Ejaculatory Function Following Stereotactic Body Radiation Therapy for Prostate Cancer.

BACKGROUND: Ejaculatory dysfunction is an important male quality of life issue which has not yet been studied in the setting of prostate stereotactic body radiation therapy (SBRT). AIM: The purpose of this study is to evaluate ejaculatory function following SBRT for prostate cancer. METHODS: Two hundred and thirty-one patients on a prospective quality of life study with baseline ejaculatory capacity treated with prostate SBRT from 2013 to 2019 were included in this analysis. Ejaculation was assessed via the Ejaculation Scale (ES-8) from the Male Sexual Health Questionnaire. Patients completed the questionnaire at 1, 3, 6, 9, 12, 18, and 24 months post-SBRT. Elderly patients (Age > 70) and those who received hormonal therapy were excluded from analysis. Patients were treated to 35-36.25 Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). OUTCOMES: Ejaculatory function was assessed by ES-8 scores (range 4-40) with lower values representing increased interference or annoyance. RESULTS: Median age at the time of treatment was 65 years. Median follow up was 24 months (IQR 19-24.5 months). 64.5% of patients had ED at baseline (SHIM < 22). The 2-year anejaculation rate was 15%. Mean composite ES-8 scores showed a decline in the first month following treatment then stabilized: 30.4 (start of treatment); 26.5 (1 month); 27.6 (3 month); 27.0 (6 month); 26.2 (9 month); 25.4 (12 month); 25.0 (18 month) and 25.4 (24 month). White race, higher pre-treatment SHIM (≥22), and higher ES-8 (≥31) at treatment start were significantly associated with a decreased probability of a clinically significant decline. Patient-reported ejaculate volume was significantly reduced at all time points post-SBRT. Ejaculatory discomfort peaked at 1 month and 9 months post-SBRT. Prior to treatment, 8.0% of men reported that they were very to extremely bothered by their ejaculatory dysfunction. The number of patients reporting this concern increased to 14.4% at one year and dropped to 11% at 24-months post-SBRT. CLINICAL TRANSLATION: Patients undergoing prostate SBRT may experience meaningful changes in ejaculatory function and should be counseled on the trajectory of these side effects. STRENGTHS & LIMITATIONS: This was a retrospective analysis of a prospectively maintained database. Subjective questionnaire responses captured limited aspects of ejaculatory function in this cohort. CONCLUSION: The high incidence of moderate to extreme bother in ejaculatory function before and after SBRT suggests a need for novel approaches to improving ejaculation. Sholklapper T, Creswell M, Cantalino J, et al. Ejaculatory Function Following Stereotactic Body Radiation Therapy for Prostate Cancer. J Sex Med 2022;19:771-780.

Erectile function after stereotactic body radiotherapy for localized prostate cancer.

OBJECTIVE: To elucidate the functional erection rate after prostate stereotactic body radiotherapy (SBRT) and to develop a comprehensive prognostic model of outcomes after treatment. PATIENTS AND METHODS: Between 2008 and 2013, 373 consecutive men with localized prostate cancer were treated with SBRT at a single academic institution as part of a prospective clinical trial or prospective registry. Prospective longitudinal patient-reported health-related quality of life (HRQoL) data was collected using the Expanded Prostate Cancer Index Composite (EPIC)-26 instrument. Functional erections were strictly defined as 'firm enough for intercourse' according to EPIC-26. Detailed comorbidity data were also collected. Logistic regression models were used to predict 24- and 60-month functional erection rates. Observed erection rates after SBRT were compared with those after other radiation therapies (external beam radiation therapy [EBRT] and brachytherapy) using prospectively validated models. RESULTS: The median (interquartile range) follow-up was 56 (37-73) months and the response rate at 2 years was 84%. For those with functional erections at baseline, 57% and 45% retained function at 24 and 60 months, respectively. On multivariable analysis for 24-month erectile function, significant variables included higher baseline sexual HRQoL (adjusted odds ratio [aOR] 1.55 per 10 points, 95% confidence interval [CI] 1.37-1.74; P < 0.001) and older age (aOR 0.66 per 10 years, 95% CI 0.43-1.00; P = 0.05). At 60 months, baseline HRQoL and age remained associated with erectile function, along with body mass index (aOR 0.45, 95% CI 0.26-0.78; P < 0.001). The 24- and 60-month models had excellent discrimination (c-index 0.81 and 0.84, respectively). Erection rates after SBRT were not statistically different from model-predicted rates after EBRT or brachytherapy for the whole cohort and the cohort with baseline erectile function. CONCLUSIONS: Intermediate- to long-term post-SBRT erectile function results are promising and not significantly different from other radiotherapy techniques. Clinicians can use our prognostic model to counsel patients regarding expected erectile function after SBRT.

Delayed postoperative C5 root palsy and the use of neurophysiologic monitoring.

