External Beam Radiotherapy Dose Research Articles

Risk Factors for Late Persistent Fatigue After Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: An Analysis From the EMBRACE-I Study

This study aimed to evaluate patient- and treatment-related risk factors for late persistent fatigue within the prospective, multicenter EMBRACE-I study. Fatigue was prospectively assessed (Common Terminology Criteria for Adverse Events, version 3) at baseline and during regular follow up in 993 patients with locally advanced cervical cancer after treatment with chemoradiotherapy and magnetic resonance imaging-guided brachytherapy. Risk factors for baseline and late persistent fatigue were evaluated with multivariable logistic regression. Late persistent fatigue was defined when either grade ≥1 or ≥2 was scored in at least half of the follow ups. The median follow-up time was 57 months. Baseline fatigue grade ≥1/≥2 (35.8%/6.3%, respectively) was associated with preexisting comorbidities, World Health Organization performance status, being underweight, severe pain, and tumor volume. Late persistent grade ≥1/≥2 fatigue (36.3%/5.8%, respectively) was associated with patient-related factors (baseline fatigue, younger age, obesity) along with the size of irradiated volumes and the level of radiation doses from external beam radiation therapy (EBRT) and brachytherapy (EBRT: V43Gy, V57Gy; EBRT+brachytherapy: V60Gy equivalent dose in 2-Gy fractions). Large-volume lymph node (LN) boost increased the risk for late persistent fatigue grade ≥2 by 18% and 5% in patients with and without baseline fatigue, respectively, compared with no LN boost. The risk for late persistent fatigue grade ≥1 increased by 7% and 4% with V43Gy <2000 cm³ versus >3000 cm³ in patients with and without baseline fatigue, respectively. Late persistent grade ≥1 fatigue occurred in 13% of patients without late persistent organ-related symptoms (gastrointestinal, genitourinary, and vaginal) versus 34% to 43%, 50% to 58%, and 73% in patients suffering from persistent symptoms involving 1, 2, or 3 organs, respectively. Late persistent fatigue occurs in a considerable number of patients after chemoradiotherapy, and is associated with patient-related factors, the size of volumes irradiated to intermediate and high EBRT and brachytherapy doses, and other persistent organ-related morbidity. These findings support the importance of ongoing efforts to better tailor the target dose and reduce irradiation of healthy tissue without compromising target coverage, using highly conformal EBRT and brachytherapy techniques.

Local control of bone metastases treated with external beam radiotherapy in recent years: a multicenter retrospective study

BackgroundOver the past decades, remarkable advancements in systemic drug therapy have improved the prognosis of patients with bone metastases. Individualization is required in external beam radiotherapy (EBRT) for bone metastases according to the patient’s prognosis. To establish individualized EBRT for bone metastases, we investigated factors that affect the local control (LC) of bone metastases.MethodsBetween January 2010 and December 2019, 536 patients received EBRT for 751 predominantly osteolytic bone metastases. LC at EBRT sites was evaluated with a follow-up computed tomography. The median EBRT dose was biologically effective dose (BED10) (39.0) (range of BED10: 14.4–71.7 Gy).ResultsThe median follow-up time and median time of computed tomography follow-up were 11 (range 1–123) months and 6 (range 1–119) months, respectively. The 0.5- and 1-year overall survival rates were 73% and 54%, respectively. The 0.5- and 1-year LC rates were 83% and 79%, respectively. In multivariate analysis, higher age (≥ 70 years), non-vertebral bone metastases, unfavorable primary tumor sites (esophageal cancer, colorectal cancer, hepatobiliary/pancreatic cancer, renal/ureter cancer, sarcoma, melanoma, and mesothelioma), lower EBRT dose (BED10 < 39.0 Gy), and non-administration of bone-modifying agents (BMAs)/antineoplastic agents after EBRT were significantly unfavorable factors for LC of bone metastases. There was no statistically significant difference in the LC between BED10 = 39.0 and BED10 > 39.0 Gy.ConclusionsRegarding tumor-related factors, primary tumor sites and the sites of bone metastases were significant for the LC. As for treatment-related factors, lower EBRT doses (BED10 < 39.0 Gy) and non-administration of BMAs/antineoplastic agents after EBRT were associated with poor LC. Dose escalation from BED10 = 39.0 Gy did not necessarily improve LC.

