A "scoping" review of prostate brachytherapy and immune responses.

PURPOSE: Whether prostate brachytherapy (BT) results in opportunistic biological changes that can improve clinical outcomes is not well studied. We sought to investigate the impact of prostate BT on the immune system. MATERIALS AND METHODS: A scoping review was performed using PubMed/Scopus for papers published between 2011-2021. Search terms were "brachytherapy" AND "immune" AND "prostate". A total of 81 records were identified and 6 were selected for further review. RESULTS: 2 low-dose-rate BT papers (n=68) evaluated changes in the peripheral blood following I-125 monotherapy. Both showed significant increases in peripheral CD3+ and CD4+ T cells post-BT. One also demonstrated significant increases in Treg subsets up to 150 days post-BT. 4 high-dose-rate (HDR) studies (n=37) were identified, and all were done in combination with EBRT. The largest study (n=24) showed a single 10 Gy fraction of HDR converted 80% of "cold" tumors into an "intermediate" or "hot" state, based on a tumor inflammation signature when comparing a pre-BT biopsy to one prior to a second HDR fraction. CONCLUSION: Prostate BT can invoke an immune activating phenotype; however, changes in immunosuppressive cells are also seen. Additional data is needed to understand how to promote synergy between BT and the immune system.

High-dose-rate fractionated brachytherapy monotherapy for localized prostate cancer: a systematic review and meta-analysis.

PURPOSE: High-dose-rate (HDR) brachytherapy as primary therapy (monotherapy) is a standard National Comprehensive Cancer Network (NCCN) endorsed treatment option for patients with localized prostate cancer. Thus far, most data are limited to single-institution experiences. Accordingly, we sought to systematically review rates of biochemical recurrence-free survival (bRFS) and toxicity associated with fractionated HDR monotherapy. MATERIAL AND METHODS: A systematic review was performed using PubMed and Embase databases for relevant articles published between January 1999 and December 2019, according to preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines. Included studies were limited to fractionated HDR monotherapy publications in full manuscript form with at least 5-year median follow-up, at least 80 patients included, and adequate reporting of bRFS and toxicity data. Meta-analyses were performed with random-effect modeling. Extent of heterogeneity between studies was determined using I 2 and Cochran's Q tests. RESULTS: Seven unique studies were identified, including 2,123 patients. NCCN low-, intermediate-, and high-risk patients comprised 40%, 40%, and 20% of patients, respectively. Median follow-up at the study group level was 74 months (range, 60-131 months). The 5-year bRFS rate was 95% (95% confidence interval [CI]: 93-96%), and after adjusting to control for publication bias, it was 96% (95% CI: 94-99%). Estimated adjusted late grade ≥ 3 genitourinary and gastrointestinal toxicity rates were 2% (95% CI: 1-4%) and 0.3% (95% CI: 0-1.1%), respectively. CONCLUSIONS: Fractionated HDR monotherapy is associated with high rates of disease control and low rates of toxicity. Future studies are needed to better define the value of this treatment modality relative to other options.

Targeted Prostate Biopsy Gleason Score Heterogeneity and Implications for Risk Stratification.

OBJECTIVES: To quantify Gleason score (GS) heterogeneity within multiparametric magnetic resonance imaging (MRI)-targeted prostate biopsies and to determine impact on National Comprehensive Cancer Network (NCCN) risk stratification. METHODS: An Institutional Review Board-approved retrospective study was performed on men who underwent Artemis (MRI-transrectal-ultrasound fusion) targeted biopsy (TB) for suspected prostate cancer between 2012 and 2015. Intratarget heterogeneity was defined as a difference in GS between 2 cores within a single target in patients with ≥2 positive cores. Prostate specific antigen, maximum tumor diameter, apparent diffusion coefficient, MRI suspicion score, prostate volume, systematic biopsy (SB) GS, and T-stage were analyzed for correlation with heterogeneity. Changes in NCCN risk based on high versus low GS on TB, SB alone, and SB+TB were compared. RESULTS: Fifty-three patients underwent TB of 73 suspected lesions. Seventy percent (51/73) had ≥2 positive cores, thus meeting inclusion criteria for heterogeneity analysis. Fifty-five percent (28/51) of qualifying targets showed GS heterogeneity. None of the evaluated factors showed a significant relationship with heterogeneity. NCCN low-risk, intermediate-risk, and high-risk groups were 30%, 49%, and 21%, respectively, with SB alone. Adding low GS TB to SB resulted in 17%, 55%, 28% in each risk group, while using high GS+SB resulted in 4%, 54%, and 42%. Overall, the addition of TB resulted in higher NCCN risk groups in 38% of cases. CONCLUSIONS: Over half of multiparametric MRI-defined targets demonstrated GS heterogeneity. The addition of high GS from TB leads to risk inflation compared with using SB alone. Further research is needed on how to integrate these findings into current risk stratification models and clinical practice.

