Intermediate Risk Prostate Carcinoma Research Articles

A Multicenter Phase 2 Study of Ultrahypofractionated Stereotactic Boost After External Beam Radiotherapy in Intermediate-risk Prostate Carcinoma: A Very Long-term Analysis of the CKNO-PRO Trial

BackgroundGenitourinary (GU) or gastrointestinal (GI) complications and tumor relapse can occur in the long term after radiotherapy for prostate cancer. ObjectiveTo assess the late tolerance and relapse-free survival (RFS) in patients undergoing hypofractionated stereotactic boost therapy after external beam radiotherapy (EBRT) for intermediate-risk prostate cancer. Design, setting, and participantsSeventy-six patients with intermediate-risk prostate carcinoma between August 2010 and April 2013 were included. The first course delivered a dose of 46 Gy by conventional fractionation; the second course was a boost of 18 Gy (3 × 6 Gy) within 10 d. Outcome measurements and statistical analysisGU and GI toxicities were evaluated as the primary outcomes. The secondary outcomes were overall survival and RFS. The cumulative incidence of toxicity was calculated using a competing-risk approach. Overall survival and RFS were estimated using the Kaplan-Meier method. Results and limitationsThe median follow-up period was 88 mo (range, 81–99 mo). Sixty (79%) patients were treated with the CyberKnife and 16 (21%) using a linear accelerator. The cumulative incidences of GU and GI grade ≥2 toxicities at 120 mo were 1.4% (95% confidence interval [CI]: 0.1–6.6%) and 11.0% (95% CI: 5.1–19.4%), respectively. The overall survival and RFS rates at 8 yr were 89.1% (95% CI: 77–95%) and 76.9% (95% CI: 63.1–86.1), respectively. ConclusionsA very long follow-up showed low GU and GI toxicities after a hypofractionated stereotactic boost after EBRT for intermediate-risk prostate cancer. Dose escalation of the boost delivered by hypofractionated radiation therapy appears safe for use in future trials. Patient summaryWe found low toxicity and good survival rates after a short and high-precision boost after external beam radiotherapy for intermediate-risk prostate cancer, with a long-term follow-up of 88 mo. This long-term treatment is safe and should be considered in future trials.

PD-0568 Long-term results of Iodine-125 seed brachytherapy in low and intermediate risk prostate carcinoma

PD-0568 Long-term results of Iodine-125 seed brachytherapy in low and intermediate risk prostate carcinoma

Long-term results with custom-linked iodine-125 seeds and real-time brachytherapy in low- and intermediate-risk prostate cancer.

PurposeBrachytherapy (BT) with iodine-125 (125I) seeds is effective in low- and intermediate-risk prostate carcinoma, with fewer side effects compared to other techniques, but relapses increase in long-term. In the present paper, 10-year biochemical relapse-free survival (BRFS) results are presented.Material and methodsBetween 2007 and 2016, 706 patients were treated with real-time technique using Bard-ProLink™ system. 145 Gy was administered to the prostate with exclusive BT and 108 Gy after 46 Gy of external radiotherapy (EBRT). Androgen deprivation therapy was applied in 19.3% of patients.ResultsMedian follow-up was 96 months (range, 24-163 months). BRFS at 5 and 10 years was 95% and 91.1%, respectively. For 480 low-risk cases, BRFS at 5 and 10 years was 95.7% and 92.7%, and for 226 intermediate-risk cases, it was 92.7% and 88%, respectively (p < 0.05). With combined treatment of EBRT + BT, 133 cases (59%) of intermediate-risk were treated without differences with exclusive BT. Gleason score 4 + 3 cases dropped to 72.8% at 10 years (p < 0.001), with androgen deprivation therapy (ADT) to 90.9% and without ADT to 66.8%; it was worse if patients had exclusive BT. 10-year BRFS for T1c was 95% compared to 84% for T2 (p < 0.001). Initial prostate specific antigen (PSA) > or < 10 showed no differences. With > 50% biopsy cores positive, it fell to 80% at 10 years (p < 0.001). In 154 patients up to 60 years of age, 10-year BRFS was 97.6%. Urinary complications appeared in 16.9% of cases in exclusive BT vs. 26.1% in EBRT + BT. Grade 2+ urinary late complications were observed in 19.1% and grade 3+ in 5.8% of patients. Rectal toxicity was 4% (2.5% in BT alone and 10.1% in RT + BT), while G3+ was seen in 0.1%.ConclusionsReal-time BT with custom-linked 125I seeds is a very effective long-term treatment in low- and intermediate-risk prostate carcinoma. With Gleason score 4 + 3 or > 50% biopsy cores positive, we recommend combined treatment with additional ADT for 6 months.