The Balance between Orthodontic Force and Radiation in the Jawbone: Microstructural, Histological, and Molecular Study in a Rat Model.

Simple SummaryPatients with head and neck cancer are frequently treated by radiation, which results in a lifelong risk of damage (necrosis) to the jawbones. Some of the irradiated young patients at a later time in life may be interested in orthodontic treatment for esthetic or functional purposes. We undertook this study in order to investigate changes that occur in irradiated jawbones when mild orthodontic force is applied in a rat laboratory model. We found that one low dose of radiation had negatively affected the jawbones and that these changes were visible in X-ray images as well as in microscopic slides. The irradiated bones seemed to be denser in the X-rays and had fewer cells that usually regulate normal bone turnover, compared to non-irradiated bones. However, when orthodontic force was applied after radiation, the changes in the irradiated bones were largely, but not completely, reversed in both X-rays and microscopy to the point that bone properties were approaching those of non-irradiated, orthodontically treated, bones. The findings of this study indicate that orthodontic force may have a beneficial effect on the maintenance of jawbone vitality after radiation, but additional studies using different time-lags between radiation and orthodontic force and higher radiation doses are warranted to support these findings.Irradiation of facial bones is associated with a lifelong risk of osteonecrosis. In a rat model, maxillae were exposed to a single 5 Gy dose of external beam radiation and orthodontic force was applied for 2 weeks on the first maxillary molar; control rats were treated identically without radiation. Tooth movement in irradiated jaws was 30% less than in controls, representing radiation-related damage. Micro-CT, histological, and molecular outcomes of orthodontic tooth movement were studied. Microstructurally, bone parameters (trabecular thickness, bone volume fraction, bone mineral density) were significantly affected by orthodontic force but not by radiation. Histological parameters were influenced only by orthodontic force, especially by an increase in osteoclasts. A molecular study revealed a differential distribution of cells expressing pre-osteoclast markers (RANK+—majority, CD11b+, CD14+—minority), with changes being influenced by orthodontic force (increased CD11b+ and CD14+ cells) and also by radiation (decreased RANK+ cells). The activation status of osteoclasts (TRAP staining) showed an orthodontic-force-related increase, which probably could not fully compensate for the radiation-associated impairment. The overall balance showed that orthodontic force had elicited a substantial microstructural, histological, and functional normalization process in irradiated maxillae but a radiation-induced impact was still conspicuous. Additional studies are needed to validate these findings.

Salvage Low-Dose-Rate Prostate Brachytherapy: Clinical Outcomes of a Phase 2 Trial for Local Recurrence after External Beam Radiation Therapy (NRG Oncology/RTOG 0526)

We report efficacy of a prospective phase 2 trial (NCT00450411) of salvage low-dose-rate (LDR) prostate brachytherapy (BT) for local failure (LF) after prior external beam radiation therapy (EBRT) with minimum 5-years' follow-up. Eligible patients had low/intermediate risk prostate cancer (PCa) before EBRT and biopsy-proven LF >30 months after EBRT, with prostate-specific antigen <10 ng/mL and no regional/distant disease. The primary endpoint, late gastrointestinal and genitourinary adverse events (Common Terminology Criteria for Adverse Events v3.0) grade ≥3 were 14%. With minimum 5-year follow-up after salvage BT, secondary clinical outcomes including disease-free survival (DFS; includes death from any cause), disease-specific survival, and overall survival (OS) were estimated using the Kaplan-Meier method and modelled using Cox proportional hazards regression. Local tumor progression (ie, LF), distant failure (DF), and biochemical failure (BF) were estimated using cumulative incidence. Time to LF, DF, and BF were modeled by cause-specific Cox proportional hazards regression. From May 2007 to January 2014, 20 centers registered 100 patients (92 analyzable). Median follow-up is 6.7 years (range, 0.3-11.2); median age 70 years (range, 55-82); median prior EBRT dose 74 Gy [interquartile range (IQR):70 - 76] at a median of 85 months prior (IQR 60-119 months). Androgen deprivation was combined with salvage BT in 16%. Ten-year OS is 70% [95% confidence interval (CI) 58% - 83%]. Nineteen patients died (5 PCa, 10 other, 4 unknown). Ten-year failure rates are local 5% (95% CI, 1-11), distant 19% (95% CI, 10-29), and biochemical 46% (95% CI, 34-57). DFS is 61% at 5 years and 33% at 10 years. No baseline characteristic was significantly associated with any clinical outcome. This is the first prospective multicenter trial reporting outcomes of salvage LDR BT for LF after EBRT. Five-year freedom from BF is 68%, comparable to other salvage modalities. Although further LF is rare (5%), BF climbs to 46% by 10 years.

