Prostate-specific Antigen Relapse-free Survival Research Articles

The Impact of Image Guided Radiation Therapy (IGRT) on Efficacy and Toxicity of Prostate Cancer: A Systematic Review and Meta-Analysis

<h3>Purpose/Objective(s)</h3> Image-guided radiation therapy (IGRT) is widely used to correct prostate localization, but there have been no consistent conclusions regarding the effect of IGRT on the toxicity and survival in the absence of level 1 evidence. The purpose of this study is to perform a systematic review and meta-analysis of efficacy and toxicity of IGRT in prostate cancer. <h3>Materials/Methods</h3> A systematic review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide-lines, was conducted using PubMed, Embase, Medline databases and Cochrane Library databases until February 2022. Two investigators independently searched and selected literature, including randomized controlled trials (RCTs) and cohort studies (CRS). The data on efficacy and toxicity were extracted for quality assessment and meta-analysis to quantify the effect of IGRT on prostate-specific antigen (PSA) relapse-free survival, biochemical failure-free survival (BFFS), overall survival (OS), gastrointestinal (GI) toxicity and genitourinary (GU) toxicity. Heterogeneity assessment was performed using the <i>χ</i>² test and the <i>I</i>² statistic. Significant heterogeneity was indicated by <i>P</i> <0.05 in Cochrane Q tests and a ratio greater than 50% in <i>I</i>² statistics, which led to the use of random-effects models according to the DerSimonian and Laird method. <h3>Results</h3> The initial search strategy identified 2816 records in total, and 19 studies with 5186 patients met inclusion criteria after removing duplicates, screening, and full article review for the final meta-analysis. The results revealed that IGRT significantly reduced not only the grade 2 (G2) or worse (G2+) acute GI toxicity (risk ratio [RR] = 0.55 [95% confidence interval (CI), 0.36-0.85]; <i>P</i> = 0.007) and GU toxicity (RR = 0.82 [95% CI, 0.72-0.95]; <i>P</i> = 0.006), but also the G2+ late GI toxicity (hazard ratio [HR] = 0.25 [95% CI, 0.07-0.87]; <i>P</i> = 0.03) compared with non-IGRT. Moreover, IGRT significantly improved PSA relapse-free survival (HR = 0.43 [95% CI, 0.20-0.92]; <i>P</i> = 0.03). However, it was found that high frequency (once daily) IGRT took no advantage in BFFS (HR = 0.68 [95% CI, 0.41-1.12]; <i>P</i> = 0.13) and OS (HR = 1.34 [95% CI, 0.60-2.99]; <i>P</i> = 0.47) in prostate cancer than low frequency (once weekly or less) IGRT. <h3>Conclusion</h3> This is the first meta-analysis to demonstrate that IGTR control in prostate cancer significantly reduces G2+ acute GI and GU toxicity and improves PSA relapse-free survival. While it is important not to underestimate the negative effects on high frequency IGRT, which has little benefit on BFFS and OS.

Multimodal therapy for oligometastatic prostate cancer: results from a single-centre study

Introduction. In recent years, interest in the use of radical prostatectomy (RPE) as one of the components of a multimodal approach in patients with lymphogenous disseminated and metastatic prostate cancer (PCa) has grown significantly. At the same time, the dearth of large randomized trials does not make it possible to use this technique in wide clinical practice outside of clinical trials.Purpose of the study. To evaluate the effectiveness of multimodal therapy using combined chemo-hormonal, surgical and radiation therapy in patients with primary oligometastatic hormone-sensitive PCa.Material and methods. The study included 48 patients with primary oligometastatic prostate cancer who received combination treatment within the internal one-research-center protocol. At the first stage, all patients underwent combined drug therapy with docetaxel (75 mg/m2 intravenously every 3 weeks for 6 courses) and degarelix. Patients who had a decrease in PSA level ≤ 2 ng/ml and registered stabilization of the disease according to radiological examination were treated surgically through RPE with extended pelvic and retroperitoneal lymph node dissection. Radiation therapy was performed only in patients with the presence of bone lesions at a dose of 50-70 Gy to the location of bone metastases in the stage 3 plan of combined multimodal therapy.Results. PCa biochemical relapse was verified in 27 (56.3%) patients during the median follow-up of 10 months. The average time to PSA increase was 9.0 ± 5.7 months (from 1 to 24 months), median — 7 months, Six-month PSA relapse-free survival (PSA-RFS) was 61.2 ± 7.5%; 1-year PSA-RFS — 38.0 ± 8.6%. The average duration before the initiation of hormonal therapy was 12 ± 6.1 months (from 3 to 27 months), median: 10 months. Six-month survival before the drug administration was 72.6 ± 6.8%; twelve-month survival: 40.9 ± 8.7%. About 40% of patients with oligometastatic PCa had no signs of progression and did not receive any other drug therapy for 12 months after completion of protocol treatment.Conclusions. Analysis of the study results demonstrates satisfactory oncological outcomes of the studied treatment option in patients with newly diagnosed oligometastatic hormone-sensitive PCa, as well as a low likelihood of side effects and complications. Nevertheless, it is necessary to continue conducting larger and more structured randomized trials to determine the possibility of applying this therapeutic approach in clinical practice.

