Evaluation and treatment of men with biochemical prostate-specific antigen recurrence following definitive therapy for clinically localized prostate cancer

Early detection and monitoring by serum prostate-specific antigen (PSA) measurement has increased the number of men presenting with potentially curable prostate cancer. Most will choose radical prostatectomy or some form of radiation therapy for treatment, but some will have evidence of biochemical disease recurrence following therapy, shown by a rising PSA level without other clinical evidence of disease. Radical prostatectomy involves the removal of all prostate tissue, causing the serum PSA to decline to undetectable levels within four to six weeks following surgery; a subsequent rise in the serum PSA to a detectable level indicates disease recurrence. Patients should be evaluated to assess whether rising PSA levels indicate local recurrence or early metastatic disease. The advantages of salvage radiation, endocrine therapy, and other treatment modalities in local disease recurrence must be weighed against potential side effects and the resulting decrease in quality of life. Radiation therapy does not immediately eradicate all PSA-producing cells; therefore the persistence of a detectable PSA does not necessarily imply residual cancer, but rising PSA levels indicate treatment failure. Salvage surgery can be performed after radiotherapy for the purpose of removing all viable cancer cells, but should be weighed against a higher incidence of surgical complications; cryoablation offers a less invasive therapeutic modality.     

Management of clinically localized prostate cancer

Critics of screening have stated that early detection of prostate cancer does not necessarily reflect a diminishing death rate from the disease. However, several recent reports have demonstrated that the death rate from prostate cancer is decreasing, representing the most compelling validation for aggressive screening. Prostate cancer can be halted only if there is no evidence of systemic or regional metastases and the disease is confined to the surgical field or the radiation template. Surgeons and radiation oncologists must make a concerted effort to exclude men with regional and systemic metastases who are unlikely to benefit from treatment. With the widespread acceptance of prostate-specific antigen screening, a greater proportion of men are being diagnosed with clinically localized prostate cancer. Both radical prostatectomy and radiation therapy are able to halt disease spread in this significant subset of men, but survival outcomes indicate that radical prostatectomy is a more reliable treatment than radiation therapy for clinically localized prostate cancer. Overall, the immediate treatment-related morbidity of radical prostatectomy and radiation therapy in the modern era is quite low. Radical prostatectomy and radiation therapy appear to have a similar impact on continence and erectile function. There is a need for neoadjuvant and adjuvant therapies that can be utilized in those cases where radical prostatectomy and radiation are less likely to completely eradicate or destroy the cancer.     

The effect of erectile dysfunction on quality of life following treatment for localized prostate cancer

All forms of prostate cancer therapy carry significant risk of erectile dysfunction, but patients value sexual function so highly that they are often willing to choose a therapy that offers a shorter life expectancy but better potency following treatment. Advances in research methodology now allow reliable collection of meaningful data regarding patients' health-related quality of life, including both objective evaluation of patients' functional status and their perceptions of their own health and its impact on their existence. In the past decade, several validated and reliable questionnaires have been developed that are specifically designed to measure HRQOL in men with prostate cancer. Studies using these instruments have found that function and perceived bother may not be correlated; patients may express satisfaction with their therapy despite loss of sexual function. Erectile aids, including sildenafil, can be helpful for patients following treatment for localized prostate cancer.     

Role of screening in detection of clinically localized prostate cancer

The aim of this study was to confirm the role of screening by determining the percentage of clinically localized prostate cancer (stage A and B) in patients with prostate cancer detected on screening and in those presenting to urologic clinic for the symptoms of urination impairment or ostalgia. During the study, 1,000 men aged > or = 50 from the community of Cepin and village of Josipovac near Osijek were examined. The subjects with elevated concentration of total prostate specific antigen and/or digital rectal examination suspect of carcinoma underwent transperineal biopsy of the prostate. Clinical staging was performed in patients with prostate cancer detected on screening, and data on clinical staging for prostate cancer patients treated during the 1996-1997 period were retrieved from patient files of the Department of Urology, University Hospital "Osijek". On screening, 28 (80%) patients with localized prostate cancer and seven (20%) patients with metastases were detected. In the group of patients examined on an outpatient basis for the signs and symptoms of prostatism, there were 30 (83.4%) patients with metastases and only six (16.6%) patients with localized prostate cancer. Study results indicated that an early diagnosis of prostate cancer could be made by use of noninvasive and inexpensive methods that cause no major discomfort to the patient. Accordingly, these results appear to strongly support such screening in men, if not in all those aged over 50, then at least in the otherwise healthy, 50-70 age group.     

