.
The study included several further limitations. The study population consisted predominantly of low-risk patients (60% of patients had low-risk disease; 77% of patients had Gleason 6 PCa), which were eligible for Active Surveillance because of their low risk for progression. Furthermore, after a median follow-up of 10 years, prostate cancer mortality was very low at 1%. There were a total of 17 prostate cancer deaths. Thus, a mortality analysis at present is too early and conclusions should be made with caution. At the time of study initiation the assumption was for a mortality of 10% after a median follow-up of 10 years. In addition, definitive treatment of the included patients has not been performed according to current standards (radiotherapy: no intensity-modulated radiation therapy (IMRT), RP: 24% positive margins), which may have influenced the results.
While RP provides excellent oncological outcomes, it can cause severe side effects such as urinary incontinence and erectile dysfunction, which negatively affect Quality of life [14, 22–25]. Numerous population-based studies or randomized controlled trials reported worse urinary continence and erectile function rates for patients that underwent RP compared to patients who received primary radiation treatment or active surveillance [26–28]. Rate of urinary incontinence (use of any pad) was 26% for RP patients within the ProtecT study, and only 15% of the patients had erections firm enough for intercourse 1 year after RP [26]. Similarly, urinary incontinence rates were up to 43% and erectile dysfunction (defined as erections not hard enough for intercourse) rates were 80% in the SPCG-4 trial 12 months after RP [29]. However, functional outcomes in high-volume centers have been reported to be better [30]. Pompe et al. reported 12-, 24- and 36-months erectile function rates of 45%, 51% and 53%, which reached up to 66% in preoperatively potent patients with bilateral nerve sparing. Urinary continence rates were 89% and 91% at 12 and 24 months postoperatively [30].
Open Versus Robotic-Assisted Radical Prostatectomy
With the introduction of robotic-assisted techniques, the surgical management of prostate cancer has evolved. The uptake has varied by country, depending on cost, patient preference, insurance coverage, and healthcare system [31]. Numerous reports have been published assessing the safety of robotic-assisted RP (RARP) and its perioperative, functional and oncologic outcomes, as compared to open RP. RARP has generally been accepted to have lower estimated blood loss and shorter hospital stay [32, 33]. Lower incidence of bladder neck contractures or anastamotic strictures [34] and lower intraoperative complication rates [32] have been reported for RARP in some series. There is conflicting evidence regarding the effect of the robotic-assisted approach on functional outcomes and no reliable data on differences in oncologic outcomes.
Gershman et al. retrospectively evaluated patient-reported functional outcomes in men undergoing RARP or ORP by high-volume surgeons at two high-volume centers in the USA and did not find any differences in urinary or sexual function outcomes depending on surgical technique [35].
Ficarra and colleagues analyzed 51 articles reporting urinary continence outcomes, of which 9 compared RARP to open RP [36]. The authors showed a mean urinary continence rate (no pad or one safety pad) of 91% at 12 months, with continence rates superior in men undergoing RARP compared to open RP (OR 1.53; p = 0.03) [36]. In a separate systematic review and meta-analysis assessing potency, 15 case series were analyzed, in 6 comparing RARP to open RP, Ficarra et al. identified 12 and 24-month potency rates of 54–90% and 63–94%, respectively. Potency rates were significantly higher in men undergoing RALP at 12-months (OR 2.84; p = 0.002), and trended towards significance at the 24-month (OR 1.89; p = 0.21) [37]. However, with variable definitions of potency and differences in the quality of the included studies, the results of the meta-analyses must be interpreted with caution.