A Pooled Analysis of Biochemical Failure in Intermediate-risk Prostate Cancer Following Definitive Stereotactic Body Radiotherapy (SBRT) or High-Dose-Rate Brachytherapy (HDR-B) Monotherapy.

OBJECTIVES: To investigate biochemical relapse-free survival (BRFS) in men with National Comprehensive Cancer Network-defined intermediate-risk prostate cancer (PC) treated with either stereotactic body radiotherapy (SBRT) or high-dose-rate brachytherapy (HDR-B) monotherapy. MATERIALS AND METHODS: A retrospective, multi-institutional analysis of 437 patients with intermediate-risk PC treated with SBRT (N=300) or HDR-B (N=137) was performed. Men who underwent SBRT were treated to 35 to 40 Gy in 4 to 5 fractions. A total of 95.6% who underwent HDR-B were treated to 42 Gy in 6 fractions. Baseline patient characteristics were compared using a T test for continuous variables and the Mantel-Haenszel χ metric or Fisher exact test for categorical variables. Kaplan-Meier curves were generated to estimate 5-year actuarial BRFS. Multivariate analysis using a Cox proportional-hazards model was used to evaluate factors associated with biochemical failure. RESULTS: The mean age at diagnosis was 68.4 (SD±7.8) years. T-category was T1 in 63.6% and T2 in 36.4%. Mean initial prostate-specific antigen was 7.4 (SD±3.4) ng/mL. Biopsy Gleason score was ≤3+4 in 82.8% and 4+3 in 17.2%. At a median of 4.1 years of follow-up, the BRFS rate (Phoenix definition) was 96.3%, with no difference when stratifying by treatment modality or biologically equivalent dose (BED1.5). On multivariate analysis, age (hazard ratio 1.08, P=0.04) and biopsy Gleason score (hazard ratio 2.48, P=0.03) were significant predictors of BRFS. CONCLUSIONS: With a median follow-up period of 4 years, SBRT and HDR-B monotherapy provide excellent BRFS in intermediate-risk PC. Longer-term follow-up is necessary to determine the ultimate efficacy of these hypofractionated approaches, but they appear promising relative to standard fractionation outcomes.

High-dose-rate brachytherapy monotherapy without androgen deprivation therapy for intermediate-risk prostate cancer.

PURPOSE: Outcomes using high-dose-rate (HDR) brachytherapy monotherapy (without androgen deprivation therapy or external beam radiation therapy) for National Comprehensive Cancer Network-defined intermediate-risk (IR) patients are limited. We report our long-term data using HDR monotherapy for this patient population. METHODS AND MATERIALS: One-hundred ninety IR prostate cancer patients were treated 1996-2013 with HDR monotherapy. Biochemical prostate-specific antigen (PSA) failure was per the Phoenix definition. Acute and late genitourinary and gastrointestinal toxicities were graded according to Common Toxicity Criteria of Adverse Events, version 4. Kaplan-Meier (KM) biochemical progression-free survival (BPFS), cause-specific survival, and overall survival rates were calculated. Univariate analyses were performed to determine relationships with BPFS. The median patient age was 66 years (43-90), and the median initial PSA was 7.4 ng/mL. The Gleason score was ≤6 in 26%, 3 + 4 in 62%, and 4 + 3 in 12%. The median treatment BED1.5 was 254 Gy; 83% of patients were treated with a dose of 7.25 Gy × six fractions delivered in two separate implants. RESULTS: With a median follow-up of 6.2 years, KM BPFS at 5/8 years was 97%/90%, cause-specific survival at 8 years was 100%, and overall survival at 5/8 years was 93%/88%. Late genitourinary toxicities were 36.3% Grade 1, 18.9% Grade 2, and 3.7% Grade 3. Late gastrointestinal toxicities were 6.3% Grade 1, 1.1% Grade 2, and no Grade ≥3. Of the patients with no sexual dysfunction before treatment, 68% maintained potency. Age, initial PSA, T stage, Gleason score, prostate volume, and percent positive cores did not correlate with BPFS. Stratifying by favorable vs. unfavorable IR groups did not affect BPFS. CONCLUSIONS: HDR brachytherapy monotherapy represents a safe and highly effective treatment for IR prostate cancer patients with long-term follow-up.

Does the addition of targeted prostate biopsies to standard systemic biopsies influence treatment management for radiation oncologists?