Low-/high-dose-rate brachytherapy boost in patients with intermediate-risk prostate cancer treated with radiotherapy: long-term results from a single institution team experience.

PurposeTo compare brachytherapy (BT) boost of low-dose-rate (LDR) and high-dose-rate (HDR) techniques in patients diagnosed with intermediate-risk prostate cancer.Material and methodsBetween January 2005 and February 2018, 142 patients (50 LDR and 92 HDR) with intermediate-risk prostate cancer were treated with a BT boost, and retrospectively analyzed. Prescribed dose was 45 Gy with external beam radiotherapy (EBRT) plus 100-108 Gy with LDR-BT, and 60 Gy with EBRT plus one fraction of 10 Gy with HDR-BT. 99% of patients received androgen deprivation therapy (ADT) for 6 months. Primary endpoint was to compare LDR and HDR boosts in terms of biochemical progression-free survival (bPFS). Secondary endpoint, after re-classifying patients into “favorable” and “unfavorable” sub-groups, was to analyze differences with a similar treatment intensity.ResultsMedian overall follow-up for the total cohort was 66.5 months (range, 16-185 months). There were no significant differences in bPFS, overall survival, cause specific survival, local failure, lymph node failure, or distant failure when LDR or HDR was employed. bPFS at 90 months was 100% for favorable, and 89% and 85% for unfavorable patients at 60 months and 90 months, respectively (log-rank test, p = 0.017). The crude incidence of genitourinary acute and chronic toxicity grade 3 was 0.7% and 4%, respectively. Twelve patients (8%) had chronic rectal hemorrhage grade 2, in whom argon was applied (4 LDR and 8 HDR).ConclusionsCombined treatment is an excellent therapeutic option in patients with intermediate-risk prostate carcinoma, with similar results in both LDR and HDR approaches and very low toxicities. Importantly, the current literature has indicated that unfavorable-risk patients belong to a different category, and should be treated as patients with high-risk factors. Therefore, the stratification and identification of both risk groups is extremely relevant.

MRI targeted single fraction HDR Brachytherapy for localized Prostate Carcinoma: a feasibility study of focal radiation therapy (ProFocAL).

The aim of the study was to establish the setup and workflow for delivering focal MRI-guided high-dose-rate (HDR) brachytherapy for prostate cancer (PCA) and to assess patient comfort and safety aspects of MRI-guided single-fraction HDR. Patients with histologically proven focal low- to intermediate-risk PCA with a single PIRADS 4/5 lesion were treated with percutaneous interstitial HDR brachytherapy in a single fraction with a minimum dose for the gross tumor volume of 20 Gy while sparing the organ at risk (OAR). Using a 3T-MRI, brachytherapy catheters were placed transgluteal in freehand technique. No antibiotic therapy or general analgesics were administered. Patient data, procedure time, patient discomfort, and complications were recorded. Quarterly PSA controls, biannual follow-up imaging, and annual re-biopsy were planned. So far, 9 patients were successfully treated and followed for 6 months. Mean intervention time was 34 min. Using the VAS scale, the pain reported for the intervention ranged from 2 to 3. Short-term follow-up showed no acute genitourinary or gastrointestinal toxicity so far. None of the patients displayed signs of infection. PSA levels in all patients decreased significantly. On follow up no residual PCA was detected treated region so far. PSA levels in all patients decreased significantly. On follow-up, no residual PCA was detected so far. MR-guided single-fraction focal HDR brachytherapy for localized PCA is feasible as well as safe for the individual patient. Catheters can be placed accurately and maximum therapeutic dose distribution can be restricted to the tumor. Countersigning the minimally invasive character of the procedure, no general anesthesia or antibiosis is necessary. • MR-guided focal HDR brachytherapy allows an accurate placement of catheters with maximum therapeutic dose distribution restricted to the tumor. • No major anesthesia or antibiosis is necessary emphasizing the minimal invasive character of the procedure. • Patients with low- and intermediate-risk prostate carcinoma in particular may benefit to halt disease progression whereas treatment-related morbidity is reduced compared with radical therapy.