The importance of pelvic lymph node dissection in men with clinically localized prostate cancer

Despite advances in noninvasive staging, pelvic lymph node dissection (PLND) remains the most accurate means of detecting lymph node metastases in men with clinically localized prostate cancer. Nomograms exist that can identify patients at low risk for lymphatic metastases according to preoperative information. In general, it seems reasonable to omit PLND in men with a biopsy Gleason sum of 6 or less and a prostate-specific antigen level of 10 ng/mL or less. Ultimately, however, this decision should be made according to physician and patient preference, considering the low contemporary morbidity associated with PLND. When PLND is performed, studies suggest that an extended dissection maximizes the detection rate of nodal involvement. Retrospective data indicate that an extended dissection might play a therapeutic role in a subset of patients with a limited lymph node burden. However, this might be an artifact of stage migration, and prospective studies are needed to evaluate this further.     

Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance

Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life.The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios.The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients.     

Androgen deprivation therapy in combination with radiotherapy for high-risk clinically localized prostate cancer

Androgen deprivation therapy (ADT) has remained the main therapeutic option for patients with advanced prostate cancer (PCa) for about 70 years. Several reports and our findings revealed that aggressive PCa can occur under a low dihydrotestosterone (DHT) level environment where the PCa of a low malignancy with high DHT dependency cannot easily occur. Low DHT levels in the prostate with aggressive PCa are probably sufficient to propagate the growth of the tumor, and the prostate with aggressive PCa can produce androgens from the adrenal precursors more autonomously than that with non-aggressive PCa does under the low testosterone environment with testicular suppression. In patients treated with ADT the pituitary-adrenal axis mediated by adrenocorticotropic hormone has a central role in the regulation of androgen synthesis. Several experimental studies have confirmed the potential benefits from the combination of ADT with radiotherapy (RT). A combination of external RT with short-term ADT is recommended based on the results of phase III randomized trials. In contrast, the combination of RT plus 6 months of ADT provides inferior survival as compared with RT plus 3 years of ADT in the treatment of locally advanced PCa. Notably, randomized trials included patients with diverse risk groups treated with older RT modalities, a variety of ADT scheduling and duration and, importantly, suboptimal RT doses. The use of ADT with higher doses of RT or newer RT modalities has to be properly assessed.     

Positive prostate biopsy following radiotherapy can predict metastasis-free survival in localized prostate cancer

Background/aim(s)To determine the impact of post-treatment biopsy results on 10-year metastasis-free survival (MFS), overall survival (OS) and cause-specific survival (CSS) in localized prostate cancer (PCa) patients treated with high-dose radiotherapy (RT).Materials/MethodsRetrospective analysis of 232 patients with T1c-T3bN0M0 PCa who underwent a prostate biopsy 24–36 months after high-dose RT. Biopsies were categorized as positive biopsy (PB) if H&E staining showed evidence of residual malignancy and negative biopsy (NB) if no malignant cells were present. Kaplan-Meier estimates of 10-year MFS, OS and CSS rates were calculated for each group and Cox proportional-hazards models were used to estimate the hazard ratios. The median follow-up was 124 months (range 26–267).ResultsSixty-two of 232 (26.7%) patients had post-treatment positive biopsies (PB). A positive post-treatment biopsy was significantly associated with a lower 10-year MFS (78.4% vs. 95.4%, p = 0.001, HR: 3.9, 95% CI: 1.8–8.3). Although patients with PB had worse outcomes that those with NB, we could not show a statistically significant difference in OS (81.0% vs. 87.9%, p = 0.282, HR: 1.3, 95% CI: 0.7–2.3) or CSS (96.2% vs. 99.4% (p = 0.201, HR. 2.4, 95% CI: 0.6–9.7). After multivariate analysis, the strongest predictor of MFS was the post-treatment biopsy status (p < 0.001, HR: 5.4, 95% CI 2.26–12.85) followed by Gleason score (p = 0.002, HR: 2.24, 95% CI 1.33–3.79).ConclusionA positive biopsy following RT can predict MFS in localized prostate cancer. These data highlight the relevance of achieving a local control and support the use of aggressive local therapeutic interventions for PCa.     