OBJECTIVES: To study the management impact that magnetic resonance imaging (MRI)-guided targeted prostate biopsies could provide relative to using only non-targeted systematic biopsies in men with clinically localized prostate cancer (PCa). PATIENTS AND METHODS: A consecutive series of untreated men undergoing Artemis (MRI-ultrasonography fusion) biopsies between March 2010 and June 2013 was evaluated in this retrospective, institutional review board-approved study. Fusion biopsy included MRI-targeted and systematic sampling at the same session. 3-Tesla multiparametric MRI was performed at a median of 2 weeks before biopsy. Patients were included if ≥1 systematic core was found to harbour PCa. The impact of the information obtained from targeted vs systematic biopsies was studied with regard to the following: Gleason score (GS), National Comprehensive Cancer Network (NCCN) risk reclassification, cancer core length, percentage of core positive for tumour involvement, and percentage of positive biopsy cores. RESULTS: The study sample included 215 men (mean ± sd age 66 ± 8 years). The median (range) prostate-specific antigen (PSA) was 6.0 (0.7-181) ng/mL. The mean number of total biopsy samples was 18 (12 systematic and six targeted samples). Of 215 men, 34 (16%) had a higher GS on targeted vs systematic biopsy. A total of 21/183 men (12%) were stratified into a higher NCCN risk group when incorporating targeted biopsy GS results and 18/101 men (18%) were upgraded to intermediate- or high-risk from the low-risk group. Among the 34 men whose cancer severity was upgraded, increases in cancer core length, percentage of tumour involvement and percentage of cores involved were all statistically significant (P < 0.01). CONCLUSION: Targeted prostate biopsy provided information about GS, NCCN risk and tumour volume beyond that obtained in systematic biopsies, specifically increasing the proportions of men in the intermediate- and high-risk groups. Such men may be recommended for additional treatments (pelvic nodal irradiation or hormonal therapy). The appropriateness of changing treatment because of targeted biopsy results is still unclear.

High-Dose-Rate Monotherapy for Localized Prostate Cancer: 10-Year Results.

PURPOSE: High-dose-rate (HDR) brachytherapy was originally used with external beam radiation therapy (EBRT) to increase the dose to the prostate without injuring the bladder or rectum. Numerous studies have reported HDR brachytherapy is safe and effective. We adapted it for use without EBRT for cases not requiring lymph node treatment. PATIENTS AND METHODS: We entered the patient demographics, disease characteristics, and treatment parameters into a prospective registry and serially added follow-up data for 448 men with low-risk (n=288) and intermediate-risk (n=160) prostate cancer treated from 1996 to 2009. Their median age was 64 years (range 42-90). The median prostate-specific antigen (PSA) level was 6.0 ng/mL (range 0.2-18.2). The Gleason score was ≤6 in 76% and 7 in 24%. The median dose was 43.5 Gy in 6 fractions. The clinical and biochemical disease control and survival rates were calculated. Adverse events were graded according to the Common Toxicity Criteria of Adverse Events. RESULTS: The median follow-up period was 6.5 years (range 0.3-15.3). The actuarial 6- and 10-year PSA progression-free survival was 98.6% (95% confidence interval [CI] 96.9%-99.4%) and 97.8% (95% CI 95.5%-98.9%). Overall survival at 10 years was 76.7% (95% CI 69.9%-82.2%). The local control, distant metastasis-free survival, and cause-specific survival were 99.7% (95% CI 97.9%-99.9%), 98.9% (95% CI 96.3%-99.7%), and 99.1% (95% CI 95.8%-99.8%). T stage, initial PSA level, Gleason score, National Comprehensive Cancer Network risk group, patient age, and androgen deprivation therapy did not significantly correlate with disease control or survival. No late grade 3 to 4 rectal toxicities developed. Late grade 3 to 4 genitourinary toxicity occurred in 4.9% (grade 3 in 4.7%). CONCLUSIONS: HDR monotherapy is a safe and highly effective treatment of low- and intermediate-risk prostate cancer.

Correlation of quantitative diffusion-weighted and dynamic contrast-enhanced MRI parameters with prognostic factors in prostate cancer.