Comparing the efficacy of laparoscopic and open radical prostatectomy: analysis of treatment outcomes in patients with prostate cancer treated in three federal centers

Background. Prostate cancer is currently one of the most challenging problems in urological oncology due to its constantly increasing incidence and mortality in Russia. Surgery remains one of the most radical treatment options for patients with localized and locally advanced prostate cancer of any risk. Multiple studies have compared long-term and functional outcomes of surgeries performed using different surgical approaches. All studies have demonstrated similar long-term and functional outcomes of open, laparoscopic, and robot-assisted surgeries. Objective: to review the existing literature on this problem and analyze outcomes of surgical treatment in patients who had undergone open or laparoscopic prostatectomy in one of three federal centers of the National Medical Research Radiology Center.Materials and methods. This retrospective study included 2,772 patients with localized and locally advanced prostate cancer who had undergone surgery in one of the three federal centers.Results. We evaluated short-term and long-term outcomes of laparoscopic and open radical retropubic prostatectomy (RRP) performed at three federal centers of the National Medical Research Radiology Center. We found that laparoscopic RRP was associated with a longer surgery, lower blood loss, and fewer lymph nodes removed compared to open RRP. Long-term oncological and functional outcomes (prostate-specific antigen relapse-free survival, time to urination recovery) did not significantly differ between patients who had laparoscopic or open RRP.Conclusion. Both open and laparoscopic RRP are equally effective surgical methods for patients with localized and locally advanced prostate cancer.

Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in Patients With Intermediate-Risk Prostate Cancer

Ultra-high single-dose radiotherapy (SDRT) represents a potential alternative to curative extreme hypofractionated stereotactic body radiotherapy (SBRT) in organ-confined prostate cancer. To compare toxic effect profiles, prostate-specific antigen (PSA) responses, and quality-of-life end points of SDRT vs extreme hypofractionated SBRT. The PROSINT single-institution phase 2 randomized clinical trial accrued, between September 2015 and January 2017, 30 participants with intermediate-risk prostate cancer to receive SDRT or extreme hypofractionated SBRT. Androgen deprivation therapy was not permitted. Data were analyzed from March to May 2020. Patients were randomized in a 1:1 ratio to receive 5 × 9 Gy SBRT (control arm) or 24 Gy SDRT (test arm). The primary end point was toxic effects; the secondary end points were PSA response, PSA relapse-free survival, and patient-reported quality of life measured with the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaires. A total of 30 men were randomized; median (interquartile range) age was 66.3 (61.2-69.9) and 73.6 (64.7-75.9) years for the SBRT and SDRT arms, respectively. Time to appearance and duration of acute and late toxic effects were similar in the 2 trial arms. Cumulative late actuarial urinary toxic effects did not differ for grade 1 (hazard ratio [HR], 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57). Actuarial grade 1 late gastrointestinal (GI) toxic effects were comparable (HR, 0.37; 90% CI, 0.07-1.94) and there were no grade 2 or greater late GI toxic effects. Declines in PSA level to less than 0.5 ng/mL occurred by 36 months in both study arms. No PSA relapses occurred in favorable intermediate-risk disease, while in the unfavorable category, the actuarial 4-year PSA relapse-free survival values were 75.0% vs 64.0% (HR, 0.76; 90% CI, 0.17-3.31) for SBRT vs SDRT, respectively. The EPIC-26 median summary scores for the genitourinary and GI domains dropped transiently at 1 month and returned to pretreatment scores by 3 months in both arms. The IPSS-derived transient late urinary flare symptoms occurred at 9 to 18 months in 20% (90% CI, 3%-37%) of patients receiving SDRT. In this randomized clinical trial among patients with intermediate-risk prostate cancer, SDRT was safe and associated with low toxicity, and the tumor control and quality-of-life end points closely match the SBRT arm outcomes. Further studies are encouraged to explore indications for SDRT in the cure of prostate cancer. ClinicalTrials.gov Identifier: NCT02570919.

OLI-P: Toxicity and efficacy of local ablative radiotherapy in PSMA-PET staged, oligometastatic prostate cancer—A phase II trial.

115 Background: After curative primary therapy, a subset of patients with prostate cancer will have PSA-progression. Modern imaging methods may detect patients with oligometastastic disease at an early time point. Local ablative therapy has shown to improve time to progression compared to standard of care. PSMA-PET hybrid imaging is an emerging method, with a high accuracy and sensitivity to detect oligometastatic disease at low PSA-levels. Methods: At two German centers, patients with PSA progression after local curative treatment had PSMA-PET- hybrid imaging. Patients with up to five PSMA-PET positive metastases were offered to participate in the clinical trial. Further relevant exclusion criteria were ongoing androgen deprivation therapy (ADT), PSA &gt;10 ng/ml or severe comorbidity. The patients had a local ablative radiotherapy (aRT) to all PSMA-PET positive metastases. The primary endpoint was toxicity within two years after aRT. Secondary endpoints included PSA-progression free survival (defined as PSA nadir +1 ng/ml or start of ADT) and therapy-free survival (i.e. time to start ADT). Results: Between 2014 and 2018, 72 patients were included; patients’ characteristics are shown in table. Nine patients were excluded as no aRT was performed. The median follow up for the remaining 63 patients was 34.2 months. Within two years, 67 % (42 of 63 pats) had no report of adverse events. Following events were recorded during follow up: rectal bleeding (Grade 1, n=1), stroke (1), urinary incontinence (grade 2: n=3) secondary malignoma (n=5, primary liver tumor (n=2), bladder cancer, acute leukemia and head and cancer). All adverse events were considered as “not related“ to aRT of the metastases. PSA progression occurred in 44 patients after a median of 14.4 months. After two years, PSA relapse free survival was 38.2 %. ADT was initiated in 36 patients after a median of 26 months; 54 % (n=34 of 63) did not start ADT within two years after aRT. Conclusions: Local ablative radiotherapy in selected patients with PSMA-PET staged oligometastatic prostate cancer is well tolerated and may improve midterm outcome and delay onset of systemic therapy. Clinical trial information: NCT02264379. [Table: see text]