Targeting the GTV in Medically Inoperable Endometrial Cancer Using Brachytherapy

Standard of care for endometrial cancer is upfront surgery. For women who are not candidates for surgery based on medical comorbidities, definitive brachytherapy (BT) +/- external beam radiation therapy (EBRT) offers an alternative approach. Consensus guidelines define the clinical target volume (CTV) as uterus, cervix, and 1-2 cm of the vagina. Guidelines discuss an optional gross tumor volume (GTV) with a recommended prescription dose of 80 Gy.We used an institutional endometrial cancer database to identify medically inoperable patients who received definitive radiation therapy from 2013-2019. Treatment plans were reviewed to determine doses to GTV, CTV, and organs at risk (OARs). In patients with a definable GTV on MRI and/or PET, BT was prospectively replanned with a goal of GTV D98 EQD2 ≥ 80 Gy, without regard for coverage of the remaining uterus and while respecting OAR dose constraints. The use of EBRT, EBRT dose, and number of BT fractions remained consistent between the original plan and GTV-only replan. Doses to OARs were compared using t-test and Chi-squared test.Fifty-four patients were identified. A definable GTV was present in 44 patients, of which 61.4% had MRI/PET images fused during the original treatment planning process to optimize dose to GTV. In the remainder of patients, diagnostic images were fused to retrospectively determine dose to GTV and target GTV for replanning. On original plans, GTV D90 EQD2 ≥ 80 Gy was achieved in 36 (81.8%) patients, and D98 EQD2 ≥ 80 Gy was achieved in 24 (54.5%) patients with a definable GTV. Local recurrence free survival was 91.1% at 2 years, including 100% in patients with GTV D90 EQD2 ≥ 80 Gy and 66.7% < 80 Gy (P = 0.001), and 100% in patients with GTV D98 EQD2 ≥ 80 Gy and 87.5% < 80 Gy (P = 0.299). Grade 3 toxicity occurred in 6 (10.4%) patients, including 4 cases of proctitis and 2 cases of urinary toxicity. On GTV-only replans, GTV D98 EQD2 ≥ 80 Gy was achieved in 39 (88.6%) patients. Mean D2cc for original plans and GTV-only replans, respectively, were: bladder 73.0 Gy, 47.1 Gy (P < 0.001); rectum 43.2 Gy, 35.3 Gy (P = 0.072); sigmoid 58.0 Gy, 47.0 Gy (P = 0.007); bowel 47.7 Gy, 41.0 Gy (P = 0.078). Bladder D2cc was ≥ 80 Gy in 11 (25.0%) original plans and 4 (9.1%) GTV-only replans (P = 0.043). Sigmoid D2cc was ≥ 65 Gy in 20 (45.4%) original plans and 10 (22.7%) GTV-only replans (P = 0.021).Uterine BT according to current inoperable endometrial cancer guidelines results in OAR doses at or near constraints, with associated toxicity in a patient population with limited functional reserve. BT targeting the GTV results in lower OAR doses compared to standard CTV-directed BT. Adequate dose to the MRI and/or PET-defined GTV is associated with excellent local control. Prospective evaluation of MRI-guided BT to a reduced, GTV-focused volume is warranted.E. Merfeld: None. J.Y. Huang: None. A. Kuczmarska-Haas: None. V. Desai: None. J. Miller: None. M. Lawless: None. C. Wallace: None. B.M. Anderson: Partner; University of Wisconsin. Research Grant; ViewRay. K.A. Bradley: None.

Can EBRT Dose-Escalation Above 80 Gy Yield Comparable Survival Rates Relative to EBRT Plus Brachytherapy Boost in Men With Unfavorable Intermediate-Risk Prostate Cancer?