INTRODUCTION: Although advances have been made in surgical technique and intraoperative monitoring, the rate of postoperative C5 palsy remains the same. We attempt to define characteristics which may predict risk of developing postoperative C5 palsy. METHODS: Retrospective chart review identified 644 patients undergoing cervical procedures. Anterior cervical discectomy and fusion was performed in 456, anterior cervical corpectomy and fusion (ACCF) in 78, posterior laminectomy and fusion (PLF) in 106, and posterior open-door laminoplasty in 4 patients. All patients had neurophysiologic monitoring [somatosensory-evoked potentials (SSEP), spontaneous electromyogram (EMG), and/or motor-evoked potential (MEP)]. RESULTS: Postoperative C5 root palsy occurred in 5 (2 with ACCF and 3 with PLF) cases (1.4%). In all cases, there were no changes in intraoperative neurophysiologic monitoring. C5 palsy did not occur before postoperative day 2. CONCLUSIONS: Patients undergoing cervical decompression remain at risk for C5 root palsy despite use of monitoring. Given that all patients experienced delayed onset of C5 palsy, MEP, SSEP, and EMG may not be sensitive enough to assess the risk of developing C5 palsy.

Embolization Prior to Radiosurgery in Treatment of Arteriovenous Malformations: Defining Radiosurgery Target Dose with Nidal Volume Reduction.

INTRODUCTION: Arteriovenous malformations (AVMs) can be treated with observation, surgery, embolization, stereotactic radiosurgery (SRS), or a combination of therapies. SRS has been used for AVMs that pose a high risk of surgery, such as in deep or eloquent anatomic locations. Smaller AVMs, <3 cm, have been shown to have higher rates of complete obliteration after SRS. For AVMs that are a larger size, embolization prior to SRS has been used to reduce the size of the AVM nidus. In this study we analyzed embolization prior to SRS to reduce nidal volume and describe imaging techniques to target for SRS post embolization. METHODS: We retrospectively reviewed all patients at a single academic institution treated with embolization prior to SRS for treatment of AVMs. We then used contrast enhanced magnetic resonance imaging (MRI) to contour AVM volumes based on pre-embolization imaging and compared to post-embolization imaging. Planned AVM volume prior to embolization was then compared to actual treated AVM volume. RESULTS: We identified 11 patients treated with embolization prior to SRS from 2011-2023. Median AVM nidal volume prior to embolization was 7.69 mL and post embolization was 3.61 ML (P < 0.01). There was a 45.5% obliteration rate at follow up in our series, with 2 minor complications related to radiosurgery. CONCLUSIONS: In our cohort, embolization prior to SRS resulted in a statistically significant reduction in AVM nidal volume. Therefore, embolization prior to SRS can result in dose reduction at time of SRS treatment allowing for decreased risk of SRS complications without higher embolization complication rates.

The association of patient and disease characteristics with the overtreatment of low-risk prostate cancer from 2010 to 2016.

BACKGROUND: Although active surveillance is the preferred management for low-risk prostate cancer (PCa), some men remain at risk of overtreatment with definitive local therapy. We hypothesized that baseline characteristics may be associated with overtreatment and represent a potential source of health disparities. We therefore examined the associations of patient and disease characteristics with the surgical overtreatment of low-risk PCa. METHODS: We identified men aged 45-75 years with cT1 cN0 cM0 prostate adenocarcinoma with biopsy Gleason score 6 and PSA < 10 ng/ml from 2010-2016 in the National Cancer Database (NCDB) and who underwent radical prostatectomy (RP). We evaluated the associations of baseline characteristics with clinically insignificant PCa (iPCa) at RP (i.e., "overtreatment"), defined as organ-confined (i.e., pT2) Gleason 3 + 3 disease, using multivariable logistic regression. RESULTS: We identified 36,088 men with low-risk PCa who underwent RP. The unadjusted rate of iPCa decreased during the study period, from 54.7% in 2010 to 40.0% in 2016. In multivariable analyses adjusting for baseline characteristics, older age (OR 0.98, 95% CI 0.97-0.98), later year of diagnosis (OR 0.62, 95% CI 0.57-0.67 for 2016 vs. 2010), Black race (OR 0.85, 95% CI 0.79-0.91), treatment at an academic/research program (OR 0.82, 95% CI 0.73-0.91), higher PSA (OR 0.91, 95% CI 0.90-0.92), and higher number of positive biopsy cores (OR 0.87, 95% CI 0.86-0.88) were independently associated with a lower risk of overtreatment (iPCa) at RP. Conversely, a greater number of biopsy cores sampled (OR 1.01, 95% CI 1.01-1.02) was independently associated with an increased risk of overtreatment (iPCa) at RP. CONCLUSIONS: We observed an ~27% reduction in rates of overtreatment of men with low-risk PCa over the study period. Several patient, disease, and structural characteristics are associated with detection of iPCa at RP and can inform the management of men with low-risk PCa to reduce potential overtreatment.

Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer.

BACKGROUND: Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery. METHODS: Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. RESULTS: From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. CONCLUSION: Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Stereotactic Body Radiation Therapy for Clinically Localized Prostate Cancer in Men With Hip Prostheses: A Cautionary Note.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been established as a safe and effective treatment for prostate cancer. SBRT requires high accuracy to reduce treatment margins. Metal hip prostheses create artifacts that distort pelvic imaging and potentially decrease the accuracy of target/organ at risk (OAR) identification and radiation dose calculations. Data on the safety and efficacy of SBRT after hip replacement is limited. This single-institution study sought to evaluate the safety and local control following SBRT for prostate cancer in men with hip replacements. METHODS: 23 patients treated with localized prostate cancer and a history of pre-treatment hip replacement, treated with SBRT from 2007 to 2017 at MedStar Georgetown University Hospital were included in this retrospective analysis. Treatment was administered with the CyberKnife® (Accuray Incorporated, Sunnyvale, CA) at doses of 35 Gy or 36.25 Gy in 5 fractions. The targets and OARs were identified and contoured by a single experienced Radiation Oncologist (SPC). The adequacy of the CT and T2W MRI images for treatment planning was assessed with a three-point scale (good, adequate, or suboptimal). During treatment planning, care was taken to avoid treatment beams that directly traversed the hip prosthesis. Toxicities were recorded and scored using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0). Local recurrence was confirmed by magnetic resonance imaging and/or prostate biopsy. RESULTS: The median follow-up was seven years. The patients were elderly (median age = 71 years) with a high rate of comorbidities (Charlson Comorbidity Index > 2 in 25%). Four patients had bilateral hip replacements. The majority of patients were low to intermediate risk per the D'Amico classification. Around 13% received upfront ADT. In total, 13 patients were treated with 35 Gy, and 10 were treated with 36.25 Gy. The rates of late > Grade 3 GU toxicity and > Grade 2 GI toxicity were 8.6% and 4.3%, respectively. There were no Grade 4 or 5 toxicities. Six patients (26%) developed a local recurrence at a median time of 7.5 years. Of these six patients, four had unilateral hip replacements and two had bilateral. Three underwent salvage cryotherapy and three received salvage ADT. CONCLUSIONS:  In the general population, high-grade toxicities and local recurrences are uncommon following prostate SBRT. However, in this cohort of patients with prior hip replacements, prostate SBRT had higher than expected rates of late toxicity and local recurrence. In the opinion of the authors, such patients should be counseled regarding an elevated risk of late toxicity and local recurrence with prostate SBRT. With its ultrasound guidance, brachytherapy would have the advantage of circumventing the need for MRI/CT-based imaging and thus may represent a preferable radiation alternative in this patient population. If these patients are treated with SBRT, they should be monitored closely for local recurrence so early salvage can be performed. We hope that recent advances in metal artifact reduction techniques and dose-calculation algorithms will improve future outcomes.

Cell therapy using ex vivo reprogrammed macrophages enhances antitumor immune responses in melanoma.

BACKGROUND: Macrophage-based cell therapies have shown modest success in clinical trials, which can be attributed to their phenotypic plasticity, where transplanted macrophages get reprogrammed towards a pro-tumor phenotype. In most tumor types, including melanoma, the balance between antitumor M1-like and tumor-promoting M2-like macrophages is critical in defining the local immune response with a higher M1/M2 ratio favoring antitumor immunity. Therefore, designing novel strategies to increase the M1/M2 ratio in the TME has high clinical significance and benefits macrophage-based cell therapies. METHODS: In this study, we reprogrammed antitumor and proinflammatory macrophages ex-vivo with HDAC6 inhibitors (HDAC6i). We administered the reprogrammed macrophages intratumorally as an adoptive cell therapy (ACT) in the syngeneic SM1 murine melanoma model and patient-derived xenograft bearing NSG-SGM3 humanized mouse models. We phenotyped the tumor-infiltrated immune cells by flow cytometry and histological analysis of tumor sections for macrophage markers. We performed bulk RNA-seq profiling of murine bone marrow-derived macrophages treated with vehicle or HDAC6i and single-cell RNA-seq profiling of SM1 tumor-infiltrated immune cells to determine the effect of intratumor macrophage ACT on the tumor microenvironment (TME). We further analyzed the single-cell data to identify key cell-cell interactions and trajectory analysis to determine the fate of tumor-associated macrophages post-ACT. RESULTS: Macrophage ACT resulted in diminished tumor growth in both mouse models. We also demonstrated that HDAC6 inhibition in macrophages suppressed the polarization toward tumor-promoting phenotype by attenuating STAT3-mediated M2 reprogramming. Two weeks post-transplantation, ACT macrophages were viable, and inhibition of HDAC6 rendered intratumor transplanted M1 macrophages resistant to repolarization towards protumor M2 phenotype in-vivo. Further characterization of tumors by flow cytometry, single-cell transcriptomics, and single-cell secretome analyses revealed a significant enrichment of antitumor M1-like macrophages, resulting in increased M1/M2 ratio and infiltration of CD8 effector T-cells. Computational analysis of single-cell RNA-seq data for cell-cell interactions and trajectory analyses indicated activation of monocytes and T-cells in the TME. CONCLUSIONS: In summary, for the first time, we demonstrated the potential of reprogramming macrophages ex-vivo with HDAC6 inhibitors as a viable macrophage cell therapy to treat solid tumors.

Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition.

Radiotherapy is a curative cancer treatment modality that imparts damage to cellular DNA, induces immunogenic cell death, and activates antitumor immunity. Despite the radiotherapy-induced direct antitumor effect seen within the treated volume, accumulating evidence indicates activation of innate antitumor immunity. Acute proinflammatory responses mediated by anticancer M1 macrophages are observed in the immediate aftermath following radiotherapy. However, after a few days, these M1 macrophages are converted to anti-inflammatory and pro-cancer M2 phenotype, leading to cancer resistance and underlying potential tumor relapse. Histone deacetylase 6 (HDAC6) plays a crucial role in regulating macrophage polarization and innate immune responses. Here, we report targeting HDAC6 function with a novel selective inhibitor (SP-2-225) as a potential therapeutic candidate for combination therapy with radiotherapy. This resulted in decreased tumor growth and enhanced M1/M2 ratio of infiltrating macrophages within tumors. These observations support the use of selective HDAC6 inhibitors to improve antitumor immune responses and prevent tumor relapse after radiotherapy.

Testosterone as a Biomarker for Quality of Life (QOL) Following Androgen Deprivation Therapy (ADT) and Stereotactic Body Radiotherapy (SBRT).

BACKGROUND: Androgen deprivation therapy (ADT) causes fatigue and sexual dysfunction. The time to testosterone recovery depends on patient and treatment-specific characteristics. The kinetics of testosterone recovery in men treated with neoadjuvant ADT and stereotactic body radiotherapy (SBRT) is not well established. This study seeks to characterize testosterone recovery and evaluate its relationship with the improvement in patient-reported hormonal and sexual function. METHODS: Institutional review board (IRB) approval was obtained for retrospective review of prospectively collected data. All patients with localized prostate cancer treated with short-course ADT (3-6 months of Leuprolide) and robotic SBRT (35-36.25 Gy in five fractions) at a single institution were included in this analysis. Testosterone levels were measured at the start of radiation, every 3 months for the first year, and every 6 months thereafter. Total testosterone recovery was defined as a serum level of >230 ng/dL. Sexual and hormonal function was recorded using the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of SBRT, and at each follow-up. The EPIC-26 subdomain scores were transformed to a 0-100 scale with higher scores reflecting less bother. RESULTS: Between January 2009 and May 2018, 122 men with a median age of 72 years (range: 55-89 years) received ADT followed by SBRT. Thirty-two percent (N=39) were black and 27% [N=39 were obese (BMI > 30)]. The median pre-SBRT testosterone level was 15 ng/dL (range: 3-89 ng/dL). Around 77% (N=94) of patients received 3 months of ADT. The median pre-ADT EPIC-26 Hormone and Sexual Domain Scores were 94 and 41, respectively. At 12 months, 71% (N=87) of patients recovered to a eugonadal state with a mean recovery time of 4 months post-SBRT. Hormonal and sexual subdomain scores declined significantly following ADT but recovered to within the minimally important difference (MID) for sexual and hormonal domain scores by 12 months post-SBRT. CONCLUSIONS: Testosterone recovery following short-course ADT with leuprolide and SBRT occurs rapidly in the majority of patients within one year after treatment. Quality of life domain improvements followed the testosterone recovery trend closely. Testosterone testing at follow-up appointments would allow for anticipatory counseling that may limit the bother associated with temporary quality of life decrements.

Intensity modulated radiation therapy with stereotactic body radiation therapy boost for unfavorable prostate cancer: five-year outcomes.

