Summary Active surveillance ( serial monitoring of disease progression) is the preferred approach for patients with less aggressive prostate cancer, especially those with prostate-specific antigen (PSA) values < 10 ng/mL and tumors with a score of Gleason 3 + 3. Surgery and radiotherapy are curative treatments for circumscribed disease, but they have adverse effects. For metastatic disease, chemotherapy as initial treatment increases survival relative to androgen deprivation therapy alone. Abiraterone, enzalutamide, and other drugs may improve outcomes in patients with metastatic cancer refractory to hormone treatment. |
Prostate cancer is the most common cancer in men in the US, where approximately 160,000 new cases are diagnosed each year. 1,2 The slow course of the disease and the possibility of adverse effects of treatment generated discussions about the usefulness of screening and early detection.3,4 However, prostate cancer continues to be the third cause of death from cancer in men.2 Since 2011, significant progress has been made in determining the risk of developing the disease and identifying therapeutic options.
METHODS
Relevant articles were identified by applying the Cochrane Highly Sensitive Search Strategy for randomized studies to the PubMed and Cochrane databases from January 1, 2011 to March 31, 2017. The authors selected articles of potential interest. to doctors in general.
ADVANCES IN DIAGNOSIS
♦ Risk stratification
The diagnosis of prostate cancer is based on the microscopic evaluation of prostate tissue obtained through needle biopsy. Systematic prostate biopsy is performed using transrectal ultrasound to obtain 10 to 12 tissue samples in a grid. When the pathologist examines these samples, he or she assigns a primary Gleason grade for the predominant histologic feature and a secondary grade for the next most common feature, both on a scale of 1 to 5 based on the microscopic architecture and appearance of the cells.
Physicians traditionally stratified the diagnosis as low, intermediate, and high risk, based on the sum of Gleason patterns, prostate-specific antigen (PSA) value, and clinical stage. Due to the heterogeneity within each risk group, other tools have been created and validated that may better differentiate 7-14 For example, the National Comprehensive Cancer Network ’s updated risk staging employs a 5-level system that subdivides low and low risk groups. high risk.7
In 2014, a consensus conference reviewed the pathological classification into 5 strata13,14 and 2 main changes were incorporated. First, it recalibrated the classification by designating the Gleason score 3 + 3 to grade 1 cancer. Second, it more accurately matched tumor behavior by differentiating between a Gleason score of 3 + 4 (grade 2) and a Gleason score of 4 + 3 (grade 3) and the intermediate Gleason scores of 4 + 4, 3 + 5, and 5 + 3 (grade 4) and the Gleason scores of 4 + 5, 5 + 4 and 5 + 5 (grade 5).
In a validation study of more than 25,000 men, this system offered the greatest prognostic discrimination.14 This new classification system was incorporated into the World Health Organization’s 2016 tumor classification, which is the international standard for tumor classification. pathologists.13
♦ Diagnostic accuracy of prostate biopsy
Risk stratification depends on the accuracy of the prostate biopsy. Although systematic prostate biopsy is the standard, this procedure misses 21% - 28% of prostate tumors and downgrades 14% - 17%.15 Several new biomarkers ( 4Kscore , Prostate Health Index , of prostate cancer antigen 3, ConfirmMDx ) that help identify possible false-negative results.
Testing for PSA variants estimates the probability of prostate cancer in patients with a negative previous biopsy.16,17 Prostate cancer antigen 3 testing is performed on urine obtained after prostate massage. The subsequent prostate biopsy is negative in 88% of patients in whom this test was negative. An epigenetic analysis applied to prostate biopsy tissue quantifies DNA methylation and has similar discriminatory power.19
New imaging technologies also increase diagnostic accuracy. The most notable is multiparametric magnetic resonance imaging (MRI).20 When standardized scoring and reporting criteria are applied ( Prostate Imaging Reporting and Data System version 2; collaboration of the American College of Radiology, European Society of Uroradiology, and AdMetech Foundation ), MRI has a sensitivity of 89% and a specificity of 73% for identifying prostate cancer.21
Targeted biopsies of suspicious lesions can also be obtained using 3 approaches: (1) MR image fusion with transrectal ultrasound using computerized software (2) percutaneous biopsy during MRI, and (3) visual review of the MRI with biopsy. sequential prostate analysis using transrectal ultrasound (cognitive biopsy).
A prospective study of 1003 men undergoing prostate biopsy by fusion of MR-ultrasound images vs. systematic prostate biopsy identified 30% more cases of disease with a score of ≥4 + 3 (173 vs 122, respectively; P < 0.001 ) and 17% fewer cases of Gleason score 3 + 3 or low-volume disease with Gleason score 3 + 4 (213 vs 258; P < 0.001).