<h3>Purpose/Objective(s)</h3> Current recommendations regarding radiotherapy treatment for unfavorable intermediate-risk prostate cancer (UIR-PCa) include external beam radiotherapy (EBRT) ± brachytherapy boost (BT) ± androgen deprivation therapy (ADT). Dose-escalated EBRT ± ADT is associated with excellent long-term outcomes, but ERBT+BT ± ADT can achieve higher dose escalation beyond what can be achieved with EBRT alone. Prior studies have shown improved biochemical control and reduced distant metastasis with EBRT+BT vs. EBRT in men with intermediate-risk disease, but it is unclear if this translates into a survival benefit. <h3>Materials/Methods</h3> Men with UIR-PCa diagnosed between 2004 and 2015 and treated with EBRT ± ADT or EBRT+BT ± ADT were identified in the National Cancer Database (NCDB). EBRT was delivered with conventional fractionation (≥ 72 Gy in 1.8-2.0 Gy per fraction), while EBRT+BT was defined as patients receiving EBRT to a total dose of 40-50.4 Gy plus high-dose rate or low-dose rate brachytherapy. Patients with a Charlson-Deyo comorbidity index (CDCI) score > 1, who received systemic therapy other than ADT, or missing key information were excluded. Propensity-weighted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios. Covariables included age, race, ethnicity, year of diagnosis, CDCI score, insurance status, educational and socioeconomic metrics, treatment at an academic center, PSA at diagnosis, Gleason score, clinical T-stage, and receipt of ADT. <h3>Results</h3> The study cohort included 32,246 unfavorable intermediate-risk prostate cancer patients treated with: (<b>i</b>) EBRT (n = 13,265), (<b>ii</b>) EBRT+ADT (n = 13,123), (<b>iii</b>) EBRT+BT (n = 3,440), or (<b>iv</b>) EBRT+BT+ADT (n = 2,418). Cumulative doses of EBRT ± ADT are summarized in Table 1. The average time to follow-up was 62 months (standard deviation ± 39 months). Propensity-weighted MVA showed that EBRT+BT ± ADT was associated with improved OS relative to increasing doses of EBRT ± ADT. However, the OS benefit associated with EBRT+BT ± ADT diminished as the cumulative dose of radiation in the EBRT ± ADT cohort increased (Table 1). <h3>Conclusion</h3> The addition of brachytherapy to EBRT correlated with reduced mortality in men with UIR prostate cancer, including patients treated with EBRT ± ADT to ≥80 Gy. The relative OS benefit associated with EBRT+BT declined as the radiation dose increased in the EBRT ± ADT cohort.

The Predictive Value of Post-Treatment PET-CT Imaging for Patients With Curable Anal Canal Cancer

<h3>Purpose/Objective(s)</h3> According to 2020 "NCCN" guidelines, post-treatment positron emission tomography (PET) – computed tomography (CT) imaging of the body is <b>not</b> recommended to predict outcomes of patients undergoing curative intent chemoradiation therapy (CRT) for anal canal cancer. This study used PERCIST (Positron Emission tomography Response Criteria In Solid Tumors) to evaluate CRT response and outcomes for our patient population at a single institution. <h3>Materials/Methods</h3> Our "IRB"-approved anal canal database was queried for patients who have undergone CRT, modified "NIGRO" protocol, for carcinoma of the anal canal. The evaluable patient dataset comprised those with both pre- and post-CRT PET-CT imaging of the body. The primary study endpoint was relapse-free survival (RFS) calculated from date of diagnosis to date of first known appearance of disease or death from any cause. Overall survival (OS) was defined using elapsed time between date of diagnosis and date of death and surviving patients were censored using date of last follow-up. Also, the range and median time to first post-CRT PET-CT imaging was determined. RFS and OS were analyzed using Kaplan-Meier method. Complete response rate (CRR) and objective response rate (ORR) were calculated along with 95% confidence intervals using Fisher's exact method. All tests were two-sided, and statistical significance was considered when <i>P</i> < 0.05. <h3>Results</h3> Out of an initial 392 patients in our database registry, 62 had pre/post-CRT PET-CT imaging from June 2008 until May 2020. There were 18 males and 44 females. The median age at diagnosis was 57.7 years (range: 38-84 years). "AJCC" (7^th edition) staging distribution was as follows: 3 Stage I, 13 Stage II, 41 Stage III, and 5 Stage IV. The median total dose of external beam irradiation was 54 Gy (range: 45-60 Gy). Time to post-CRT PET-CT imaging ranged from 0.2 to 27.8 months (mos) [median: 2.9 mos]. Respective PET-response rates regarding primary tumor (N = 62); largest groin node (N = 33); and largest pelvic node (N = 39) were as follows: 31 CR (Complete Response), 26 PR (Partial Response), 5 SD (Stable Disease), and 0 DP (Disease Progression); 30 CR, 3 PR, 0 SD, 0 DP; and 36 CR, 1 PR, 2 SD, 0 DP. Patient follow-up ranged from 6.8 to 114 mos (median: 38.6 mos). At time of last follow-up, there were 53 alive and 9 dead. Estimated 3-year RFS was 72% (95% "CI": 58.2-81.9%). Estimated 3-year OS was 88.8% (95% CI: 76.6-94.9%). Respective CRRs and ORRs for the primary tumor were 50% (95% CI = 37-63%) and 91.9% (95% CI = 82.2-97.3%); for the groin node 48.4% (95% CI = 35.5-61.4%) and 53.2% (95% CI = 40.1-66%); and for the pelvic node 58.1% (95% CI = 44.8-70.5%) and 59.7% (95% CI = 46.4-71.9%). CRRs and ORRs were not significant prognostic factors for either RFS or OS. <h3>Conclusion</h3> After applying PERCIST to our institutional study cohort, the use of post-treatment PET-CT imaging to predict outcomes for this patient population remains unproven.