Purpose: Intensity-modulated radiation therapy (IMRT) with brachytherapy boost for unfavorable prostate cancer has been shown to improve biochemical relapse-free survival compared to IMRT alone. Stereotactic body radiation therapy (SBRT) is a less-invasive alternative to brachytherapy. Early outcomes utilizing SBRT boost suggest low rates of high-grade toxicity with a maintained patient-reported quality of life. Here, we report the 5-year progression-free survival (PFS) and prostate cancer-specific survival (PCSS) of patients treated with IMRT plus SBRT boost. Materials and methods: Between 2008 and 2020, 255 patients with unfavorable prostate cancer were treated with robotic SBRT (19.5 Gy in three fractions) followed by fiducial-guided IMRT (45-50.4 Gy) according to an institutional protocol. For the first year, the patient's PSA level was monitored every 3 months, biannually for 2 years, and annually thereafter. Failure was defined as nadir + 2 ng/mL or a rising PSA with imaging suggestive of recurrence. Detection of recurrence also included digital rectal examination and imaging studies, such as MRI, CT, PET/CT, and/or bone scans. PFS and PCSS were calculated using the Kaplan-Meier method. Results: The median follow-up period was 71 months. According to the NCCN risk classification, 5% (13/255) of the patients had favorable intermediate-risk disease, 23% (57/255) had unfavorable intermediate-risk disease, 40% (102/255) had high-risk disease, and 32% (83/255) had very high-risk disease. Androgen deprivation therapy was administered to 80% (204/255) of the patients. Elective pelvic lymph node IMRT was performed in 28 (10%) patients. The PFS for all patients at 5 years was 81% (favorable intermediate risk, 91%; unfavorable intermediate risk, 89%; high-risk, 78%; and very-high risk, 72%). The PCSS for all patients at 5 years was 97% (favorable intermediate risk, 100%; unfavorable intermediate risk, 100%; high risk, 100%; and very high risk, 89%). Conclusion: The incidence of failure following IMRT plus SBRT for unfavorable prostate cancer remains low at 5 years.

Association of baseline self-reported fatigue with overall survival after stereotactic body radiation therapy for localized prostate cancer.

Introduction: Stereotactic Body Radiation Therapy (SBRT) has emerged as a definitive therapy for localized prostate cancer (PCa). However, more data is needed to predict patient prognosis to help guide which patients will benefit most from treatment. The FACIT-Fatigue (FACIT-F) is a well validated, widely used survey for assessing fatigue. However, the role of fatigue in predicting PCa survival has yet to be studied. Herein, we investigate the role of FACIT-F as a baseline predictor for overall survival (OS) in patients undergoing SBRT for localized PCa. Methods: A retrospective review was conducted of 1358 patients who received SBRT monotherapy between January 2008 to April 2021 at an academic, tertiary referral center. FACIT-F scores (range 0 to 52) were summed for patients who answered all 13-items on the survey. FACIT-F total scores of ≥35 represented severe fatigue. Patients receiving androgen deprivation therapy were excluded. Differences in fatigue groups were evaluated using chi-squared tests. OS rates were determined using the Kaplan-Meier method and predictors of OS were evaluated using Cox proportional hazard method. Results: Baseline full FACIT-F scores and survival data was available for 891 patients. 5-year OS was 87.6% and 95.2%, respectively, for the severely fatigued and non-fatigued groups. Chi-squared analysis of fatigue groups showed no significant difference in the following categories: D'Amico risk group, age, ethnicity, grade group, T-stage, or PSA density. Severe fatigue was associated with a significant decrease in OS (hazard ratio 2.76; 95%CI 1.55 - 4.89). The Cox proportional hazard model revealed that age and FACIT-F were both statistically significant (p <0.05). Conclusion: Baseline FACIT-F scores are significantly associated with OS. Higher FACIT-F scores, representing less fatigued patients, are associated with an overall survival benefit. These results indicate that the FACIT-F survey could serve as an additional metric for clinicians in determining prognostic factors for patients undergoing SBRT.

Rationale for Utilization of Hydrogel Rectal Spacers in Dose Escalated SBRT for the Treatment of Unfavorable Risk Prostate Cancer.

In this review we outline the current evidence for the use of hydrogel rectal spacers in the treatment paradigm for prostate cancer with external beam radiation therapy. We review their development, summarize clinical evidence, risk of adverse events, best practices for placement, treatment planning considerations and finally we outline a framework and rationale for the utilization of rectal spacers when treating unfavorable risk prostate cancer with dose escalated Stereotactic Body Radiation Therapy (SBRT).

Patient-Reported Financial Burden Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer.

Introduction and Objectives: In patients with localized prostate cancer, 5-fraction, stereotactic body radiation therapy (SBRT) has been found to offer comparable oncologic outcomes and potential for improved treatment compliance compared to conventional, 40-plus fraction radiation therapy (RT). Recent studies of oncologic patient experiences have highlighted both the impact of therapy-associated financial toxicity (FT) on treatment adherence and health-related quality of life (HRQOL). Methods: A cross-sectional assessment of FT after SBRT was performed using the 12-item COST questionnaire. The total questionnaire score (range 0-44) was used to evaluate the FT grade (0-3), with a higher COST value representing lower grade. The patient zip code was used to approximate the distance from the index hospital. Univariate and multivariate analyses of the average COST score (0-4) are performed. Results: The response rate was 57.5% (332 of 575 consented patients) with 90.7%, 8.2%, and 1.1% experiencing grade 0, 1, and 2 FT, respectively, with no grade 3. Unemployment or disability, non-white race, low income, and concurrent hormonal therapy were associated with a statistically significant worse FT (lower COST value) on univariate and multivariate analyses (p < 0.05). Education level and insurance status significant were evaluated on univariate analysis only. There was a non-statistically significant difference in age, marital status, time since treatment, and distance from the index hospital. Conclusions: SBRT was associated with low FT. However, statistically significant socioeconomic disparities in FT remain despite ultra-hypofractionated treatment.