A Multicenter Phase 2 study of Hypofractionated Stereostatic Boost in Intermediate Risk Prostate Carcinoma: A 5-Year Analysis of the CKNO-PRO Trial

The aim of this analysis was to assess the 5-year tolerance and survival in patients undergoing hypofractionated stereotactic boost after external beam radiation therapy (EBRT) for intermediate-risk prostate cancer. Between August 2010 and April 2013, 76 patients with intermediate-risk prostate carcinoma were included in the study. A first course delivered 46 Gy using conventional fractionation. The second course delivered a boost of 18 Gy (3 × 6 Gy) within 10 days using stereotactic body radiation therapy (SBRT). Gastrointestinal and genitourinary toxicities were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0. Secondary outcome measures were overall, biochemical relapse-free, and relapse-free survival; prostate-specific antigen kinetics; and patient functional status (urinary and sexual) according to the International Index of Erectile Function and International Prostate Symptom Score questionnaires. Sixty patients (79%) were treated by CyberKnife and 16 (21%) by linear accelerator. Median follow-up was 62 months (range, 29-69). The cumulative incidence of genitourinary and gastrointestinal grade ≥2 toxicities at month 60 after the end of radiation therapy was 1.4% (95% confidence interval [CI], 0.1%-6.6%) and 9.3% (95% CI, 4.1%-17.1%), respectively. Biochemical relapse-free and relapse-free survival rates at 5 years were 87.4% (95% CI, 77.1%-93.2%) and 86.2% (95% CI, 75.8-92.3), respectively. The mean (standard deviation) prostate-specific antigen variation within 3 months and 5 years post-radiation therapy was -1.20 ng/mL/mo (0.79) and -1.30 ng/mL/y (1.05), respectively. There was no significant difference between the International Prostate Symptom quality of life score between inclusion and month 60. For the International Index of Erectile Function, there was a significant difference between inclusion and month 60 (P = .005), with a higher proportion of severe/noninterpretable disorders at 60 months. The results of the trial demonstrate that the EBRT and SBRT combination is well tolerated and yields good efficacy results. These data provide a good basis for comparing EBRT and brachytherapy boost to EBRT and SBRT boost in future prospective studies.

2187 - SHARP hypofractionated stereotactic radiotherapy is low and intermediate-risk prostate carcinoma patients – PSA outcome

2187 - SHARP hypofractionated stereotactic radiotherapy is low and intermediate-risk prostate carcinoma patients – PSA outcome

Hypofractionated stereotactic body radiotherapy in low- and intermediate-risk prostate carcinoma.