Treatment of localized prostate cancer

This article provides an overview of treatment of localized prostate cancer, which was discussed in detail in the second scientific session of the 16th International Prostate Cancer Update. The role of radical prostatectomy in localized disease was presented by Bob Djavan, MD. Benefits and risks of radical prostatectomy were addressed by Gerald Chodak, MD. Robert E. Donohue, MD, presented the role of radical prostatectomy in Gleason grade 8, 9, and 10 tumors. Impact of positive margins on outcomes after radical prostatectomy was presented by James A. Eastham, MD. E. David Crawford, MD, provided an overview of the role of targeted therapy. Indications and results of brachytherapy were presented by Mack Roach, III, MD. Finally, Michael J. Manyak, MD, described the evolution of radioimmunoscintigraphy and clinical outcomes data.     

Value of percent free prostate-specific antigen for the prediction of pathological stage in men with clinically localized prostate cancer

PURPOSE: To analyze if the percentage of free prostate-specific antigen (PSA) can provide additional information to the combination of local clinical stage, serum PSA and Gleason score in the prediction of final stage and pathological features of prostate cancer. MATERIALS AND METHODS: A group of 480 men with clinically localized prostate cancer underwent lymphadenectomy and radical prostatectomy. Total and free PSA were measured in preoperative serum. Clinical stage was T1 in 70.4% of patients and T2 in 29.6%. The biopsy Gleason score ranged between 2 and 4 in 5.6%, between 5 and 7 in 78.4%, and was higher than 7 in 16%. Total serum PSA was below 4.1 ng/mL in 4.3%, between 4.1 and 10 ng/mL in 66.4%, between 10.1 and 20 ng/mL in 22.5%, and higher than 20 in 6.7% of patients. The tumor was organ-confined in 49.8% and specimen-confined in 64.2%, and its pathological features were favorable in 35%. RESULTS: Multiple logistic regression analysis demonstrated that percent free PSA has independent predictive value for pathological stage only in the subset of patients with cT1 tumors and serum PSA between 4.1 and 10 ng/mL. In this group the probability of organ-confined cancer was 68.3% if the percent free PSA was above 15 and 56.3% if it was lower (p<0.001). The probability of specimen-confined disease was 86.6% and 71.3%, respectively (p<0.007), and the probability of favorable pathology was 59.8% and 39.6%, respectively (p<0.002). We also found higher rates of organ- and specimen-confined tumors and favorable pathology for every Gleason score when the percent free PSA was higher than 15. CONCLUSIONS: Percent free PSA seems to provide additional information to the combination of clinical stage and Gleason score for the prediction of pathological features only in patients with clinical stage T1c and serum PSA between 4.1 and 10 ng/mL.     

Apoplexy of clinically silent pituitary adenoma during prostate cancer treatment with LHRH analog

LHRH analogs have become a promising modality in prostate cancer therapy as an alternative to surgical castration, and the use of these agents is generally considered to be safe. Since now, only few cases of an apoplexy of previously undiagnosed pituitary adenoma (usually gonadotropinoma) at the beginning of therapy have been described in the medical literature. We present a case of a 74 year old patient who was diagnosed of prostate cancer at the age of 68. There was no evidence of metastatic disease. Radical prostatectomy was performed and LHRH analog gosereline (Zoladex 3.6 mg s.c.) was administered. During the first day after gosereline injection the patient developed headaches that became more severe over the next 3 days. Then the patient experienced nausea and vomiting, double vision and eyelid ptosis. On the 5th day the patient temporarily lost consciousness and was admitted to hospital. Imaging (computerized tomography, magnetic resonance imaging) revealed the presence of a pituitary tumor and hemorrhage within the gland. There was no evidence of pituitary dysfunction in hormonal studies. Neurosurgical intervention was postponed for 5 days after admission. Pathological mass with signs of recent hemorrhage was removed via transsphenoidal route. The tumor had negative immunohistochemical GH, ACTH and PRL staining. Neurological impairment resolved within 9 months after the operation. As a result the patient required adrenal and thyroid replacement. During 6 years of follow-up there was no evidence of prostate cancer recurrence.     