Refining the definition of biochemical failure in the era of stereotactic body radiation therapy for prostate cancer: The Phoenix definition and beyond.

BACKGROUND AND PURPOSE: The Phoenix definition for biochemical failure (BCF) after radiotherapy uses nadir PSA (nPSA) + 2 ng/mL to classify a BCF and was derived from conventionally fractionated radiotherapy, which produces significantly higher nPSAs than stereotactic body radiotherapy (SBRT). We investigated whether an alternative nPSA-based threshold could be used to define post-SBRT BCFs. MATERIALS AND METHODS: PSA kinetics data on 2038 patients from 9 institutions were retrospectively analyzed for low- and intermediate-risk PCa patients treated with SBRT without ADT. We evaluated the performance of various nPSA-based definitions. We also investigated the relationship of relative PSA decline (rPSA, PSA18month/PSA6month) and timing of reaching nPSA + 2 with BCF. RESULTS: Median follow-up was 71.9 months. BCF occurred in 6.9% of patients. Median nPSA was 0.16 ng/mL. False positivity of nPSA + 2 was 30.2%, compared to 40.9%, 57.8%, and 71.0% for nPSA + 1.5, nPSA + 1.0, and nPSA + 0.5, respectively. Among patients with BCF, the median lead time gained from an earlier nPSA + threshold definition over the Phoenix definition was minimal. Patients with BCF had significantly lower rates of early PSA decline (mean rPSA 1.19 vs. 0.39, p < 0.0001) and were significantly more likely to reach nPSA + 2 ≥ 18 months (83.3% vs. 21.1%, p < 0.0001). The proposed criterion (rPSA ≥ 2.6 or nPSA + 2 ≥ 18 months) had a sensitivity and specificity of 92.4% and 81.5%, respectively, for predicting BCF in patients meeting the Phoenix definition and decreased its false positivity to 6.4%. CONCLUSION: The Phoenix definition remains an excellent definition for BCF post-SBRT. Its high false positivity can be mitigated by applying additional criteria (rPSA ≥ 2.6 or time to nPSA + 2 ≥ 18 months).

Lobar Gross Endobronchial Disease Predicts for Overall Survival and Grade 5 Pulmonary Toxicity in Medically Inoperable Early Stage Non-Small Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) is considered standard of care for medically inoperable early stage non-small cell lung cancer (ES-NSCLC). Central tumor location is a known risk factor for severe SBRT related toxicity. Bronchoscopy allows for visualization of the central airways prior to treatment. Five fraction SBRT approaches have been advocated to mitigate treatment induced toxicity. In this report, we examine the mature clinical outcomes of a diverse cohort of ES-NSCLC patients with both peripheral and central tumors treated with a conservative 5 fraction SBRT approach and evaluate the role of lobar gross endobronchial disease (LGED) in predicting overall survival and treatment-related death. METHODS: Medically inoperable biopsy-proven, lymph node-negative ES-NSCLC patients were treated with SBRT. Bronchoscopy was completed prior to treatment in all centrally located cases. The Kaplan-Meier method was used to estimate overall survival (OS), local control (LC), regional control (RC), distant metastasis free survival (DMFS) and disease-free survival (DFS). Overall survival was stratified based on clinical stage, histology, tumor location and LGED. Toxicities were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. RESULTS: From December 2010 to December 2015, 50 consecutive patients were treated uniformly with a 50 Gy in 5 fraction SBRT approach (tumor BED10 ≥ 100 Gy) and followed for a minimum of 5 years or until death. At a median follow up of 42 months for all patients, 3-year OS was 50%. Three-year OS did not statistically differ between stage I and stage II disease (51% vs. 47%; p=0.86), adenocarcinoma and squamous cell carcinoma (50% vs. 45%; p=0.68), or peripheral and central tumors (56% vs. 45%; p=0.46). Five central tumors were found to have LGED, and 3-year OS for this cohort was quite poor at 20%. Cox regression analysis identified LGED as a predictor of OS while controlling for age, stage and location (OR:4.536, p-value=0.038). Despite the relatively low dose delivered, treatment likely contributed to the death of 4 patients with central tumors. Lobar gross endobronchial disease was an independent predictor for grade 5 pulmonary toxicity (n=4, p=0.007). Specifically, 3 of the 5 patients with LGED developed fatal radiation-induced bronchial stricture. Three-year LC, RC, DMFS and DFS results for the group were similar to contemporary studies at 90%, 90%, 82% and 65%. CONCLUSIONS: Central location of ES-NSCLC is a well-established predictor for severe SBRT-related toxicity. Here we identify LGED as a significant predictor of poor overall survival and grade 5 pulmonary toxicity. The relatively high rates of severe treatment-related toxicity seen in patients with central ES-NSCLC may be due in part to LGED. Underlying LGED may cause irreparable damage to the lobar airway, unmitigated by SBRT treatment thus increasing the risk of severe treatment-related toxicity. These findings should be verified in larger data sets. Future prospective central ES-NSCLC clinical trials should require staging bronchoscopy to identify LGED and further assess its clinical significance.