Sooriakumaran et al. recently presented results of the LAParoscopic Prostatectomy Robot Open Trial LAPPRO (LAParoscopic Prostatectomy Robot Open) trial, a prospective non-randomized study, which included 2545 Swedish men PCa who underwent either RARP or open RP at 14 different Swedish institutions by 50 experienced surgeons over a 3-year period [38]. While the authors have previously reported on perioperative [39] and urinary continence outcomes [40], they focused on erectile function (EF) recovery and oncologic outcomes in this study [38]. Erectile function recovery was significantly better in the RARP patients through 24 months than in the open RP patients (51% for RARP and 39% for ORP at 24 months). The authors report 10% vs. 17% PSM rates in pT2 tumors for open and robot-assisted surgery, respectively [38]. Corresponding rates for pT3 tumours were 48% and 33% [38]. The reported differences were associated with biochemical recurrence in pT3 but not pT2 disease.
In their systematic review and meta-analysis of 79 papers, Novara et al. reported a positive surgical margin (PSM) rate of 15% for all RARPs, while the rate was 9% in patients with localized disease. Similar overall PSM rates (RARP vs. RP: OR 1.21; p = 0.19), PSM rates in localized ≤ pT2 disease (OR 1.25; p = 0.31) and similar BCR-free survival (HR 0.9; p = 0.526) have been demonstrated when comparing RARP to ORP [41]. However, all of the data included was from high-volume centers with experienced surgeons, thus limiting the generalizability of the analysis.
To date, only one randomized controlled trial (RCT) assessing RARP and ORP has been conducted and reported [32, 42]. In the initial publication of early 12-week results in 308 randomized patients, no significant difference in the 6-week and 12-week urinary continence and erectile function recovery rates between the two groups has been seen [32]. Moreover, there was no significant difference in the surgical margin rates between the two treatment arms. Coughlin et al. recently presented the 24-months outcomes of this study, which again showed similar functional outcomes for RARP compared to open RP after 12 and 24 months [42].
However, this randomized study has a relatively low sample size (n = 308) compared to the available retrospective studies and was performed at a single institution by two surgeons, making the generalizability of results difficult.
Role of Lymphadenectomy at the Time of Radical Prostatectomy
Extended lymphadenectomy includes 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 [43].
Fossati et al. recently published a systematic review on pelvic lymphadenectomy (PLND) during RP and found that PLND was not associated with improved oncological outcomes [44]. Nevertheless, extended lymph node dissection is recommended by the EAU (European Association of Urology) guidelines in all patients with high risk PCa and patients with intermediate risk PCa, who have a risk of metastasis of more than 5% (e.g. estimated by the Briganti nomogram [45, 46]), because of information for staging and prognosis [43]. If RP is performed in low-risk PCa, pelvic LN dissection is not necessary (risk of positive lymph nodes ≤5%). This risk stratified application of which patients should undergo PLND with RP eliminates PLND in up to 70% of patients undergoing RP, depending on the risk distribution in one’s practice.
Radiation Treatment
External Beam Radiation Therapy (EBRT)
Radiation therapy uses high-energy particles to damage cellular DNA and induce apoptosis in cancer cells. Intensity-modulated radiotherapy (IMRT), with or without image-guided radiotherapy, is the gold standard for external beam radiation therapy (EBRT) [43]. IMRT uses dynamic multileaf collimators to provide a high dose to the target while minimizing toxicity to surrounding tissue. A dose of 76–78 Gy is recommended for EBRT plus androgen deprivation (ADT) in intermediate and high-risk PCa patients [43]. In intermediate-risk patients not willing to undergo ADT, an escalated dose of EBRT (76–80 Gy) or a combination with brachytherapy is recommended [43].
Brachytherapy
For low-dose rate brachytherapy (LDR brachytherapy) radioactive seeds are permanently implanted into the prostate. Inclusion criteria for this treatment option according to the EAU guidelines are as follows [47]: Stage cT1b-T2a N0, M0; ISUP grade 1 with ≤50% of biopsy cores involved with cancer or ISUP grade 2 with ≤33% of biopsy cores involved with cancer; An initial PSA level of ≤10 ng/mL; a prostate volume of <50 cm3; and an International Prostatic Symptom Score (IPSS) ≤12 and maximal flow rate >15 mL/min on urinary flow tests. For ISUP grade 1 patients 10-year BCR-free survival was reported to range from 65 to 85% [48–55].