Targeted prostate biopsy also outperformed the combination of targeted and systematic biopsy in detecting high-volume disease with Gleason score 3 + 4 or greater).22 In another prospective study of 1042 men, 16% of those with negative MRI had disease. with Gleason score 3 + 4 or greater on systematic biopsy, which would have been missed with targeted biopsy alone.23
♦ Molecular and imaging-based prognostic biomarkers
Currently, new molecular biomarkers are available (Decipher, Prolaris, Oncotype DX) that classify the aggressiveness of the tumor. Using biopsy tissue, a cell cycle progression score based on 31 genes can predict clinical progression and mortality due to prostate cancer.25 A 17-gene analysis applied to biopsy tissue can predict risk of adverse pathological anatomy in prostatectomy, biochemical recurrence and metastasis.26
A 22-marker genomic classifier test created to quantify the risk of metastasis based on the prostatectomy specimen also provides prognostic information.27 These molecular biomarkers may help identify slow-growing tumor classified as Gleason score 3 + 4 or aggressive tumors diagnosed on biopsy as Gleason score 3 + 3.
MRI results may also have prognostic value in certain situations. More than 80% of lesions seen on MRI with high Prostate Imaging Reporting and Data System scores contain clinically significant disease.21 Conversely, a negative MRI had a negative predictive value of 84% in a large prospective study.23
MRI results can provide guidance for untreated patients who are being monitored for progression. In a retrospective study of 113 patients with very low-risk prostate cancer, those with negative MRI or low-suspicious lesions had 24% - 29% higher risk cancer on repeat biopsy relative to 45% - 100% in patients with suspicious lesions on MRI.28 The topic continues under investigation.
♦ Update on prostate cancer staging
Despite its limitations, 99-technetium methylene diphosphonate bone scanning and imaging with computed tomography (CT) or MRI remain recommended for patients at risk of metastasis (e.g., initial clinical stage T3-T4 in which the tumor extends beyond the capsule, PSA is >20ng/ml, or there is >10% risk of lymph node involvement) and may be considered for those with evidence of possible relapse (PSA >0.2ng/ml after prostatectomy or increase of 2 ng/ml above its lowest value after radiation).7,29
There is increasing interest in molecular or functional imaging studies with positron emission tomography (PET). Multiple radiotracers demonstrate activity in prostate cancer and three are authorized by the US Food and Drug Administration (FDA).13,30
PET-CT with C-choline has a sensitivity of 38%-98%) and specificity of 50%-100% depending on the site of the disease (local, nodal, distant) and the PSA value. 18F-fluciclovine PET-CT provides 89% - 100% sensitivity and 67% specificity for recurrent or metastatic prostate cancer. PET-CT with 18F-sodium fluoride has sensitivity of 87% - 89% and specificity of 80% - 91%, but is limited to bone metastases. Prostate-specific membrane antigen-based PET-CT and PET-MRI are useful for patients with low PSA values and for the detection of regional nodal metastases.
THERAPEUTIC ADVANCES
♦ Concomitant risks and shared decision making
Treatment was always considered according to life expectancy and risk of death from other causes. According to several randomized studies, the risk of death from other causes exceeds the risk of death from prostate cancer.31,32 According to data obtained from the Prostate Cancer Outcomes Study ,33 the 10-year risk of death due to prostate cancer was 3% - 18% depending on risk category, while 10-year mortality from other causes in patients with a concomitant disease was 33% or higher.33
Patients’ preferences and values are increasingly important in medical decision making. 34 Shared decision making is a process in which patients and doctors make joint decisions. Although a meta-analysis of 14 randomized studies investigating shared decision making revealed only a negligible association with health outcomes, 35 more recent studies demonstrated improved decision making and therapeutic choice, suggesting the importance of this topic.
♦ Treatment for circumscribed prostate cancer
Watchful waiting is treating symptoms for palliative purposes, while active surveillance includes a series of complementary tests
Patients with circumscribed cancer (that is, without identifiable regional nodes or metastases) have three therapeutic options: watchful waiting, surgery and radiotherapy. Expectant management (monitoring cancer progression but not treating) consists of watchful waiting and active surveillance.36
Watchful waiting is treating symptoms for palliative purposes, while active surveillance includes a series of PSA tests, physical examinations, prostate biopsies or a combination of all of these to monitor progression with the aim of curing those who progress to significant illness. Several cohort studies support the usefulness of this approach.
For example, the study by Tosoian et al 39 of 1298 patients, most with very low-risk disease, monitored for up to 60 months found metastasis in 5 men (0.4%) and death from prostate cancer in 2 (0.4%). fifteen%).