PurposeStereotactic body radiotherapy (SBRT) takes advantage of low α/β ratio of prostate cancer to deliver a large dose in few fractions. We examined clinical outcomes of SBRT using CyberKnife for the treatment of low- and intermediate-risk prostate cancer.Materials and MethodsThis study was based on a retrospective analysis of the 33 patients treated with SBRT using CyberKnife for localized prostate cancer (27.3% in low-risk and 72.7% in intermediate-risk). Total dose of 36.25 Gy in 5 fractions of 7.25 Gy were administered. The acute and late toxicities were recorded using the Radiation Therapy Oncology Group scale. Prostate-specific antigen (PSA) response was monitored.ResultsThirty-three patients with a median 51 months (range, 6 to 71 months) follow-up were analyzed. There was no biochemical failure. Median PSA nadir was 0.27 ng/mL at median 33 months and PSA bounce occurred in 30.3% (n = 10) of patients at median at median 10.5 months after SBRT. No grade 3 acute toxicity was noted. The 18.2% of the patients had acute grade 2 genitourinary (GU) toxicities and 21.2% had acute grade 2 gastrointestinal (GI) toxicities. After follow-up of 2 months, most complications had returned to baseline. There was no grade 3 late GU and GI toxicity.ConclusionOur experience with SBRT using CyberKnife in low- and intermediate-risk prostate cancer demonstrates favorable efficacy and toxicity. Further studies with more patients and longer follow-up duration are required.

Stereotactic body radiotherapy as treatment for organ confined low- and intermediate-risk prostate carcinoma, a 7-year study.

Objectives: Stereotactic body radiation therapy (SBRT) takes advantage of the prostate’s low α/β ratio to deliver a large radiation dose in few fractions. Initial studies on small groups of low-risk patients support SBRT’s potential for clinical efficacy while limiting treatment-related morbidity and maintained quality of life. This prospective study expands upon prior studies to further evaluate SBRT efficacy for a large patient population with organ confined, low- and intermediate-risk prostate cancer patients.Methods: Four hundred seventy-seven patients with prostate cancer received CyberKnife SBRT. The median age was 68.6 years and the median PSA was 5.3 ng/mL. Three hundred twenty-four patients were low-risk (PSA <10 ng/mL and Gleason <7), 153 were intermediate-risk (PSA 10–20 ng/mL or Gleason = 7). Androgen deprivation therapy was administered to 51 patients for up to 6 months. One hundred fifty-four patients received 35 Gy delivered in five daily fractions; the remaining patients received a total dose of 36.25 Gy in five daily fractions. Biochemical failure was assessed using the phoenix criterion.Results: Median follow-up was 72 months. The median PSA at 7 years was 0.11 ng/mL. Biochemical failures occurred for 11 low-risk patients (2 locally), 14 intermediate-risk patients (3 locally). The actuarial 7-year freedom from biochemical failure was 95.6 and 89.6% for low- and intermediate-risk groups, respectively (p < 0.012). Among patients with intermediate-risk disease, those considered to have low intermediate-risk (Gleason 6 with PSA >10, or Gleason 3 + 4 with PSA <10; n = 106) had a significantly higher bDFS than patients with high intermediate-risk (Gleason 3 + 4 with PSA 10–20 or Gleason 4 + 3; n = 47), with bDFS of 93.5 vs. 79.3%, respectively. For the low-risk and low intermediate-risk groups, there was no difference in median PSA nadir or biochemical disease control between doses of 35 and 36.25 Gy.Conclusion: CyberKnife SBRT produces excellent biochemical control rates. Median PSA levels compare favorably with other radiation modalities and strongly suggest durability of response. These results also strongly suggest that 35 Gy is as effective as 36.25 Gy for low- and intermediate-risk patients.

EP-1292: Stereotactic boost in intermediate risk prostate carcinoma: preliminary results of a french multicentric study

EP-1292: Stereotactic boost in intermediate risk prostate carcinoma: preliminary results of a french multicentric study

PO-1029: Outcome of young patients treated with 125I-brachytherapy for low and intermediate risk prostate carcinoma

PO-1029: Outcome of young patients treated with 125I-brachytherapy for low and intermediate risk prostate carcinoma

Protease nexin 1: a novel regulator of prostate cancer cell growth and neo-angiogenesis