Pure Single-site Robot-assisted Radical Prostatectomy Using Single-port Versus Multiport Robotic Radical Prostatectomy: A Single-institution Comparative Study

BackgroundPure single-site robot-assisted extraperitoneal prostatectomy (EPP) using a single-port (SP) robotic platform has been shown to be feasible and safe in previous descriptive studies. ObjectiveTo compare the perioperative outcomes of patients undergoing SP-EPP versus conventional multiport (MP) transperitoneal robot-assisted radical prostatectomy (RARP). Design, setting, and participantsFrom January 2019 to January 2020, data of 100 consecutive patients who underwent SP-EPP performed by the same surgeon and 110 consecutive patients who underwent MP-RARP by three surgeons from the same institution were prospectively collected. InterventionAll SP-EPPs were performed in a pure single-site fashion without Trendelenburg. Outcome measurements and statistical analysisDemographic characteristics as well as intra- and postoperative data of patients in both groups were analyzed. Quantitative data were described in terms of median and quartiles. Results and limitationsAfter SP-EPP, the rate of patients discharged the same day was nine times higher than that after MP-RARP (p < 0.001), and the median length of postoperative hospital stay was significantly shorter: 4.3 h (interquartile range [IQR] 3.3–17.4) versus 26.1 h (IQR 21.5–44.8). The rate of opioid use in the hospital and after discharge in the SP group was at least half that in the MP group (respectively, 32% vs 64%, p < 0.001, and 35% vs 87%, p < 0.001). The overall positive surgical margin rate as well as continence rate at 12 mo (85% vs 88%, p = 0.97) and the prostate-specific antigen relapse-free survival (p = 0.09) were statistically comparable between the SP and MP groups. ConclusionsPure single-site SP-EPP was associated with a shorter length of stay as well as a decreased need for postoperative pain medication and narcotic administration in comparison with conventional transperitoneal multiport prostatectomy, with comparable postoperative complications and readmission rate. Patient summarySurgical treatment of localized prostate cancer using a single-port robotic platform allows for a shorter hospital stay, less pain, and less opioid use than conventional robotic surgery without more morbidity. Take Home MessagePure single-site single-port extraperitoneal prostatectomy was associated with a shorter length of stay as well as a decreased need for postoperative pain medication and narcotic administration in comparison with conventional transperitoneal multiport prostatectomy, with comparable postoperative complication and readmission rate.

A randomized phase III trial between adjuvant docetaxel and surveillance after radical radiotherapy (RT) for intermediate and high-risk prostate cancer (PC): Quality-of-life results (QoL) in SPCG-13 trial.

313 Background: Six docetaxel cycles did not improve PSA relapse free survival as an adjuvant treatment after radical RT (Kellokumpu-Lehtinen EURURO-8532). Here we report SPCG-13 trials QoL results. Methods: A total of 376 PC patients (T2 with Gleason score (GS) 4+3, PSA&gt;10; T2, GS 8-10 any PSA; or any T3) were randomised to receive either 6 cycles of docetaxel 75mg/m2 every 3 weeks (Arm A, n=188) or surveillance (Arm B, n=188) after radical RT NTC006653848. Neoadjuvant/adjuvant ADT was mandatory. Primary end-point was a rising PSA &gt; 2 ng/ml above the nadir. Patients were followed for 5 years with PSA every 3 months for two years and thereafter every 6 month. FACT-P QoL questionnaires were used at baseline, during and after docetaxel treatment and in the follow-ups (at 1 year, 2 years and 4 years after treatment) in both groups, and analysed using analysis of variance (ANOVA) models. Results: Median follow-up was 59.4 months (range 1 to 111 months). 147 (78.2%) patients completed all six cycles in arm A. Mean age was 66.2 years in Arm A and 66.4 years in Arm B. The total QoL scores at baseline did not differ between the Arms (mean 119.0, SD±18.9, n=177 vs 118.2, SD±18.1, n=180). In Arm A the total score declined to 116.3 (SD+15.2), at 24 weeks and was 118.5 (SD±21.3) after chemotherapy. In Arm B at 24 weeks the QoL score had increased to 123.3 (SD±19.2) and was significantly higher than in Arm A (estimated difference of 8.2 with p&lt;0.0001, ANOVA model adjusted for baseline). However, in the first follow-up (1 year) the QoL score was same in both Arms (123.7 vs 123.6, respectively, p=0.344, ANOVA model adjusted for baseline) and remained at the same level during further follow-ups. The decline in QoL scores during the docetaxel treatment were seen only in two sub-scores; functional and physical. Conclusions: Adjuvant docetaxel did decrease the QoL of patients during the treatment. However, in the later follow-ups it increased to the same level as those patients without docetaxel treatment. These results further support our conclusions of showing no benefit from docetaxel as adjuvant treatment in this patient group after radical curative treatment. Clinical trial information: RT NTC006653848.