The Prostate Testing for Cancer and Treatment (ProtecT) study randomized 1643 patients with localized prostate cancer to active control ( n = 545), surgery ( n = 553), or radiation therapy ( n = 545). At 120 months, 8 of 545 men (1.5%) in active control were found to have died due to prostate cancer, which was not significantly different from the 5 deaths (0.9%) after surgery or the 4 deaths (0.7%) after radiotherapy.41 These data support active surveillance as the best option for patients with low-risk disease.7,36,43
Surgery and radiation therapy remain effective treatments for patients with more significant cancer, such as those with PSA values >10 ng/ml and those with palpable nodes on digital rectal examination. The Prostate Cancer Intervention versus Observation Trial (PIVOT) study randomized 731 patients to radical prostatectomy or watchful waiting. In patients with PSA >10 ng/ml, lower all-cause mortality (48.4% vs 61.6%, respectively; P = 0.02) and lower prostate cancer-specific mortality (5.6%) were found. %vs 12.8%; P = 0.02) after surgery.31
The Scandinavian Prostate Cancer Group 4 study randomized 695 patients to surgery vs watchful waiting. The benefits of surgery were found to become more pronounced over time. Between 10 - 18 years after treatment, the number to treat to avoid one death with radical prostatectomy decreased from 20 to 8.32 During this time, significant decreases in metastatic disease and a reduced need for androgen suppression treatment were also observed.32 In In the ProtecT study, surgery and radiotherapy, in conjunction with watchful waiting, reduced the risk of progression and metastatic disease.
ProtecT also provided the first randomized comparison between surgery and radiotherapy, where no difference was found in prostate cancer mortality, overall mortality or metastases, but there was a difference in functional outcomes. For example, patients treated with radiotherapy had better urinary control and sexual function, but more nocturia and intestinal dysfunction than those who underwent surgery.41,42
Two prospective studies reported on adverse effects of treatment.45,46 They found short-term decreases in urinary obstruction and irritation and bowel and hormonal function after radiotherapy and long-term decreases in sexual function and urinary control after surgery in relationship with patients with active surveillance. In contrast, some patients experienced improvements in urinary obstruction and irritation after radical prostatectomy.45,46 The information provided by these data stimulates shared decision making in the treatment of prostate cancer.
One difficulty in interpreting data from randomized studies is that surgery and radiation therapy evolved at the same time. In surgery, open radical prostatectomy was largely replaced by robotic radical prostatectomy.
Two meta-analyses of observational studies suggest that robotic surgery is associated with better one-year outcomes in urinary and sexual function relative to open surgery.47,48 However, in another study, with 326 patients, prostatectomy Robotics achieved less bleeding and shorter hospitalization time than open prostatectomy, but without a significant difference in functional results at 3 months.49
Technological advances also occurred in radiotherapy. Intensity-modulated radiation therapy has largely replaced 3D conformal radiation therapy. Both use computer programs and imaging and CT studies for planning. The first emits non-uniform rays that can adapt to irregularly shaped organs and thus reduce radiation to neighboring tissues and subsequent urinary and intestinal toxic effects.50,51 In this way it is possible to administer higher doses of radiotherapy and produce thus better results.52-54
Hypofractionation shortens the duration of treatment by administering radiotherapy in higher doses, but in fewer sessions. Although the efficacy of this method is similar to that of traditional radiotherapy,55,56 some studies report a slight increase in early intestinal and late urinary toxic effects.57,58
Stereotactic radiation therapy is an extreme form of hypofractionation that delivers external beam radiation therapy in 5 – 7 sessions using specialized planning and monitoring, guided by imaging studies. Phase 2 studies indicate comparable short-term cancer control, but potential for increased urinary toxic effects.59 Some centers report favorable results with high-dose rate brachytherapy.60
Unlike low-dose rate brachytherapy (permanent radioactive seeds), this method delivers high doses of radiation through temporary probes over several sessions. A randomized study evaluating the addition of high-dose rate brachytherapy to external beam radiation therapy in 218 patients demonstrated greater local improvement with lower than usual doses.61
Focal treatment of the tumors was also carried out with cryotherapy, high-intensity focused ultrasound, laser removal, brachytherapy or other forms of energy. Cohort studies tend to include patients with less aggressive tumors, but success rates are variable, with residual tumors in 5.1% - 45.9% of cases.62
Guidelines recommend coadministration of androgen suppression therapy (AST) for patients receiving radiation therapy, especially those with significant disease.7 Randomized studies confirmed the usefulness of 6-month treatment with ASD for intermediate-risk disease and ≥ 24 months for high-risk disease.63,64
For patients treated with surgery, clinical studies support the usefulness of complementary radiotherapy for local control and biochemical recurrence in those with adverse pathological anatomy (e.g., T3 disease, positive margins).65,66 It is necessary to discuss the topic with patients, before and after surgery.
