Underutilization of Androgen Deprivation Therapy with External Beam Radiotherapy in Men with High-grade Prostate Cancer.

Multiple randomized trials have shown a survival benefit to long durations of androgen deprivation therapy (ADT) in patients with Gleason grade group (GG) 4-5 (ie, Gleason score 8-10) prostate cancer (PCa) undergoing definitive external beam radiotherapy (EBRT). We conducted a population-based retrospective study utilizing the complete Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2008 to 2011, extracting PCa patients of non-Hispanic white (NHW) and African-American (AA) race diagnosed with GG 4-5PCa who received EBRT with or without concomitant ADT. Of 961 patients receiving definitive EBRT, 225 (23.4%) received no ADT, 297 (30.9%) received 1-6mo of ADT, 313 (32.6) received 7-23mo of ADT, and 126 (13.1%) received ≥24mo of ADT. On multinomial logistic regression after inverse probability treatment weighting to balance for differences in other covariates, AA men still had significantly lower odds of receiving 1-6mo of ADT versus no ADT compared with NHW men (odds ratios 0.519 [95% confidence interval, 0.384-0.700]). In conclusion, long-duration ADT is underutilized, with nearly 90% of patients with GG 4-5PCa receiving <24mo of concomitant ADT, and AA men are less likely to receive ADT than NHW men. PATIENT SUMMARY: In this report, we examined the utilization of concomitant androgen deprivation therapy (ADT) among men with high-grade prostate cancer undergoing definitive external beam radiotherapy. We found that long-duration ADT was underutilized overall; moreover, African-American men were less likely to receive concomitant ADT than non-Hispanic white men.

Clinical Assessment of Prostate Displacement and Planning Target Volume Margins for Stereotactic Body Radiotherapy of Prostate Cancer.

Purpose: To assess the optimal planning target volume (PTV) margins for stereotactic body radiotherapy (SBRT) of prostate cancer based on inter- and intra-fractional prostate motion determined from daily image guidance. Methods and Materials: Two hundred and five patients who were enrolled on two prospective studies of SBRT (8 Gy × 5 fractions) for localized prostate cancer treated at a single institution between 2012 and 2017 had complete inter- and intra-fractional shift data available. All patients had scheduled kilovoltage planar imaging during SBRT with rigid registration to intraprostatic fiducials prior to each of four half-arcs delivered per fraction, as well as cone beam CT verification of anatomy prior to each fraction. Inter- and intra- fractional shift data were obtained to estimate the required PTV margins based on the classic van Herk formula. Inter- and intra-fractional motion were compared between patients with and without severe toxicities using the independent two-sample Wilcoxon test. Results: The margins required to account for inter-fractional motion were estimated to be 0.99, 1.52, and 1.45 cm in lateral (LR), longitudinal (SI), and vertical (AP) directions, respectively. The margins required to account for intra-fractional motion were estimated to be 0.19, 0.27, and 0.31 cm in LR, SI and AP directions, respectively. Large intra-fractional shifts were mostly observed in the SI and AP directions, with 2.0 and 5.4% of patients experiencing average intra-fractional motion >3 mm in the SI and AP directions, respectively, compared with none experiencing mean shifts >3 mm in the LR direction. Six patients experienced grade 3 gastrointestinal or genitourinary toxicity. There were no significant differences in mean inter- or intra-fractional motion in any of the cardinal directions compared to patients without severe toxicity (inter-fractional p = 0.46-0.99, intra-fractional p = 0.10-0.84). Conclusion: The inter- and intra-fractional margins estimated from this study are in line with prior reported values. Intra-fractional prostate motion was generally small with larger margins required for the SI and AP directions, notably just slightly exceeding the commonly used 3 mm posterior PTV margin even with realignment between half-arcs. Development of severe toxicity was not significantly associated with the degree of inter- or intra-fractional motion.

Cost-effectiveness of Linac-based single-isocenter non-coplanar technique (HyperArcTM) for brain metastases radiosurgery.