Salvage Brachytherapy for Recurrent Prostate Cancer after Definitive Radiation Treatment and Factors That May Impact Outcomes

Salvage low-dose-rate (LDR) brachytherapy is a potential treatment option for patients with locally recurrent prostate cancer following primary radiation therapy. Here we report our single institution outcomes and toxicity when utilizing LDR brachytherapy in the salvage setting. Nineteen patients with biopsy-proven locally recurrent prostate cancer underwent salvage LDR brachytherapy under transrectal ultrasound guidance utilizing 103 Pd to 120 Gy from August 2010 through February 2018. Prostate-specific antigen (PSA) failure was determined utilizing the Phoenix (nadir+2) definition. Toxicity was graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and patient reported questionnaires including the Expanded Prostate Cancer Index Composite (EPIC) and American Urological Association (AUA). Median follow-up was 41 months. The 4- and 5- year PSA relapse-free survival (RFS) following salvage treatment were 78.9% and 68.4%, respectively. Androgen deprivation therapy was utilized in conjunction with salvage treatment in 7 patients (37%). On univariate analysis, 5- year PSA relapse was associated with both patients who experienced early failures after initial definitive treatment (p=.012), or if the patient had received stereotactic body radiation treatment (SBRT) (p=.005) prior to salvage treatment. Of the four patients who were treated following a biopsy-proven recurrence after initial SBRT treatment, two patients (50%) experienced PSA failure at a median of 9 months after their salvage treatment. AUA and EPIC scores showed a significant increase at one-month follow-up after salvage brachytherapy (p = .023) and returned to baseline within six months. Three patients (16%) experienced Grade 3 acute or late urinary toxicity, five patients experienced Grade 2 acute urinary toxicity, and one patient experienced Grade 2 acute rectal toxicity. Post-implant dosimetry did not predict for toxicity. There were no Grade 4 or 5 toxicities. LDR brachytherapy is a viable treatment option in the salvage setting with minimal morbidity. While longer follow-up is needed, early failures from initial radiation treatment and prior SBRT may portend for worse outcomes following salvage LDR brachytherapy.

High efficacy of hypofractionated proton therapy with 4 fractions of 5 Gy as a boost to 50 Gy photon therapy for localized prostate cancer

PurposeWe report the outcome of hypofractionated proton boost as an alternative to high dose-rate brachytherapy boost, aimed at an equivalent dose exceeding 86 Gy in 2 Gy fractions, for patients with localized prostate cancer and all risk groups. MethodsProton boost of 20 Gy given in 4 daily fractions to the prostate was followed after a one-week rest by photon therapy to 50 Gy in 2 Gy fractions. Outcomes are presented per risk group according to both NCCN and ISUP classifications. Advanced imaging was performed for adequate staging, and at an early stage of rising PSA, to identify the relapse site. Endpoints were PSA relapse-free-, locoregional relapse-free-, and distant metastasis-free- survival. Prostate cancer-specific-, metastasis-free-, and overall survival were also estimated. Genitourinary (GU) and gastrointestinal (GI) toxicity were based on patients‘ questionnaires and physicians‘ records. ResultsWe treated 531 patients between 2002 and 2015; 504 had localized disease. The cohort included 180 patients with T3/T4 disease (36%). The majority of the 50% with high-/very high-risk disease received ADT, 9–24 months; 92 had adjuvant pelvic node treatment. Median follow-up was 113 months (43–193). For low-, intermediate-, high-, and very high-risk patients, the 5-year PSA relapse-free survival was 100%, 94%, 82%, and 72%, respectively. Prolonged ADT improved biochemical control and nodal treatment regional control. The NCCN classification had higher predictive discrimination than the ISUP classification. The 5-year prevalence grade 3+ was 2% for GU and 0% for GI toxicity in pre-treatment symptom-free patients, and not worsened by nodal treatment. ConclusionDose escalation with hypofractionated proton boost was as effective as reported with high dose-rate brachytherapy boost, and the GU and GI toxicity profile was very similar. The proton boost was also appropriate for patients with larger prostate volume, higher T-stage, and high-risk disease encompassing elective regional node photon therapy.