♦ Treatment for metastatic prostate cancer
Androgen suppression remains the first-line treatment for patients with metastatic prostate cancer, although it may have toxic effects. In addition to the proven adverse effects (decreased bone density, metabolic changes, sexual dysfunction, hot flashes), cardiac morbidity and cognitive dysfunction were reported.68,69 Intermittent administration of TSA was also investigated. A meta-analysis reported non-inferiority of this method relative to continuous TSA with respect to disease progression, cancer-specific survival, and overall survival.72
Two randomized clinical trials pointed to the emerging importance of docetaxel, which was previously reserved for patients who did not respond to TSA. In one of them ( ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer, CHAARTED),73 docetaxel increased the median survival from 44.0 to 57.6 months in 790 patients with metastatic disease and delayed the progression of 11 .7 to 20.2 months.
In the other ( Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) 74 in 2962 patients with locally advanced or metastatic prostate cancer, docetaxel increased the time to biochemical recurrence, progression, or death due to cancer prostate in 17 months and overall survival in 10 months.74 In both studies, tolerability of docetaxel was good.73,74
In many cases, metastatic prostate cancer does not respond to TSA. For these patients, there are numerous drugs and therapeutic innovations that improve survival and quality of life in randomized studies.75-82
Two of these drugs act on the androgenic axis : abiraterone acetate inhibits androgen biosynthesis, while enzalutamide interferes with androgen receptor signals 75,76,79,80
Sipuleucel-T, an autologous cellular immunotherapy , is the first FDA-authorized cancer vaccine in the US, which, compared to placebo, increased median survival by 4.1 months. This treatment is for asymptomatic patients or those with minimal symptoms and has a greater effect when administered to patients with low PSA values. 82,83 Cabazitaxel increased median survival by 2.4 months, but had many toxic effects (neutropenia, diarrhea).77
Bone health is another therapeutic target in the treatment of metastatic prostate cancer that does not respond to TSA. Denosumab, a human monoclonal antibody, promotes the formation and propagation of osteoclasts. Relative to zoledronic acid, which is the standard preventive treatment for castration patients with recurrent prostate cancer and bone metastases, denosumab delayed the first bone episode by 3.6 months with similar toxic effects but greater ease of administration.80
Radium-223 emits α particles that selectively bind to bone metastases and prolonged median survival by 3.6 months and time to first skeletal-related event by 5.8 months compared with placebo. Likewise, with radium 223 the decrease in quality of life was slower in some patients.81
Multimodal treatment and precision medicine may emerge as future advances for prostate cancer. Recent data suggest that patients with lymph node involvement may benefit from radiotherapy in addition to TSA 84,85
Treatment of metastatic prostate cancer can increasingly be tailored to the molecular biology of each patient’s tumor. Based on recent studies, repair of DNA defects in genetic aberrations (e.g., BRCA1 , BRCA2 ) can be used to choose more effective treatments.87,88
♦ Prostate cancer survival
Pelvic floor training may help restore urinary control in patients with incontinence after prostatectomy
The 5-year survival rate for prostate cancer approaches 100% 2,31-33,41,89 and almost all patients will have to face the consequences of their diagnosis and treatment. The American Cancer Society created recommendations for prostate cancer survival (that is, the life and health of patients after treatment).89 These include health promotion, cancer surveillance and screening, as well as information on physical and psychosocial burdens, social support, and health care coordination.
Pharmacological, psychological and behavioral supports are available to reduce the suffering or discomfort that may manifest during survival. For affected patients, phosphodiesterase type 5 inhibitors may improve sexual function, and partner or group therapy may help improve sexual experience.90-93
Pelvic floor training may help restore urinary control in patients with incontinence after prostatectomy.94,95 Diet and exercise are beneficial for quality of life, especially for those receiving TSA for metastatic disease.96,97 Behavioral therapy may also be helpful.98,99
CONCLUSIONS
Advances in the diagnosis and treatment of prostate cancer have improved the ability to stratify patients by risk and allowed doctors to recommend treatment based on cancer prognosis and patient preference. Initial treatment with chemotherapy may improve survival compared with androgen deprivation treatment. Abiraterone, enzalutamide, and other drugs may improve outcomes in patients with metastatic prostate cancer refractory to traditional hormonal treatment.