INTRODUCTION: The aim of this study was to determine if correlations exist between quantitative parameters from dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI with National Comprehensive Cancer Network (NCCN) risk group, Gleason score (GS), maximum tumour diameter (MTD), pre-treatment prostate-specific antigen (PSA), clinical T stage and MRI prostate volume in prostate cancer. METHOD: We retrospectively reviewed 3T multiparametric MRI reports on biopsy-proven prostate cancer patients performed during radiation treatment evaluation or an active surveillance protocol. DCE-MRI parameters included K(trans) (influx volume transfer coefficient), Kep (efflux reflux rate constant) and iAUC (initial area under the curve). Average DCE and apparent diffusion coefficient (ADC) values were recorded for regions of interest on DW-MRI. Relationships between MRI metrics and risk group, GS, MTD, PSA, clinical T stage and MRI prostate volume were examined using analysis of variance. Central and peripheral tumours were also analysed separately in a sub-analysis. Statistical significance was defined as P < 0.0125. RESULTS: Of 58 patients, 29%, 52% and 19% had low (L), intermediate (I), or high (H) NCCN risk disease, respectively. K(trans) significantly correlated with PSA. For central tumours, K(trans) significantly correlated with MTD and PSA, and Kep significantly correlated with PSA. For peripheral tumours, iAUC was significantly different when stratified by L/I/H risk and GS, and ADC score with L/I/H risk, GS, and clinical T stage. CONCLUSIONS: DCE- and DW-MRI metrics correlate with some risk stratification factors in prostate cancer. Further work is required to determine if MRI metrics are complementary or independent prognostic factors.

Multiparametric MRI identifies and stratifies prostate cancer lesions: implications for targeting intraprostatic targets.

PURPOSE: To assess the ability of multiparametric (mp) MRI (mp-MRI) to identify, stratify, and localize biopsy-proven prostate cancer lesions in a risk-stratified patient population. METHODS AND MATERIALS: We retrospectively analyzed 57 patients who had mp-MRI and core needle biopsy during diagnostic prostate cancer evaluation. The MRI sequences were scored for suspicion of cancer with a previously described system. Distributions of mp-MRI scores were compared across National Comprehensive Cancer Network prostate cancer risk groups. The mp-MRI-identified lesions were compared with the location of positive core needle biopsies to assess mp-MRI localization of true lesions. RESULTS: The mp-MRI scoring system identified lesions in 84% (48/57) of the patients, including 100% (12/12) in the high-risk group. Scores assigned to lesions in patients in intermediate- and high-risk groups were statistically higher than those in the low-risk group, with a relative risk of 6.72 (95% confidence interval: 2.32-19.51, p<0.001) of having an aggressive score assigned in high-risk patients compared with the low-risk patients. In comparing the localization data from core needle biopsy, 68% of the patients had an MRI-identified lesion in or within one adjacent sextant of the same prostate hemigland, including 85% of aggressive lesions. CONCLUSIONS: Use of mp-MRI at the time of diagnosis can identify intraprostatic lesions and assign suspicion for high-risk disease. These data show that high-risk patients are more likely to have suspicious imaging-identified lesions that correlate to the location of biopsy-proven prostate cancer. At this time, the use of mp-MRI to define focal targets represents a complementary tool to patient evaluation for focal therapy strategies.

A phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas.

PURPOSE: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. METHODS AND MATERIALS: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). RESULTS: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. CONCLUSIONS: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer.

Granulin-epithelin precursor (GEP/progranulin) is an autocrine growth factor for ovarian cancer. We examined the production and function of GEP and report that: (1) GEP production is regulated by endothelin (ET-1), lysophosphatidic acid (LPA), and cAMP; (2) cAMP signals GEP production through exchange protein activated by cAMP (EPAC); (3) ET-1 and cAMP/EPAC induce GEP through ERK1/2; and (4) neutralization of GEP results in apoptosis. Exposure of HEY-A8 and OVCAR3 ovarian cancer cells to LPA and ET-1 yielded GEP production and secretion in a dose- and time-dependent fashion; neither stimulated significant concentrations of cAMP directly. Stimulation of cAMP production with pertussis and cholera toxin, or forskolin induced GEP in a PKA-independent fashion. EPAC, an intracellular cAMP receptor, is activated specifically by the cAMP analog, 8-CPT-2'-O-Me-cAMP (8-CPT); 8-CPT treatment stimulated GEP production and secretion. The MEK inhibitor, U0126, abrogated GEP production in response to ET-1 and 8-CPT, confirming involvement of MAPK. A partial inhibition of basal and stimulated GEP production was observed when cells were treated with a internal calcium chelator, BAPTA. Neutralizing anti-GEP antibody reversed basal as well as LPA, ET-1 and 8-CPT-induced ovarian cancer cell growth and induced apoptosis as demonstrated by caspase-3 and PARP cleavage, DNA fragmentation, and nuclear condensation. These results indicate that GEP is a growth and survival factor for ovarian cancer, induced by LPA and ET-1 and cAMP/EPAC through ERK1/2.