Important Factors for Local Control After Radiotherapy of Bone Metastases in Cases of Long-Term Survivors

<h3>Purpose/Objective(s)</h3> With the advance of systemic therapy, long-term survivors have increased and importance of long-term local control of bone metastases has increased in recent years. The purpose of this study was to search for factors affecting local control of bone metastatic lesions in external-beam radiotherapy (EBRT) for cases with long-term survival of ≥1-year. <h3>Materials/Methods</h3> Between December 2010 and April 2019, 349 lesions (vertebral body, 214; pelvic, 73; rib/ sternal, 22; extremity, 35; skull, 6) in 259 patients received EBRT, and survived for ≥1-years after EBRT. Local control was evaluated by follow-up CT. Doses of EBRT were 8-50 Gy (median 30 Gy). <h3>Results</h3> One and three-year control rates at EBRT sites were 95% and 86%, respectively. Local recurrence was observed in 9.7% (34 lesions in 31 patients). Sex, age of > 70, bone metastases other than vertebrae, bone metastases from unfavorable primary tumor sites (hepatobiliary/pancreatic/colorectal/thyroid/renal cell carcinoma), and without bone modified agents (BMAs) and/or systemic therapy (ST) after EBRT were statistically significant poor local control factors (<i>P</i> = 0.036, 0.038, 0.001, < 0.001, < 0.001, and 0.001, respectively). There were no statistically significant differences in control rates according to EBRT dose (≤30 Gy vs. > 30 Gy), bone cortex destruction and without ST before EBRT (<i>P</i> = 0.623, 0.887, and 0.568, respectively). In multivariate analysis, bone metastases other than vertebrae, bone metastases from unfavorable primary tumor sites and without BMAs were significant unfavorable factors for local control (<i>P</i> = 0.011, 0.0004, and 0.028, respectively). <h3>Conclusion</h3> EBRT dose escalation of > 30 Gy did not seem to be useful. Although further studies are needed, primary tumor and bone metastatic sites were associated with local control. In addition, the use of BMAs is useful in terms of local control.

Interstitial Brachytherapy for Locally Advanced Tongue Cancer: Analysis of the Long-Term Treatment Results for Survival and Complications