Oncological Outcome of Cytoreductive Radical Prostatectomy in Prostate Cancer Patients With Bone Oligometastases

ObjectiveTo explore the role of cytoreductive radical prostatectomy (CRP) for locally resectable and distant oligometastatic prostate cancer (CaP). Patients and MethodsOligometastases were defined as the presence of 5 or fewer metastatic lesions detected on 99mTc bone scan and no suspicious visceral involvement at pretreatment imaging. Clinical data on 111 consecutive patients who were diagnosed as oligometastatic CaP in our center from 2005 to 2016 was retrospectively collected. In this retrospective cohort study, 35 patients underwent CRP and androgen deprivation therapy, and 76 patients underwent androgen deprivation therapy alone. Oncological outcomes were analyzed by employing Kaplan-Meier method. ResultsThe median follow-up of both groups was 35 months. In whole cohort analyses, prostate-specific antigen (PSA) decrease velocity (P = .167), PSA half-time (P = .263), and PSA nadir (P = .196) were not significantly different between 2 groups. Meanwhile, the differences in oncological outcomes between 2 groups did not reach statistical significance with regard to PSA relapse-free survival (P = .184), clinical progression-free survival (P = .118), and cancer-specific survival (P = .773). In addition, similar results were also observed in prespecified subgroup analyses (lower PSA group [0-100 ng/mL, P = .543], lower Gleason score group [6-7, P = .266], lower clinical T stage group [2-3 stage, P = .962], lower radiological N stage group [0 stage, P = .364]). ConclusionIn our study, significant benefit from CRP has not been detected in patients with oligometastatic CaP. Facing current trend, it demands deliberate consideration to select candidates for cytoreductive surgery, and the selection criteria should be further refined by incorporating additional prognostic factors.

NEOADJUVANT AND ADJUVANT CHEMOHORMONAL THERAPY IN PATIENTS WITH HIGH-RISK AND VERY HIGH-RISK PROSTATE CANCER: OUR EXPERIENCE

Background. The approach to the management of prostate cancer with lymph node metastases has recently moved towards aggressive multimodal treatment with the use of the most rational combinations that are currently available.Objective: to assess the efficacy and tolerability of chemohormonal therapy (CHT) in patients with high-risk and very high-risk prostate cancer.Materials and methods. An open prospective clinical trial evaluating the efficacy and tolerability of neoadjuvant and adjuvant CHT in patients with high-risk and very high-risk prostate cancer was initiated in 2016 at the P.A. Herzen Moscow Oncology Research Institute. Patient recruitment is still ongoing.A total of 64 patients with high-risk and very high-risk prostate cancer (сT3N0–T3N+М0, prostate specific antigen (PSA) ≥20 ng/mL, and Gleason score of 8–10) were recruited since July 2016. All patients were examined prior to treatment initiation and after 3 and 6 courses of therapy. The examination included pelvic magnetic resonance imaging, ultrasound imaging of the abdominal cavity and retroperitoneal space, transrectal ultrasound imaging, and chest radiography or computed tomography. Serum PSA level was evaluated before each course of therapy. Bone scintigraphy was performed before treatment and after its completion. Study participants were divided into two groups. Group A included patients that initially underwent surgical treatment and then 6 courses of CHT no later than 6 weeks after surgery: docetaxel 75 mg/m2 given intravenously on day 1 of a 21-day cycle and oral prednisolone 10 mg/day. Patients also received hormonal therapy with luteinizing hormone-releasing hormone analogue (aLHRH) given in depot injections every 28 days.Group B included patients that initially received 6 courses of CHT: docetaxel 75 mg/m2 given intravenously on day 1 of a 21-day cycle and oral prednisolone 10 mg/day. After that, patients underwent radical prostatectomy with pelvic lymphadenectomy no later than 4 weeks after the completion of chemotherapy. Patients also received hormonal therapy with aLHRH given in depot injections every 28 days. The total treatment duration was 6 months.Results. The group of adjuvant CHT included 24 patients with high-risk prostate cancer (T3b–4N+М0 with at least 5 regional lymph node metastases detected by morphological examination of surgical specimens). All patients had Gleason score 8–10 tumors. Mean age of patients was 63.0 ± 7.7 years (range: 46–72 years). In total, all patients received 142 courses of CHT. By the time of publishing this article, 23 (96 %) of patients completed their treatment.The group of neoadjuvant CHT included 40 patients with very high-risk prostate cancer (T3b–4N+М0 with metastases to pelvic and retroperitoneal lymph nodes detected by instrumental examination). All patients had Gleason score 8–10 tumors. Mean age of patients was 61.0± 6.4 years (range: 43–69 years). In total, all patients received 236 courses of CHT. By the time of publishing this article, 36 (90 %) of patients completed their treatment. Thirty-five patients (87 %) underwent radical prostatectomy with extensive pelvic and paraaortic lymphadenectomy. Routine pathological examination demonstrated that all patients had signs of tumor destruction. Thirty-three participants (94 %) had grade II therapeutic pathomorphosis, whereas 2 patients (6 %) had grade III therapeutic pathomorphosis.Median PSA relapse-free survival (PSA-RFS) rate in the neoadjuvant CHT group was 10 months. Serum PSA of 0.1 ng/mL 1 month postoperatively correlated with longer RFS (р = 0.04). Biochemical relapse (PSA level &gt;0.2 ng/mL) was observed in 6 patients (15 %) from this group. Later these patients received hormonal therapy with aLHRH. Median PSA-RFS in the adjuvant CHT group was 11 months.The main adverse events in the two groups were hematological toxicity, observed in 24 patients (34.29 %), and gastrointestinal toxicity, observed in 9 patients (12.86 %) (diarrhea (n = 6) and stomatitis (n = 3)). Only grade I–II toxicity was registered so far. Two patients (3.1 %) had febrile neutropenia, which required cytostatic dose reduction by 20 %. Relatively good tolerability and acceptable quality of life allowed the vast majority of patients to be treated on an outpatient basis.Conclusion. So far, we can make only a preliminary conclusion that adjuvant and neoadjuvant CHT is a promising treatment strategy for high-risk and very high-risk prostate cancer.