Impact of Age on Patient-Reported Outcomes Following Stereotactic Body Radiation Therapy for Prostate Cancer.

Purpose Stereotactic body radiation therapy (SBRT) delivers large radiation doses to the prostate while minimizing exposure to adjacent normal tissues. Large fraction sizes may increase the risks of functional decrements. Elderly men may be at an increased risk of these toxicities due to poor baseline function and hence limited reserve. This study describes patient-reported outcomes following SBRT for clinically localized prostate cancer in the elderly. Methods Between 2007 and 2017, 179 hormone-naive elderly patients (≥ 70 years old) and 210 patients under 70 years old with clinically localized prostate cancer were treated with 35-36.25 Gy SBRT in five fractions utilizing the CyberKnife Radiosurgical System (Accuray Inc.). Quality of life (QOL) was assessed using the Expanded Prostate Index Composite-Short Form (EPIC-26) questionnaire at baseline and at 1, 3, 6, 12, 18, 24, 30, and 36 months following the completion of treatment. EPIC scores range from 0 to 100, with lower values representing worsening symptoms. Results EPIC scores in the elderly cohort mirrored those in the younger cohort. EPIC urinary obstructive/irritative scores declined at one month post-SBRT (mean change from baseline ≥70: -7.9; <70: -11.1) before returning to baseline at three months post-SBRT (mean change from baseline ≥70: -0.4; <70: -1.4). The EPIC urinary incontinence scores declined slowly over the three years following treatment without recovery (mean change from baseline ≥70: -6.6; <70: -4.8). EPIC Bowel scores transiently declined at one month post-SBRT (mean change from baseline ≥70: -8.5; <70: -9.1) and then experienced a second more protracted decline over the next three years without recovery (mean change from baseline ≥70: -4.5; <70: -1.8). Hormonal EPIC scores were not impacted by radiation treatment or age. Older men had lower baseline and post-treatment EPIC sexual summary scores at all time points. However, there was no clinically significant difference in the EPIC sexual bother score between younger and older men at baseline and following treatment. Conclusions In the first three years following treatment, the impact of SBRT treatment on patient-reported outcomes was minimal. Our findings suggest that SBRT for clinically localized prostate cancer should not be deferred in older men solely due to concerns of increased morbidity. Further studies should be conducted to evaluate the impact of age on outcomes or morbidity following SBRT.

Treatment Interruptions During Stereotactic Body Radiotherapy for Prostate Cancer.

BACKGROUND: During the course of radiation treatment for prostate cancer, patients may have unintentional interruptions in their treatment course due to a wide variety of factors. Stereotactic body radiation therapy (SBRT) decreases the number of treatments compared to conventionally fractionated radiation; hence, it has the potential to decrease treatment delays and non-completion. This study sought to determine the incidence of treatment delay and characterize the etiology and length in a large cohort of men treated with SBRT for their prostate cancer. METHODS: One thousand three hundred and thirty-six patients treated with SBRT from 2008 to 2021 at the Georgetown University Hospital for prostate cancer were included in this retrospective study. A treatment delay was defined as a patient requiring longer than 14 days to complete 5 fractions of SBRT. Non-completion was defined as patients treated with less than 5 fractions. In the patients who experienced delays, chart review was performed to characterize the length and etiology of each delay. Multivariate analysis was performed via binary logistic regression modeling on PSPP. RESULTS: All individuals in the cohort eventually completed the planned 5-fraction regimen. Thirty-three patients experienced a treatment delay. Median length of time to complete treatment was 11 days (range 5-155 days). In patients who experienced a delay, nearly half (45.5%) experienced only a one-day delay. The most common reason for a delay was a technical issue (48.5%), including the machine maintenance, fiducial misalignment, or inadequate pretreatment bowel preparation. Other reasons included unplanned breaks due to acute side effects (21.2%), logistical issues (18.2%), non-treatment related health issues (9.1%), and inclement weather (3.0%). There were no significant sociodemographic, oncologic, or treatment variables that predicted treatment interruption on multivariate analysis. CONCLUSIONS: The incidence of treatment interruptions in patients undergoing SBRT for their prostate cancer was low. Most treatment delays were short.