Biochemical failure and toxicity in treatment with brachytherapy and external beam radiotherapy compared with radical prostatectomy in localized prostate cancer

BackgroundLocalized prostate cancer (T1–3N0M0) has therapeutic options such as radical prostatectomy (RP), external beam radiation therapy (EBRT) and brachytherapy (BT). However, the evidence of the outcome of these treatments is limited and no studies have been conducted comparing biochemical failure (BF) and toxicity associated with surgical treatment and EBRT + high-dose brachytherapy (HDBT) in the region.Materials and methodsRetrospective cohort study, clinical records of patients diagnosed with localized prostate cancer between 2014 and 2018 were reviewed at one of the main private neoplasm centers in Lima, Peru; Cox regression was used for both the BF outcome and the grade 2 toxicity outcome, calculating the hazard ratio (HR) with 95% confodence interval (CI).ResultsOf 549 patients, 76.3% (419) received RP as primary treatment, and 72% were between 50 and 70 years old at the time of diagnosis. The patients treated with EBRT + HDBT presented worse characteristics. The EBRT + HDBT group had a 40% lower risk of presenting BF (HR = 0.6; 95% CI: 0.4–0.9), and also a 50% greater risk of presenting toxicity greater than or equal to grade 2 (HR = 1.5; 95% CI: 1.0–2.0) than the group treated with RP.ConclusionOur results show that when comparing patients treated with EBRT + HDBT and RP, BF was greater in RP, and post-treatment toxicity was greater in EBRT + HDBT.     

Selecting treatment for high-risk, localized prostate cancer: the case for radical prostatectomy

The most common treatment options for men with clinically localized prostate cancer include radical prostatectomy and radiation therapy. The choice between these options is often controversial, and selecting the optimal treatment poses a great challenge for patients and physicians. Factors important to the decision include age and life expectancy of the patient, the natural history of the prostate cancer, how curable the disease is, and the morbidity of treatment. Use of these criteria to select treatment for a healthy, 70-year-old man presenting with a nonpalpable tumor, stage T1c disease, serum prostate-specific antigen of 12 ng/mL, and an adenocarcinoma with a Gleason score of 8 that is present in 2 of 12 biopsy cores would lead to the choice of radical prostatectomy over radiation therapy. Data show that such a patient has a life expectancy of more than 12.3 years if the prostate cancer can be cured and a high probability of dying from the disease if it is not cured. Data further show that radical prostatectomy in such a patient would confer a survival advantage over radiation therapy without resulting in greater complications or reduction in quality of life.     

Success and failure of single-modality treatment for early prostate cancer

Many men who undergo radical prostatectomy or radiotherapy for early prostate cancer have an excellent outcome; however, a significant proportion subsequently experience disease recurrence and/or cancer-related death. Adjuvant hormonal therapy after treatment of curative intent is given with the aim of eradicating undetected cancer cells outside the surgical margins or radiation field and/or micrometastatic disease. In the analogous setting of early breast cancer, adjuvant hormonal therapy is already established as standard care. Efficacy and tolerability data from the ongoing bicalutamide ('Casodex') Early Prostate Cancer program are expected to determine the role of adjuvant hormonal therapy with antiandrogens in early prostate cancer.     

Selecting treatment for high-risk, localized prostate cancer: the case for radiation therapy

Prostate cancers that clinically appear to be localized may nonetheless respond poorly to curative treatment. Pretreatment prostate-specific antigen (PSA) level, biopsy Gleason score, and percentage of positive biopsies are all at least as important as clinical stage in predicting treatment outcome. A patient with a nonpalpable tumor, stage T1c disease, serum PSA of 12 ng/mL, and a Gleason score of 8 to 10 in 2 of 12 biopsy cores has a relatively poor prognosis. In a high-risk patient such as this one, the recommended treatment strategy involves a combination of brachytherapy and conformal external beam radiotherapy. In studies comparing treatments in patients stratified according to a variety of risk measures, this combination has shown biochemical disease-free survival rates superior to those seen following radical prostatectomy. The role of androgen suppression remains unclear.     

A tumor-associated macrophages related model for predicting biochemical recurrence and tumor immune environment in prostate cancer

ObjectiveTo identify tumor-associated macrophages (TAMs) related molecular subtypes and develop a TAMs related prognostic model for prostate cancer (PCa).MethodsConsensus clustering analysis was used to identify TAMs related molecular clusters. A TAMs related prognostic model was developed using univariate and multivariate Cox analysis.ResultsThree TAMs related molecular clusters were identified and were confirmed to be associated with prognosis, clinicopathological characteristics, PD-L1 expression levels and tumor microenvironment. A TAMs related prognostic model was constructed. Patients in low-risk group all showed a more appreciable biochemical recurrence-free survival (BCRFS) than patients in high-risk group in train cohort, test cohort, entire TCGA cohort and validation cohort. SLC26A3 attenuated progression of PCa and prevented macrophage polarizing to TAMs phenotype, which was initially verified.ConclusionsWe successfully identified molecular clusters related to TAMs. Additionally, we developed a prognostic model involving TAMs that exhibits excellent predictive performance for biochemical recurrence-free survival in PCa.