Stereotactic body radiation therapy for clinically localized prostate cancer

Background. In the last decade, we observed a significant increase in the number of patients undergoing radiotherapy for prostate cancer (PC). It became possible with the development of new equipment that can significantly increase radiation efficiency and reduce the frequency and severity of side effects. Active investigation of new fractionation regimens led to the development of stereotactic radiotherapy (StR) technique. In this article, we describe our own experience of using StR in patients with localized PC.Material and methods. The study included 48 patients treated with CyberKnife robotic radiosurgery system. The patients received a total dose of 36.25 Gy delivered in 5 fractions.Results. At a median follow-up of 24 months, the estimated four-year prostate-specific antigen (PSA) relapse-free survival rate was 95.8 %. The median PSA nadir was 0.48 ng/mL. We observed no grade III–IV side effects (either early or late).Conclusion. Our results suggest that the use of StR allows achieving good biochemical control comparable to that achieved by other methods and demonstrates comparable and sometimes even lower toxicity.

Long-Term Outcomes after Deferred Radical Prostatectomy in Men Initially Treated with Active Surveillance

We sought to determine long-term outcomes after deferred radical prostatectomy. The study population consisted of all 132 men with screening detected prostate cancer who underwent deferred radical prostatectomy from January 1, 1995 to December 31, 2014 after active surveillance in the Göteborg Randomized, Population-based Prostate Cancer Screening Trial. The last date of followup was May 15, 2017. Followup during active surveillance was performed with prostate specific antigen tests every 3 to 6 months and repeat biopsies every 2 to 4 years. Triggers for radical prostatectomy were disease progression based on prostate specific antigen, grade and/or stage, or patient request. Outcomes included adverse pathology findings at radical prostatectomy, defined as Gleason score greater than 3 + 4, extraprostatic extension, positive margins, seminal vesicle invasion and/or N+, whether the index tumor at radical prostatectomy was identified at biopsy and prostate specific antigen relapse-free survival. Kaplan-Meier analysis was performed. Median time from diagnosis to surgery was 1.9 years (IQR 1.2-4.2) and median postoperative followup was 10.9 years (IQR 7.5-14.5). A total of 52 men (39%) experienced at least 1 unfavorable pathology feature at radical prostatectomy. The 10-year prostate specific antigen relapse-free survival was 79.5%. The index tumor was not identified in the diagnostic biopsy in 38 of the 132 men (29%) or at the last repeat biopsy that preceded radical prostatectomy 22 of 105 (21%). A large proportion of men had unfavorable pathology findings at deferred radical prostatectomy and the index tumor was frequently not identified. There is a clear need for better risk classification and protocols to determine disease progression during active surveillance.

Image-guided radiotherapy reduces the risk of under-dosing high-risk prostate cancer extra-capsular disease and improves biochemical control

BackgroundTo determine if reduced dose delivery uncertainty is associated with daily image-guidance (IG) and Prostate Specific Antigen Relapse Free Survival (PRFS) in intensity-modulated radiotherapy (IMRT) of high-risk prostate cancer (PCa).MethodsPlanning data for consecutive PCa patients treated with IMRT (n = 67) and IG-IMRT (n = 35) was retrieved. Using computer simulations of setup errors, we estimated the patient-specific uncertainty in accumulated treatment dose distributions for the prostate and for posterolateral aspects of the gland that are at highest risk for extra-capsular disease. Multivariate Cox regression for PRFS considering Gleason score, T-stage, pre-treatment PSA, number of elevated clinical risk factors (T2c+, GS7+ and PSA10+), nomogram-predicted risk of extra-capsular disease (ECD), and dose metrics was performed.ResultsFor IMRT vs. IG-IMRT, plan dosimetry values were similar, but simulations revealed uncertainty in delivered dose external to the prostate was significantly different, due to positioning uncertainties. A patient-specific interaction term of the risk of ECD and risk of low dose to the ECD (p = 0.005), and the number of elevated clinical risk factors (p = 0.008), correlate with reduced PRFS.ConclusionsImprovements in PSA outcomes for high-risk PCa using IG-IMRT vs. IMRT without IG may be due to improved dosimetry for ECD.

Dose escalation of external beam radiotherapy for high-risk prostate cancer—Impact of multiple high-risk factor

ObjectiveTo retrospectively investigate the treatment outcomes of external beam radiotherapy with androgen deprivation therapy (ADT) in high-risk prostate cancer in three radiotherapy dose groups. MethodsBetween 1998 and 2013, patients with high-risk prostate cancer underwent three-dimensional conformal radiotherapy or intensity-modulated radiotherapy of 66 Gy, 72 Gy, or 78 Gy with ADT. Prostate-specific antigen (PSA) relapse was defined using the Phoenix definition. PSA relapse-free survival (PRFS) was evaluated in each radiotherapy dose group. Moreover, high-risk patients were divided into H-1 (patients with multiple high-risk factors) and H-2 (patients with a single high-risk factor) as risk subgroups. ResultsTwo hundred and eighty-nine patients with a median follow-up period of 77.3 months were analyzed in this study. The median duration of ADT was 10.1 months. Age, Gleason score, T stage, and radiotherapy dose influenced PRFS with statistical significance both in univariate and multivariate analyses. The 4-year PRFS rates in Group-66 Gy, Group-72 Gy and Group-78 Gy were 72.7%, 81.6% and 90.3%, respectively. PRFS rates in the H-1 subgroup differed with statistical significance with an increasing radiotherapy dose having a more favorable PRFS, while PRFS rates in H-2 subgroup did not differ with increase in radiotherapy dose. ConclusionDose escalation for high-risk prostate cancer in combination with ADT improved PRFS. PRFS for patients in the H-1 subgroup was poor, but dose escalation in those patients was beneficial, while dose escalation in the H-2 subgroup was not proven to be effective for improving PRFS.