Prostate adenocarcinoma (CaP) is the most frequent cancer and second leading cause of cancer death among men in the Western world [1]. Hh signaling may augment the development of CaP as emerging data suggests that components of the pathway are potential indicators of worse prognosis [2]. One major clinical difficulty, however, is that many prostate cancers are indolent and cause no difficulty while others are aggressive and lead to morbidity and mortality. Current methods to distinguish CaP types are inadequate and could lead to overtreatment in many cases. We recently have shown that genetic alteration in the Hedgehog (Hh) pathway impacts CaP growth experimentally and may correlate with clinical outcome [3]. Examination of a cohort of intermediate risk prostate carcinoma patients by comparative genomic hybridization (CGH) for a panel of hedgehog related genes indicated a more rapid progression to PSA (prostate antigen) failure, bolstering this argument. Thus, studying the pathway may reveal promising avenues for distinguishing outcomes and identifying new targets for therapy. Our work has shown that Hh signaling can be regulated in part by a protein normally expressed in the prostate, protease nexin 1 (PN1, also known as serpinE2) [3]. PN1 is a serine protease inhibitor (serpin) with the ability to bind and neutralize the activity of thrombin, trypsin, and urokinase (uPA) [4]. The regulation of uPA is meaningful in cancer because of its role in the cleavage and activation of plasminogen to plasmin, which in turn activates matrix metalloproteinases (MMPs) and ECM remodelling [5]. Previously, we established that PN1-mediated inhibition of uPA served to inhibit metastatic prostate cell invasion in Matrigel [6]. Our new study features several components. Firstly, we show that PN1 inhibits Hh signaling by reduction in the hedgehog ligand, Sonic (SHH). This regulation is dependent upon uptake of PN1 through the LRP receptor and on the inhibitory activity of PN1. The immediate functional impact of PN1 is to reduce proliferation of prostate metastatic cells both in culture and in vivo. Indeed, inducing expression of PN1 in several different prostate cancer cells was as effective in the inhibition of proliferation as treatment with the Hh-pathway inhibitor cyclopamine. Hh signaling inhibition also substantially reduced neo-angiogenesis. Xenografts from PC3 prostate cancer cells expressed high levels of SHH, producing small, disorganized vessels typical of tumour vasculature. These results are in line with other reports linking the Hedgehog pathway with the formation of new blood vessels and increases in tumor growth and metastasis [7]. By contrast, tumors treated with hedgehog inhibitors like GDC-0449 and pre-treated with PN1 recombinant protein exhibited altered vasculature with fewer vessels and larger overall diameters. The consequence of reduction in hedgehog signaling was decreased overall vascular density and slower tumor growth. The capacity to reduce tumor growth and vessel formation suggests a new physiological significance for PN1 and perhaps other serpins with similar functions. Interestingly, PN1 features some similarities to maspin, a tumor suppressor and angiogenesis blocker. Maspin has also been reported to reduce uPA-mediated CaP [8]. However, PN1 is more stable in a purified recombinant state than maspin and may actually have a larger range of inhibitory targets or cell type interactions [8]. For example, a recent report has observed that PN1 may be able to interact with endothelial cells, the initiators of angiogenesis [9]. As a regulatory toggle, we have shown that PN1 is also a target of MMP9-mediated degradation. The localisation of PN1 in the ECM allows for its regulation by MMP9, an important factor in metastasis that can cleave collagen and basement membrane to drive this process. We extended these findings to show that higher MMP9 levels are inverse to PN1 levels and that this ratio is important in controlling hedgehog signaling. We demonstrate competing regulation of hedgehog signaling by PN1 and MMP9 in tissue culture, normal prostate tissues, xenografts, and orthotopic prostate cancers. The presence of PN1 in normal and BPH (benign prostate hypertrophy) tissues and decline in higher Gleason score samples may indicate that its loss is a marker of malignant transition in the prostate epithelium, amplifying Hh signaling. Indeed, one aim was to utilize Hh signalling as a stratifier of intermediate grade prostate cancer as the transitional status of these patients often makes treatment uncertain. Implications are that pharmacological inhibition of hedgehog signaling might be useful in this subset of patients. Thus, PN1 itself might be a potential therapeutic agent and, in combination with other SHH inhibitors, may be useful in the encouragement of CaP growth lag or inhibition. This work further indicates the potential important of hedgehog signaling in prostate cancer (Figure ​(Figure1).1). Given its emerging abilities to affect changes in proliferation, angiogenesis, and invasion, PN1 expression may be a suitable target for improving prostate cancer therapy. Figure 1 Expression of SHH in prostate cancer