In the last few years, the major change has occurred in the expansion of indications for radiosurgery (SRS) to include patients with more than four brain metastases (BM). To address the expanding indications for SRS in the treatment of multiple BMs, HyperArcTM (Varian Medical System, Palo Alto, CA, U.S.) was recently introduced in order to automate and simplify sophisticated treatments such as SRS/FSRT for multiple lesions (up to 20 BM). In this editorial some consideration about HyperArc cost-effectiveness were discussed in terms of reduction of treatment delivery time (multiple intracranial targets can be treated in a few minutes), the reduction of overall treatment time (treatment course of SRS of multiple BMs in a single session, rather than having to irradiate lesion per lesion during separate sessions on different days); reduction of costs for health systems. In summary HyperArc™ system is a promising, safe and accurate solution for SRS/SFRT to treat multiple BMs in a single or few sessions. This has the potential to impact direct and indirect costs of SRS/SFRT delivery.

Content Validity of Anatomic Site-Specific Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Sets for Assessment of Acute Symptomatic Toxicities in Radiation Oncology.

PURPOSE: To improve assessment of symptomatic toxicity in cancer clinical trials and complement clinician-based toxicity reporting, the US National Cancer Institute developed a measurement system called the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). The objective of this study was to examine the content validity of PRO-CTCAE in patients undergoing radiation therapy and to establish anatomic site-specific item sets for implementation in cancer research. METHODS AND MATERIALS: Patients receiving radiation to the brain, head and neck, breast, thorax, abdomen, or pelvis were recruited during the final week of radiation. Participants described side effects qualitatively and completed anatomic site-specific checklists indicating the presence or absence of symptomatic toxicities drawn from the PRO-CTCAE library. Items endorsed by ≥20% of participants were selected for inclusion. Symptomatic toxicities described qualitatively were content analyzed and summarized. Symptomatic toxicities not reflected in the PRO-CTCAE item library were tabulated. RESULTS: We conducted 389 interviews of patients receiving radiation to the brain (n = 46), head and neck (n = 69), breast (n = 134), thorax (n = 30), abdomen (n = 27), female pelvis (n = 36), or male pelvis (n = 47). Median age was 62 years; 62% were female. The 53 solicited PRO-CTCAE symptoms reflected all reported radiation-induced toxicities with the exception of phlegm/mucus production and mouth/throat pain with swallowing in patients receiving head and neck radiation, eye dryness/irritation in patients undergoing brain radiation, and obstructive urinary symptoms in men receiving pelvic radiation. The PRO-CTCAE items "skin burns" and "pain" require greater specificity to adequately reflect toxicities experienced during radiation. CONCLUSIONS: PRO-CTCAE demonstrates strong content validity as a measure of symptomatic toxicities in patients receiving radiation. These results provide empirical support for the definition of site-specific PRO-CTCAE item sets to assess the symptomatic toxicities of radiation therapy. The site-specific PRO-CTCAE item sets developed herein are currently being deployed in our department via an electronic platform to capture treatment-related toxicity.

Time-driven activity-based costing of low-dose-rate and high-dose-rate brachytherapy for low-risk prostate cancer.

PURPOSE: Cost estimates through traditional hospital accounting systems are often arbitrary and ambiguous. We used time-driven activity-based costing (TDABC) to determine the true cost of low-dose-rate (LDR) and high-dose-rate (HDR) brachytherapy for prostate cancer and demonstrate opportunities for cost containment at an academic referral center. METHODS AND MATERIALS: We implemented TDABC for patients treated with I-125, preplanned LDR and computed tomography based HDR brachytherapy with two implants from initial consultation through 12-month followup. We constructed detailed process maps for provision of both HDR and LDR. Personnel, space, equipment, and material costs of each step were identified and used to derive capacity cost rates, defined as price per minute. Each capacity cost rate was then multiplied by the relevant process time and products were summed to determine total cost of care. RESULTS: The calculated cost to deliver HDR was greater than LDR by $2,668.86 ($9,538 vs. $6,869). The first and second HDR treatment day cost $3,999.67 and $3,955.67, whereas LDR was delivered on one treatment day and cost $3,887.55. The greatest overall cost driver for both LDR and HDR was personnel at 65.6% ($4,506.82) and 67.0% ($6,387.27) of the total cost. After personnel costs, disposable materials contributed the second most for LDR ($1,920.66, 28.0%) and for HDR ($2,295.94, 24.0%). CONCLUSIONS: With TDABC, the true costs to deliver LDR and HDR from the health system perspective were derived. Analysis by physicians and hospital administrators regarding the cost of care afforded redesign opportunities including delivering HDR as one implant. Our work underscores the need to assess clinical outcomes to understand the true difference in value between these modalities.