Modified risk stratification grouping using standard clinical and biopsy information for patients undergoing radical prostatectomy: Results from SEARCH.

Prostate cancer is a heterogeneous disease, and risk stratification systems have been proposed to guide treatment decisions. However, significant heterogeneity remains for those with unfavorable-risk disease. This study included 3335 patients undergoing radical prostatectomy without adjuvant radiotherapy in the SEARCH database. High-risk patients were dichotomized into standard and very high-risk (VHR) groups based on primary Gleason pattern, percentage of positive biopsy cores (PPBC), number of NCCN high-risk factors, and stage T3b-T4 disease. Similarly, intermediate-risk prostate cancer was separated into favorable and unfavorable groups based on primary Gleason pattern, PPBC, and number of NCCN intermediate-risk factors. Median follow-up was 78 months. Patients with VHR prostate cancer had significantly worse PSA relapse-free survival (PSA-RFS, P < 0.001), distant metastasis (DM, P = 0.004), and prostate cancer-specific mortality (PCSM, P = 0.015) in comparison to standard high-risk (SHR) patients in multivariable analyses. By contrast, there was no significant difference in PSA-RFS, DM, or PCSM between SHR and unfavorable intermediate-risk (UIR) patients. Therefore, we propose a novel risk stratification system: Group 1 (low-risk), Group 2 (favorable intermediate-risk), Group 3 (UIR and SHR), and Group 4 (VHR). The c-index of this new grouping was 0.683 for PSA-RFS and 0.800 for metastases, compared to NCCN-risk groups which yield 0.666 for PSA-RFS and 0.764 for metastases. Patients classified as VHR have markedly increased rates of PSA relapse, DM, and PCSM in comparison to SHR patients, whereas UIR and SHR patients have similar prognosis. Novel therapeutic strategies are needed for patients with VHR, likely involving multimodality therapy.

Dose-Escalated Intensity Modulated Radiation Therapy for Prostate Cancer: 15-Year Outcomes Data

To report 15-year outcomes data for dose-escalated IMRT for localized prostate cancer (PC) by evaluating biochemical relapse, distant metastases (DM), overall survival, and long-term toxicity. A database search was conducted for the first cohort of patients treated at this institution with 81 or 86.4 Gy between 1996 and 1998 using IMRT. Toxicity data was scored according to the Common Terminology Criteria for Adverse Events Version 3.0. The median follow-up was 11.6 years (range 5 to 21 years). During this time, 301 patients were treated with 81 Gy (n = 269, 89%) or 86.4 Gy (n = 32, 11%). Patients were also analyzed by NCCN risk group, with 29% low risk (LR) patients, 49% intermediate risk (IR), and 22% high risk (HR). Late grade 3 gastrointestinal (GI) toxicity was seen in 3 patients (1.0%). All 3 cases were due to rectal bleeding requiring transfusion, and 1 required embolization. No grade 4 GI toxicity events occurred. Median time from RT to late grade 3 GI toxicity was 2.9 years, and 1 event occurred after 10 years. Late grade 3 and 4 genitourinary (GU) toxicity were seen in 6 (2.0%) and 1 (0.3%) patient, respectively. Grade 3 toxicities were due to stricture requiring procedural intervention or hematuria/cystitis requiring bladder irrigation/debridement. Grade 4 toxicity was due to persistent hematuria ultimately requiring cytectomy. Median time to late grade 3+ GU toxicity was 5.5 years, and 2 events occurred after 10 years. 38 (12.6%) had second primary malignancies (SPM) diagnosed after prostate RT, 8 (22%) of which were in-field malignancies including colorectal and bladder cancers and 1 case of pubic bone sarcoma. Median time from RT to all SPM and in-field SPM was 10 years. The 15-year PSA relapse-free survival was 76%, 65%, and 55% in the LR, IR, and HR groups, respectively. DM-free survival was 88%, 75%, and 63% for LR, IR, and HR patients. Prostate cancer-specific mortality was 1.9%, 7.1%, and 12.2% for LR, IR, and HR risk patients. This report represents the longest follow-up data set to our knowledge of patients treated with high-dose IMRT for PC. Our findings indicate that it is well tolerated with 1.0% and 2.3% incidence of long-term grade 3+ GI and GU toxicity, respectively. The cohort had excellent PC-specific survival.