Optimal treatment of intermediate‐risk prostate carcinoma with radiotherapy

The clinical heterogeneity of intermediate-risk prostate carcinoma presents a challenge to urologic oncology in terms of prognosis and management. There is controversy regarding whether patients with intermediate-risk prostate carcinoma should be treated with dose-escalated external beam radiotherapy (EBRT) (e.g., doses > 74 gray [Gy]), or conventional-dose EBRT (e.g., doses < 74 Gy) combined with androgen deprivation (AD). Data for this review were identified through searches for articles in MEDLINE and in conference proceedings, indexed from 1966 to 2004. Currently, the intermediate-risk prostate carcinoma grouping is defined on the basis of prostate-specific antigen (PSA), tumor classification (T classification), and Gleason score. Emerging evidence suggests that additional prognostic information may be derived from the percentage of positive core needle biopsies at the time of diagnosis and/or from the pretreatment PSA doubling time. Novel prognostic biomarkers include protein expression relating to cell cycle control, cell death, DNA repair, and intracellular signal transduction. Preclinical data support dose escalation or combined AD with radiation as a means to increase prostate carcinoma cell kill. There is Level I evidence that patients with intermediate-risk prostate carcinoma benefit from dose-escalated EBRT or AD plus conventional-dose EBRT. However, clinical evidence is lacking to support the uniform use of AD plus dose-escalated EBRT. Patients in the intermediate-risk group should be entered into well designed, randomized clinical trials of dose-escalated EBRT and AD with sufficient power to address biochemical failure and cause-specific survival endpoints. These studies should be stratified by novel prognostic markers and accompanied by strong translational endpoints to address clinical heterogeneity and to allow for individualized treatment.

TU‐EE‐A4‐02: Impact of Ultrasound‐Guided Patient Setup On OAR Dose in Conformal Radiation Therapy for Prostate Carcinoma

Purpose: To evaluate the impact of daily ultrasound‐guided patient repositioning on bladder and rectal dose in the treatment of prostate carcinoma with conformal radiation therapy. Method and Materials: Standard‐of‐care for the treatment of low and intermediate risk prostate carcinoma currently includes 3D conformal radiation therapy (3D‐CRT). During external beam therapy, ultrasound‐guided isocenter realignment can be performed daily to correct patient setup for prostate motion (up to 1 cm) relative to bony anatomical landmarks. In this study, five patients with substantial ultrasound‐documented inter‐fraction prostate motion during their treatment course were selected. Starting with the original treatment plan, two additional plans were retrospectively generated for each patient. In one set, using the ultrasound documented displacements, organ contours were moved for each fraction, thus simulating positioning with misalignment caused by organ motion if ultrasound guidance were not used. In a second set of plans, the isocenter was shifted, as were the organ contours, simulating realignment based on the ultrasound image. In all cases, the number of planned monitor units was set to those of the original plan. For a given patient, isodose distributions, DVHs and EUDs were calculated for the prostate, bladder, and rectum for each fraction and then combined for each shift condition. Results: In all reconstructed plans, there were no substantial changes in dose coverage of the prostate (&lt;0.21 % change in EUD) compared to the original plan. However, in some cases with no realignment, higher dose maxima were predicted in the bladder and rectum, with the consequent EUD for each organ significantly greater compared to the original plan. Conclusion: Although fractional organ motions may have little effect on the overall dose delivery to the prostate, the effect on the dose to OARs (rectum and bladder) can be significant if no daily realignment is performed.

357 Oral Results of escalated dose 3D-conformal radiotherapy (3D-CRT) for intermediate risk prostate carcinoma- biochemical response and local control

357 Oral Results of escalated dose 3D-conformal radiotherapy (3D-CRT) for intermediate risk prostate carcinoma- biochemical response and local control