Clinical Indicators of Psychosocial Distress Predict for Acute Radiation-Induced Fatigue in Patients Receiving Adjuvant Radiation Therapy for Breast Cancer: An Analysis of Patient-Reported Outcomes.

PURPOSE: To assess the magnitude and predictors of patient-reported fatigue among breast cancer patients receiving radiation therapy (RT). METHODS AND MATERIALS: Patients receiving breast RT completed a survey querying fatigue at each weekly on-treatment visit. Patient-reported fatigue severity and interference was assessed on an ordinal scale of 0 to 4, using a validated scoring system. Baseline anxiety and depression scores were also obtained. The kinetics of mean fatigue scores per week and the maximum fatigue scores over the course of the entire treatment were assessed, and clinical predictors were identified by univariate and multivariate regression. RESULTS: The average fatigue severity and interference scores were 0.6 and 0.46. The average fatigue scores increased to an equivalent extent from week to week, with expected increases of 0.99 in fatigue severity and 0.85 in interference over 7 weeks. Patients treated with hypofractionated RT (HF-RT) versus conventionally fractionated RT (CF-RT) had significantly fewer maximum fatigue severity or interference scores that were >2 (ie, severe or very severe; 29% vs 10% for severity, and 26% vs 8% for interference, P<.01). Age ≤45 years, presence of psychiatric/pain-related comorbidities, and baseline sadness and anxiety severity were predictive of average and maximum fatigue scores (P<.05), but variables related to treatment intensity (eg, mastectomy vs lumpectomy, chemotherapy use, radiation target volumes) and other host factors (working, children, marital status, proximity to RT facility) were not. CONCLUSION: Patient-reported fatigue modestly increases over RT courses, with less maximum fatigue reported with HF-RT. Younger age and baseline sadness, anxiety, and psychiatric/pain-related comorbidities are powerful predictors of fatigue, whereas other factors, such as treatment intensity, are not. Future studies will investigate interventions for patients at high risk for fatigue.

Utilizing time-driven activity-based costing to understand the short- and long-term costs of treating localized, low-risk prostate cancer.

BACKGROUND: Given the costs of delivering care for men with prostate cancer remain poorly described, this article reports the results of time-driven activity-based costing (TDABC) for competing treatments of low-risk prostate cancer. METHODS: Process maps were developed for each phase of care from the initial urologic visit through 12 years of follow-up for robotic-assisted laparoscopic prostatectomy (RALP), cryotherapy, high-dose rate (HDR) and low-dose rate (LDR) brachytherapy, intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and active surveillance (AS). The last modality incorporated both traditional transrectal ultrasound (TRUS) biopsy and multiparametric-MRI/TRUS fusion biopsy. The costs of materials, equipment, personnel, and space were calculated per unit of time and based on the relative proportion of capacity used. TDABC for each treatment was defined as the sum of its resources. RESULTS: Substantial cost variation was observed at 5 years, with costs ranging from $7,298 for AS to $23,565 for IMRT, and they remained consistent through 12 years of follow-up. LDR brachytherapy ($8,978) was notably cheaper than HDR brachytherapy ($11,448), and SBRT ($11,665) was notably cheaper than IMRT, with the cost savings attributable to shorter procedure times and fewer visits required for treatment. Both equipment costs and an inpatient stay ($2,306) contributed to the high cost of RALP ($16,946). Cryotherapy ($11,215) was more costly than LDR brachytherapy, largely because of increased single-use equipment costs ($6,292 vs $1,921). AS reached cost equivalence with LDR brachytherapy after 7 years of follow-up. CONCLUSIONS: The use of TDABC is feasible for analyzing cancer services and provides insights into cost-reduction tactics in an era focused on emphasizing value. By detailing all steps from diagnosis and treatment through 12 years of follow-up for low-risk prostate cancer, this study has demonstrated significant cost variation between competing treatments.