Salvage brachytherapy for recurrent prostate cancer after definitive radiation therapy: A comparison of low-dose-rate and high-dose-rate brachytherapy and the importance of prostate-specific antigen doubling time

BackgroundSalvage brachytherapy is a treatment option for patients with locally recurrent prostate cancer after primary radiation therapy. We reviewed our experience using low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy to compare the outcome and toxicity profiles of each approach in the salvage brachytherapy setting. Methods and MaterialsNinety-eight patients with biopsy-proven locally recurrent prostate cancer who underwent salvage brachytherapy (LDR = 37; HDR = 61) following an initial course of definitive radiotherapy between 4/2003 and 4/2015 were retrospectively reviewed. All patients underwent salvage brachytherapy using LDR or HDR. Androgen deprivation therapy was used in 45% of the patients. Prostate-specific antigen (PSA) failure was determined using the Phoenix (nadir+2) definition. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and patient-reported questionnaires. ResultsMedian followup was 31 months. The 3-year PSA relapse-free survival (RFS) was 60.1% (95% CI, 49.6–72.5%). There was no difference between LDR and HDR brachytherapy in terms of PSA RFS (p = 0.84 by log-rank test). On multivariate analysis, only prostate-specific antigen doubling time (PSADT) <12 months was significantly associated with PSA relapse. The 3-year PSA RFS for patients with a PSADT <12 months was 39% compared with 73% for PSADT ≥12 months (p = 0.002 by long-rank test). There were no statistically significant differences in toxicity between LDR and HDR brachytherapy. There was a higher peak in urinary symptoms in LDR patients; however by 24–36 months, most patients in both groups returned to baseline. ConclusionsBoth LDR and HDR salvage brachytherapy are an excellent treatment options for appropriately selected patients with comparable outcome and toxicity. Patients with a PSADT < 12 months seem to have worse outcomes.

Unification of favourable intermediate‐, unfavourable intermediate‐, and very high‐risk stratification criteria for prostate cancer

To improve on the existing risk-stratification systems for prostate cancer. This was a retrospective investigation including 2 248 patients undergoing dose-escalated external beam radiotherapy (EBRT) at a single institution. We separated National Comprehensive Cancer Network (NCCN) intermediate-risk prostate cancer into 'favourable' and 'unfavourable' groups based on primary Gleason pattern, percentage of positive biopsy cores (PPBC), and number of NCCN intermediate-risk factors. Similarly, NCCN high-risk prostate cancer was stratified into 'standard' and 'very high-risk' groups based on primary Gleason pattern, PPBC, number of NCCN high-risk factors, and stage T3b-T4 disease. Patients with unfavourable-intermediate-risk (UIR) prostate cancer had significantly inferior prostate-specific antigen relapse-free survival (PSA-RFS, P < 0.001), distant metastasis-free survival (DMFS, P < 0.001), prostate cancer-specific mortality (PCSM, P < 0.001), and overall survival (OS, P < 0.001) compared with patients with favourable-intermediate-risk (FIR) prostate cancer. Similarly, patients with very high-risk (VHR) prostate cancer had significantly worse PSA-RFS (P < 0.001), DMFS (P < 0.001), and PCSM (P = 0.001) compared with patients with standard high-risk (SHR) prostate cancer. Moreover, patients with FIR and low-risk prostate cancer had similar outcomes, as did patients with UIR and SHR prostate cancer. Consequently, we propose the following risk-stratification system: Group 1, low risk and FIR; Group 2, UIR and SHR; and Group 3, VHR. These groups have markedly different outcomes, with 8-year distant metastasis rates of 3%, 9%, and 29% (P < 0.001) for Groups 1, 2, and 3, respectively, and 8-year PCSM of 1%, 4%, and 13% (P < 0.001) after EBRT. This modified stratification system was significantly more accurate than the three-tiered NCCN system currently in clinical use for all outcomes. Modifying the NCCN risk-stratification system to group FIR with low-risk patients and UIR with SHR patients, results in modestly improved prediction of outcomes, potentially allowing better personalisation of therapeutic recommendations.

Local tumor control and DNA-PK activity of peripheral blood lymphocytes in prostate cancer patients receiving radiotherapy.

Repair of DNA damage is critical for genomic stability, and DNA-dependent protein kinase (DNA-PK) has an important role in repairing double-strand breaks. We examined whether the DNA-PK activity of peripheral blood lymphocytes (PBLs) was related to biochemical (prostate-specific antigen: PSA) relapse and radiation toxicity in prostate cancer patients who have received radiotherapy. A total of 69 patients with localized adenocarcinoma of the prostate participated in this study. Peripheral blood was collected 2 years or later after radiotherapy and centrifuged, then DNA-PK activity was measured by a filter binding assay. The high DNA-PK activity group had a significantly higher PSA relapse–free survival rate than the low DNA-PK activity group. The 10-year PSA relapse–free survival was 87.0% in the high DNA-PK activity group, whereas it was 52.7% in the low DNA-PK activity group. Multivariate analysis showed the Gleason score and the level of DNA-PK activity were significant predictors of PSA relapse after radiotherapy. In addition, the low DNA-PK activity group tended to have a higher incidence of Grade 1–2 urinary toxicity than the high DNA-PK activity group. Prostate cancer patients with low DNA-PK activity had a higher rate of PSA relapse and a higher incidence of urinary toxicity. DNA-PK activity in PBLs might be a useful marker for predicting PSA relapse and urinary toxicity, possibly contributing to personalized treatment of prostate cancer.