<h3>Purpose/Objective(s)</h3> The purpose of this study was to evaluate the long-term treatment results of interstitial brachytherapy (IBT) in patients with locally advanced tongue cancer. <h3>Materials/Methods</h3> between 1994 and 2015, 60 patients (18 females and 42 males) with locally advanced tongue cancer treated by IBT using Ir-192 sources and Au-198 seeds were analyzed. The median age was 63 years (range, 22–86 years). All histological type was squamous cell carcinoma. T3/T4a/T4b was noted in 51/9/0 patients, respectively. The median depth of invasion was 11 mm (3–27 mm). The growth type was infiltrative/exophytic/superficiality in 54/0/6 patients, respectively. In all cases, no lymph node metastasis was not found at diagnosis. IBT was performed using Ir-192 in 56 patients and Au-198 in 4 patients. Median irradiation doses of Ir-192 and Au-198 were 60 Gy (29–77 Gy) and 68 Gy (64–73 Gy), respectively. External beam radiation therapy (EBRT) was performed before IBT in 41 patients (68%). Median dose of EBRT was 30 Gy (30–50 Gy). Chemotherapy was combined with IBT in 42 patients. <h3>Results</h3> Median follow-up time for survivors was 103 months (36–230 months). CR rate was 98%. The 10-year overall/cause specific survival (OS, CSS) rate was 67/84%, respectively. According to T factors, the 10-year OS/CSS rates for T3 and T4a were 64/85% and 77/77%, respectively. There was no significant difference in OS and CSS between T3 and T4a. The10-year local/regional control rates were 78/72%, respectively. The 75% of the regional metastasis was occurred within 1 year, and more than 90% was within 2 years. The 10-year local control rates for T3 and T4a were 75% and 88%, respectively. The 10-year regional control rates for T3 and T4a were 71% and 77%, respectively. There was no significant difference in local/regional control between T3 and T4a. In the multivariate analysis, significant differences in OS were seen with elderly age, patients having double cancer and having late regional lymph node recurrence. According to CTCAE ver. 5.0, grade 2 soft tissue complications were observed in 33 (55%) patients and grade 2 mandibular complications in 2 (3%) patients. There were no grade 3 or more late complications. <h3>Conclusion</h3> Our 10-year treatment results of IBT for locally advanced tongue cancer showed favorable survival and low occurrence rate in patients with severe late complications.

The Impact of Demographics and Medicare Payments on Quality of External Beam Radiotherapy for Bone Metastases in US Hospitals

External Beam Radiotherapy (EBRT) has a well-established role in palliation of metastatic bone disease, yet the adherence to evidence based palliative EBRT doses and fractionation schemes is not universal across United States outpatient treatment facilities. We aimed to explore potential disparities in palliative EBRT quality in relation to Medicare visit payments and population demographics.Centers for Medicare & Medicaid Services (CMS) EBRT for Bone Metastases process measure score for 2018 included in the Hospital Outpatient Quality Reporting Program (Hospital OQR) was available for a total of 824 facilities across the US. Radiation Oncology Office Visit Costs per zip code for new and established patients were obtained from CMS. Demographics (percentage of total population representing males, females, 5 years or younger, under 18 years, 65 or older, white, black or African American, Latino) were obtained from US census. Linear regression analysis was carried out with score representing the dependent variable.The median score was 95% (range 5-100%), average 88.86%. In the final multivariate model, the score was significantly positively associated with the percentage of white population (P = 0.04) and negatively associated with the percentage of population under 18 (P = 0.03), and there was a trend toward association with the mode of Medicare pricing for a new patient visit (P = 0.06). Of note, the percentage of population under 18 was positively correlated with percentage of Latino population (P = 3.155e-09) but not black population (P = 0.9.) There was no association with gender, or with the percentage of those patients who were very young (under 5) or over the age of 65 years.The quality of palliative EBRT in US outpatient facilities is associated with demographic diversity of a given area, with predominantly non-diverse neighborhoods generally receiving higher quality EBRT-based palliative care. Additionally, it appears to be affected by Medicare payments. This data suggests that disparities in healthcare quality are directly mediated by race and partially by geography.

Clinical and Genomic Determinants of Survival in Ugandan Women With Cervical Cancer

Clinical and Genomic Determinants of Survival in Ugandan Women With Cervical Cancer

EQD2 Dose Accumulation Based on Deformable Image Registration of HR-CTV, Bladder, Rectum and Bowel for Combined External-Beam Radiotherapy and Brachytherapy for Cervical Cancer