Multiparametric magnetic resonance imaging for prostate cancer improves Gleason score assessment in favorable risk prostate cancer.

PURPOSE: Magnetic resonance imaging (MRI) guidance may improve the accuracy of Gleason score (GS) determination by directing the biopsy to regions of interest (ROI) that are likely to harbor high-grade prostate cancer (CaP). The aim of this study was to determine the frequency and predictors of GS upgrading when a subsequent MRI-guided biopsy is performed on patients with a diagnosis of GS 6 disease on the basis of conventional, transrectal ultrasound-guided biopsy. METHODS AND MATERIALS: A consecutive series of 245 men with a diagnosis of low-risk CaP (ie, cT1c, GS 6, prostate-specific antigen <10) based on transrectal ultrasound-guided biopsy was enrolled in an active surveillance protocol that used subsequent MRI-guided biopsy for confirmation of GS. ROIs were categorized on a scale of 1 to 5. The Artemis ultrasound-MRI fusion device was used to perform targeted biopsies of ROIs as well as systematic biopsies from a software-based 12-point map. Predictors of GS upgrading were analyzed using univariate and multivariate analyses. RESULTS: Fusion biopsy resulted in 26% of patients having GS upgrading (GS 3+4 in 18%, 4+3 in 5%, and 8-9 in 3%). Of the 72% of patients with ROIs appropriate for targeting, targeted cores upgraded the GS in 18%, whereas systematic cores upgraded the GS in 24%. In patients without targeted biopsy, GS upgrading was seen in 14%. On multivariate analysis, a category 5 ROI was the most significant predictor of GS upgrading with an odds ratio of 10.56 (P < .01). CONCLUSIONS: Nearly 25% of men with GS 6 CaP diagnosed by standard transrectal ultrasound biopsy may experience GS upgrading when a subsequent MRI-ultrasound fusion biopsy is performed. The most important single predictor of upgrading is a category 5 ROI on multiparametric MRI. GS upgrading may influence treatment decisions. Therefore, MRI-guided biopsy should be considered prior to formulating a management strategy in patients whose conventional biopsy reveals low-risk CaP.

Near Real-Time Assessment of Anatomic and Dosimetric Variations for Head and Neck Radiation Therapy via Graphics Processing Unit-based Dose Deformation Framework.

PURPOSE: The purpose of this study was to systematically monitor anatomic variations and their dosimetric consequences during intensity modulated radiation therapy (IMRT) for head and neck (H&N) cancer by using a graphics processing unit (GPU)-based deformable image registration (DIR) framework. METHODS AND MATERIALS: Eleven IMRT H&N patients undergoing IMRT with daily megavoltage computed tomography (CT) and weekly kilovoltage CT (kVCT) scans were included in this analysis. Pretreatment kVCTs were automatically registered with their corresponding planning CTs through a GPU-based DIR framework. The deformation of each contoured structure in the H&N region was computed to account for nonrigid change in the patient setup. The Jacobian determinant of the planning target volumes and the surrounding critical structures were used to quantify anatomical volume changes. The actual delivered dose was calculated accounting for the organ deformation. The dose distribution uncertainties due to registration errors were estimated using a landmark-based gamma evaluation. RESULTS: Dramatic interfractional anatomic changes were observed. During the treatment course of 6 to 7 weeks, the parotid gland volumes changed up to 34.7%, and the center-of-mass displacement of the 2 parotid glands varied in the range of 0.9 to 8.8 mm. For the primary treatment volume, the cumulative minimum and mean and equivalent uniform doses assessed by the weekly kVCTs were lower than the planned doses by up to 14.9% (P=.14), 2% (P=.39), and 7.3% (P=.05), respectively. The cumulative mean doses were significantly higher than the planned dose for the left parotid (P=.03) and right parotid glands (P=.006). The computation including DIR and dose accumulation was ultrafast (∼45 seconds) with registration accuracy at the subvoxel level. CONCLUSIONS: A systematic analysis of anatomic variations in the H&N region and their dosimetric consequences is critical in improving treatment efficacy. Nearly real-time assessment of anatomic and dosimetric variations is feasible using the GPU-based DIR framework. Clinical implementation of this technology may enable timely plan adaptation and improved outcome.