Bleeding Risk Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer in Men on Baseline Anticoagulant or Antiplatelet Therapy.

PURPOSE: Patients on anticoagulant/antiplatelet medications are at a high risk of bleeding following external beam radiation therapy for localized prostate cancer. SBRT may reduce the bleeding risk by decreasing the volume of bladder/rectum receiving high doses. This retrospective study sought to evaluate the rates of hematuria and hematochezia following SBRT in these patients. METHODS: Localized prostate cancer patients treated with SBRT from 2007 to 2017 on at least one anticoagulant/antiplatelet at baseline were included. The minimum follow-up was 3 years with a median follow-up of 72 months. Patients who had a rectal spacer placed prior to SBRT were excluded. Radiotherapy was delivered in 5 fractions to a dose of 35 Gy or 36.25 Gy utilizing the CyberKnife system. Hematuria and hematochezia were prospectively assessed before and after treatment using the Expanded Prostate Cancer Index Composite (EPIC-26). Toxicities were scored using the CTCAE v4. Cystoscopy and colonoscopy findings were retrospectively reviewed. RESULTS: Forty-four men with a median age of 72 years with a history of taking at least one anticoagulant and/or antiplatelet medication received SBRT. Warfarin (46%), clopidogrel (34%) and rivaroxaban (9%) were the most common medications. Overall, 18.2% experienced hematuria with a median time of 10.5 months post-SBRT. Altogether, 38.6% experienced hematochezia with a median time of 6 months post-SBRT. ≥ Grade 2 hematuria and hematochezia occurred in 4.6% and 2.5%, respectively. One patient required bladder neck fulguration and one patient underwent rectal cauterization for multiple non-confluent telangiectasia. There were no grade 4 or 5 toxicities. Cystoscopy revealed bladder cancer (40%) and benign prostatic bleeding (40%) as the most common hematuria etiology. Colonoscopy demonstrated hemorrhoids (54.5%) and radiation proctitis (9.1%) as the main causes of hematochezia. There was no significant change from the mean baseline EPIC-26 hematuria and hematochezia scores at any point during follow up. CONCLUSION: In patients with baseline anticoagulant usage, moderate dose prostate SBRT was well tolerated without rectal spacing. High grade bleeding toxicities were uncommon and resolved with time. Baseline anticoagulation usage should not be considered a contraindication to prostate SBRT.

Toxicity After Stereotactic Body Radiation Therapy for Prostate Cancer in Patients With Inflammatory Bowel Disease: A Multi-institutional Matched Case-Control Series.

PURPOSE: To evaluate the safety of stereotactic body radiation therapy (SBRT) for prostate cancer in men with inflammatory bowel disease (IBD). METHODS AND MATERIALS: We queried a consortium database for patients with IBD receiving SBRT for prostate cancer between 2006 and 2012. Identified patients were matched with patients without a history of IBD in a 3:1 fashion based on dose, fractionation, use of androgen deprivation therapy, and age distribution. Logistic regression was used to evaluate the association between having IBD and experiencing acute and late gastrointestinal (GI) and genitourinary (GU) toxicities as scored on the Common Terminology Criteria for Adverse Events scale. Time to late toxicity was evaluated using proportional hazard Cox models. Our study was limited by absence of data on prostate size, baseline International Prostate Symptom Score, and rectal dose-volume histogram parameters. RESULTS: Thirty-nine patients with flare-free IBD at time of treatment (median follow-up 83.9 months) and 117 matched controls (median follow-up 88.7 months) were identified. A diagnosis of IBD was associated with increased odds of developing any late grade GI toxicity (odds ratio [OR] 6.11, P <.001) and GU toxicity (odds ratio 6.14, P < .001), but not odds of developing late grade ≥2 GI (P = .08) or GU toxicity (P = .069). Acute GI and GU toxicity, both overall and for grade ≥2 toxicities, were more frequent in men with IBD (P < .05). Time to late GI and GU toxicity of any grade was significantly shorter in patients with IBD (P < .001). Time to late grade ≥2 GU, but not grade ≥2 GI toxicity, was also shorter in patients with IBD (P = .044 for GU and P = .144 for GI). CONCLUSIONS: Patients with IBD who received SBRT for PCa had a higher likelihood of developing acute GI and GU toxicity, in addition to experiencing lower grade late toxicities that occurred earlier. However, patients with IBD did not have a higher likelihood for late grade ≥2 GI or GU toxicity after SBRT compared with the control cohort. Interpretation of this data are limited by the small sample size. Thus, men with IBD in remission should be properly counseled about these risks when considering SBRT.