<h3>Purpose/Objective(s)</h3> Evaluate the accuracy of DVH parameter summation between brachytherapy (BT) and external-beam radiotherapy (EBRT) for cervical cancer, by comparing deformable image registration (DIR) EQD2 dose accumulation. DVH summation of dosimetric parameters can overestimate cumulative organ at risk (OAR) doses due to daily variations in relative OAR position. <h3>Materials/Methods</h3> Ten patients were studied. Nine out of 10 patients received BT+EBRT. All women were treated with intracavitary tandem and ring BT. In phase I, CT simulation images from each BT fraction were rigidly fused with first fraction BT images, (BT1) focusing on the applicator and uterus. Hybrid-based DIR was then conducted using MIM software. Contours used for DIR were CTV_HR, bladder, rectum and bowel space. For phase II, EBRT and BT1 utero-cervix contours were rigidly fused, followed by contour-based DIR using utero-cervix, bladder and rectum. Each BT fraction and sum EBRT dose was accumulated onto BT1 and converted to EQD2 (Gy) via the linear quadratic equation with a/b of 10 for tumor and 3 for OARs. The absolute dose differences were reported for D0.1cc, D1cc and D2cc (OARs) and D90% (CTV_HR). The dice similarity coefficient (DSC) of all contours was reported. For phase I, the D2cc isodose level and OAR overlap structure was assessed for each BT fraction and the initial and deformed D2cc reported. The mean distance-to-agreement (MDA) and DSC of D2cc were reported for DIR accuracy assessment. <h3>Results</h3> For phase I, average DSC values for CTV_HR, bladder, rectum and bowel were 0.84 ± 0.07, 0.86 ± 0.08, 0.82 ± 0.05, 0.81 ± 0.07 and average DSC of initial vs. deformed D2cc were 0.88 ± 0.02, 0.89 ± 0.02, 0.88 ± 0.03 respectively. Average D2cc MDA values were 0.28 ± 0.04, 0.29 ± 0.05, 0.33 ± 0.06 for the bladder, rectum and bowel, respectively with absolute D2cc differences in Gy of 0.04 ± 0.04, 0.01 ± 0.01, and 0.03 ± 0.03. For CTV_HR, absolute D90 difference in EQD2 was 2.69 ± 1.98 Gy. For bladder, rectum and bowel, absolute EQD2 differences in Gy for D0.1cc were 5.57 ± 3.73, 2.78 ± 2.27, 5.10 ± 2.70 respectively. For D1cc, values in Gy were 3.27 ± 1.80, 1.62 ± 1.04, and 4.20 ± 2.51. For D2cc, 2.42 ± 0.80 Gy, 1.16 ± 0.72 Gy, and 2.83 ± 2.23 Gy. For phase II, average DSC values for utero-cervix, bladder and rectum were 0.82 ± 0.12, 0.80 ± 0.08, and 0.82 ± 0.17 respectively. Average absolute EQD2 difference in Gy for CTV_HR D90 was 7.43 ± 3.10 and 12.87 ± 6.84 and 6.02 ± 4.80 respectively for bladder and rectum D0.1cc. For D1cc and D2cc, absolute EQD2 differences in Gy were 10.46 ± 5.10 and 8.10 ± 4.48 respectively for bladder and 3.84 ± 2.95 and 3.21 ± 2.17 for rectum. <h3>Conclusion</h3> Arithmetic DVH addition over-estimated OAR D2cc in 7 of 10 patients. D2cc overestimation of bladder occurred in 6 of 9 patients and 7 of 9 patients for rectum. Our results show good estimation of accumulated dose with DVH parameter addition for both BT only and BT + EBRT.

A case of CRPC with multiple bladder invasions treated with EBRT followed by HDR-BT boost

We report a case of post-operative local recurrence of castration-resistant prostate cancer with multiple bulky bladder invasions treated using external beam radiotherapy (EBRT) followed by a high-dose-rate brachytherapy (HDR-BT) boost. The EBRT dose was 46 Gy delivered in 23 fractions with intensity-modulated radiotherapy to the entire pelvis. The HDR-BT dose was 15 Gy delivered in 1 fraction using ultrasound, CT, and MRI-guided brachytherapy with 18 interstitial needles. We achieved excellent local control of cancer in the prostate bed and multiple bulky bladder invasions. EBRT plus HDR-BT boost can allow higher doses to be delivered than EBRT alone for locally recurrent bulky prostate cancer following prostatectomy.

Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer: 12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease.