Stereotactic body radiation therapy for prostate cancer: Rational and reasonable.

Stereotactic body radiation therapy (SBRT), a treatment procedure that uses large doses per fraction, is currently being used to treat prostate cancer with external radiation therapy in 4 to 5 treatments. Published series in the clinical use of SBRT in patients with localized prostate cancer demonstrate high efficacy within the available follow-up time periods. Rectal and sexual toxicity profiles have been favorable compared with other radiation techniques and surgery. Urinary toxicity profiles might be more comparable to those observed with brachytherapy, more pronounced in the acute setting. SBRT is technically more challenging, requiring precise geometric targeting with in-room image guidance. The use of large doses per fraction potentially provides unique biological effects on both tumor and normal tissues. Immunologic responses in normal tissues, local stromal microenvironment, and specific antigen-presenting cells induced by such high doses likely contribute to effective tumor kill. Ultimately, SBRT for prostate cancer offers significant logistical advantages, with increased convenience to patients and decreased overall cost to the health care delivery system.

Late rectal toxicity after low-dose-rate brachytherapy: incidence, predictors, and management of side effects.

As clinical outcomes for patients with clinically localized prostate cancer continue to improve, patients and physicians are increasing making treatment decisions based on concerns regarding long-term morbidity. A primary concern is late radiation proctitis, a clinical entity embodied by various signs and symptoms, ranging from diarrhea to rectal fistulas. Here, we present a comprehensive literature review examining the clinical manifestations and pathophysiology of late radiation proctitis after low-dose-rate brachytherapy (BT), as well as its incidence and predictors. The long-term risks of rectal bleeding after BT are on the order of 5-7%, whereas the risks of severe ulceration or fistula are on the order of 0.6%. The most robust predictor appears to be the volume of rectum receiving the prescription dose. In certain situations (e.g., salvage setting, for patients with increased radiosensitivity, and following aggressive biopsy after BT), the risk of these severe toxicities may be increased by up to 10-fold. A variety of excellent management options exist for rectal bleeding, with endoscopic methods being the most commonly used.

Assessment of interfraction patient setup for head-and-neck cancer intensity modulated radiation therapy using multiple computed tomography-based image guidance.