For high-dose rate brachytherapy (HDR brachytherapy) the radioactive source is only temporarily introduced into the prostate. HDR brachytherapy is often combined with EBRT of at least 45 Gy [47]. Only limited data exists regarding the superiority of EBRT with brachytherapy compared to EBRT alone in the treatment of intermediate- and high-risk PCa (also see Section “Management of Locally Advanced Prostate Cancer”).
Focal Treatment
Focal treatment of prostate cancer represents the targeted destruction of cancer within a specific part of the prostate gland, while sparing the rest of the prostate and nearby tissue. It is intended to potentially reduce side effects when compared with established standard treatments. Success of focal therapy depends on the ability to identify and target the lesion. Several energy sources, such as high-intensity focused ultrasound (HIFU), cryotherapy, photodynamic therapy (PDT) or irreversible electroporation (IRE), have been employed for focal therapy [56]. None of these ablative technologies has been demonstrated to be successful all of the time and rates of positive control biopsy range from 20 to 30% for all of them [56].
Because of lack of validated data, focal treatment remains experimental and should only be performed in a clinical trial setting [43].
Management of Locally Advanced Prostate Cancer
An inverse stage migration towards more aggressive and locally advanced tumors has been demonstrated during the last decade [57, 58]. This can be attributed to both the increasing acceptance of local therapy in locally advanced PCa as well as the increasing use of active surveillance in low-risk PCa patients. Moreover, the USPSTF (U.S. Preventive Services Task Force) issued a draft guideline in October 2011 discouraging prostate specific antigen (PSA) based screening for PCa (grade D recommendation), which has led to a decrease in incident diagnoses of prostate cancer, while the incidence of men presenting with metastatic disease seems to be rising recently [59, 60].
Locally advanced PCa is a clinical diagnosis and is defined as a tumor which extends through the prostate capsule, the seminal vesicles or has spread into tissue around the prostate, e.g. rectum, bladder, urinary sphincter or the pelvic wall. Patients with evidence of lymph node metastases are not regarded as locally advanced.
According to the current EAU Guidelines on PCa no standard for treatment of locally advanced PCa can be currently defined [43]. Treatment options include surgery as part of a multimodal therapy or upfront external beam radiation treatment (EBRT) combined with androgen deprivation (ADT), while HIFU, cryotherapy or focal therapies are not recommended in the management of locally advanced PCa.
Natural History of Patients with Locally Advanced Prostate Cancer
Akre and colleagues analyzed data from the register-based nationwide cohort study within the Prostate Cancer DataBase Sweden including 12,184 men with locally advanced PCa (defined as local clinical stage T3 or T4 or with T2 with serum levels of prostate-specific antigen (PSA) between 50 and 99 ng/mL and without signs of metastases) managed with noncurative intent [61]. PCa-specific mortality at 8 year of follow-up was 28% for Gleason score (GS) 2–6, 41% for GS 7, 52% for GS 8, and 64% for GS 9–10 [61]. Even for men in the oldest age group (>85 years at diagnosis), PCa was a major cause of death. Gleason score was the most important predictor of tumor progression in this study.
Albertsen et al. utilized data from a retrospective population-based cohort study from the Connecticut Tumor Registry of 767 men aged 55 to 74 years with clinically localized prostate cancer diagnosed between 1971 and 1984 [62]. Patients were treated with either observation or immediate or delayed ADT therapy, with a median observation of 24 years. The authors showed that men with well differentiated tumors rarely died from their disease, while men with poorly differentiated tumors frequently died within 5–10 years of diagnosis despite aggressive interventions.
Outcomes of Radical Prostatectomy in Locally Advanced PCa
Currently, there has been an increase in radical prostatectomy number for locally advanced PCa [63]. To assess the benefits of RP in this setting, oncological, functional and perioperative results have to be taken into account.
Oncolocial results after radical prostatectomy (RP) in patients with locally advanced prostate cancer (PCa)a
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