PURPOSE: Various image guidance systems are commonly used in conjunction with intensity modulated radiation therapy (IMRT) in head-and-neck cancer irradiation. The purpose of this study was to assess interfraction patient setup variations for 3 computed tomography (CT)-based on-board image guided radiation therapy (IGRT) modalities. METHODS AND MATERIALS: A total of 3302 CT scans for 117 patients, including 53 patients receiving megavoltage cone-beam CT (MVCBCT), 29 receiving kilovoltage cone-beam CT (KVCBCT), and 35 receiving megavoltage fan-beam CT (MVFBCT), were retrospectively analyzed. The daily variations in the mediolateral (ML), craniocaudal (CC), and anteroposterior (AP) dimensions were measured. The clinical target volume-to-planned target volume (CTV-to-PTV) margins were calculated using 2.5Σ + 0.7 σ, where Σ and σ were systematic and random positioning errors, respectively. Various patient characteristics for the MVCBCT group, including weight, weight loss, tumor location, and initial body mass index, were analyzed to determine their possible correlation with daily patient setup. RESULTS: The average interfraction displacements (± standard deviation) in the ML, CC, and AP directions were 0.5 ± 1.5, -0.3 ± 2.0, and 0.3 ± 1.7 mm (KVCBCT); 0.2 ± 1.9, -0.2 ± 2.4, and 0.0 ± 1.7 mm (MVFBCT); and 0.0 ± 1.8, 0.5 ± 1.7, and 0.8 ± 3.0 mm (MVCBCT). The day-to-day random errors for KVCBCT, MVFBCT, and MVCBCT were 1.4-1.6, 1.7, and 2.0-2.1 mm. The interobserver variations were 0.8, 1.1, and 0.7 mm (MVCBCT); 0.5, 0.4, and 0.8 mm (MVFBCT); and 0.5, 0.4, and 0.6 mm (KVCBCT) in the ML, CC, and AP directions, respectively. The maximal calculated uniform CTV-to-PTV margins were 5.6, 6.9, and 8.9 mm for KVCBCT, MVFBCT, and MVCBCT, respectively. For the evaluated patient characteristics, the calculated margins for different patient parameters appeared to differ; analysis of variance (ANOVA) and/or t test analysis found no statistically significant setup difference in any direction. CONCLUSIONS: Daily random setup errors and CTV-to-PTV margins for treatment of head-and-neck cancer were affected by imaging quality. Our data indicated that larger margins were associated with MVFBCT and MVCBCT, compared with smaller margins for KVCBCT. IGRT modalities with better image quality are encouraged in clinical practice.

Validation of a computational method for assessing the impact of intra-fraction motion on helical tomotherapy plans.

In this work, a method for direct incorporation of patient motion into tomotherapy dose calculations is developed and validated. This computational method accounts for all treatment dynamics and can incorporate random as well as cyclical motion data. Hence, interplay effects between treatment dynamics and patient motion are taken into account during dose calculation. This allows for a realistic assessment of intra-fraction motion on the dose distribution. The specific approach entails modifying the position and velocity events in the tomotherapy delivery plan to accommodate any known motion. The computational method is verified through phantom and film measurements. Here, measured prostate motion and simulated respiratory motion tracks were incorporated in the dose calculation. The calculated motion-encoded dose profiles showed excellent agreement with the measurements. Gamma analysis using 3 mm and 3% tolerance criteria showed over 97% and 96% average of points passing for the prostate and breathing motion tracks, respectively. The profile and gamma analysis results validate the accuracy of this method for incorporating intra-fraction motion into the dose calculation engine for assessment of dosimetric effects on helical tomotherapy dose deliveries.

Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.

PURPOSE: To analyze changes in parotid gland dose resulting from anatomic changes throughout a course of radiotherapy in a cohort of head-and-neck cancer patients. METHODS AND MATERIALS: The study population consisted of 10 head-and-neck cancer patients treated definitively with intensity-modulated radiotherapy on a helical tomotherapy unit. A total of 330 daily megavoltage computed tomography images were retrospectively processed through a deformable image registration algorithm to be registered to the planning kilovoltage computed tomography images. The process resulted in deformed parotid contours and voxel mappings for both daily and accumulated dose-volume histogram calculations. The daily and cumulative dose deviations from the original treatment plan were analyzed. Correlations between dosimetric variations and anatomic changes were investigated. RESULTS: The daily parotid mean dose of the 10 patients differed from the plan dose by an average of 15%. At the end of the treatment, 3 of the 10 patients were estimated to have received a greater than 10% higher mean parotid dose than in the original plan (range, 13-42%), whereas the remaining 7 patients received doses that differed by less than 10% (range, -6-8%). The dose difference was correlated with a migration of the parotids toward the high-dose region. CONCLUSIONS: The use of deformable image registration techniques and daily megavoltage computed tomography imaging makes it possible to calculate daily and accumulated dose-volume histograms. Significant dose variations were observed as result of interfractional anatomic changes. These techniques enable the implementation of dose-adaptive radiotherapy.