The European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 (NCT00021450) showed that 6 months of concomitant and adjuvant androgen suppression (AS) improves event- (EFS, Phoenix) and clinical disease-free survival (DFS) of intermediate- and high-risk localized prostatic carcinoma, treated by external-beam radiotherapy (EBRT) at 70-78 Gy. We report the long-term results in intermediate-risk patients treated with 74 or 78 Gy EBRT, as per current guidelines. Of 819 patients randomly assigned between EBRT or EBRT plus AS started on day 1 of EBRT, 481 entered with intermediate risk (International Union Against Cancer TNM 1997 cT1b-c or T2a with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≤ 7 and PSA ≤ 20 ng/mL, N0M0) and had EBRT planned at 74 (342 patients, 71.1%) or 78 Gy (139 patients, 28.9%). We report the trial primary end point EFS, DFS, distant metastasis-free survival (DMFS), and overall survival (OS) by intention-to-treat stratified by EBRT dose at two-sided α = 5%. At a median follow-up of 12.2 years, 92 of 245 patients and 132 of 236 had EFS events in the EBRT plus AS and EBRT arm, respectively, mostly PSA relapse (48.7%) or death (45.1%). EBRT plus AS improved EFS and DFS (hazard ratio [HR] = 0.53; CI, 0.41 to 0.70; P < .001 and HR = 0.67; CI, 0.49 to 0.90; P = .008). At 10 years, DMFS was 79.3% (CI, 73.4 to 84.0) with EBRT plus AS and 72.7% (CI, 66.2 to 78.2) with EBRT (HR = 0.74; CI, 0.53 to 1.02; P = .065). With 140 deaths (EBRT plus AS: 64; EBRT: 76), 10-year OS was 80.0% (CI, 74.1 to 84.7) with EBRT plus AS and 74.3% (CI, 67.8 to 79.7) with EBRT, but not statistically significantly different (HR = 0.74; CI, 0.53 to 1.04; P = .082). Six months of concomitant and adjuvant AS statistically significantly improves EFS and DFS in intermediate-risk prostatic carcinoma, treated by irradiation at 74 or 78 Gy. The effects on OS and DMFS did not reach statistical significance.

The Relationship Between Late Morbidity and Dose-Volume Parameter of Rectum in Combined Intracavitary/Interstitial Cervix Cancer Brachytherapy: A Mono-Institutional Experience.

PurposeTo establish a dose volume–effect relationship for predicting late rectal complication (LRC) in locally advanced cervical cancer patients treated with external beam radiotherapy (EBRT) followed by combined intracavitary/interstitial brachytherapy (IC/IS-BT).Materials and MethodsA retrospective analysis was performed in 110 patients with locally advanced cervical cancer who underwent definitive radiotherapy combined with IC/IS-BT from July 2010 to September 2018. We report the 90% of the target volume receiving the minimum dose for high risk clinical target volume (HR-CTV D90) and intermediate risk clinical target volume (IR-CTV D90), and the minimum doses to the most exposed 0.1, 1, and 2 cm³ doses at the International Commission on Radiation Units and Measurements (DICRU) for organs at risk (OARs). The total dose of EBRT plus brachytherapy was transformed to the biologically equivalent dose in 2 Gy fractions (EQD2) with α/β value of 10 Gy for target, 3 Gy for organs at risk using the linear quadratic model. The morbidity was scored according to the Radiation Therapy Oncology Group (RTOG) criteria. The Probit model was used to establish a prediction model on rectum between the organs at risk for dose and LRC. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of dose volume parameters for LRC.ResultsThe median follow-up time was 72.3 months. The mean ( ± standard deviation) , and DICRU values of rectum were 64.72 ± 7.47 GyEQD2, 70.18 ± 5.92 GyEQD2, 79.32 ± 7.86 GyEQD2, and 67.22 ± 7.87 GyEQD2, respectively. The Probit model showed significant relationships between , and the probability of grade1–4, grade 2–4 rectal events at 1 year, and between and the probability of grade2–4 rectal events at 3 and 5 years. The dose values for 10% complication rates (ED10) of were 74.18 (70.42–76.71) GyEQD2, 67.80 (59.91, 71.08) GyEQD2, 66.37 (52.00, 70.27) GyEQD2 for grade 2–4 with rectal morbidity at 1, 3, and 5 years, respectively.ConclusionOur study proved that were considered as useful dosimetric parameters for predicting the risk of grade1–4 and grade2–4 LRC at 1-year, and might be an indicator for predicting grade2-4 LRC at 3/5years. The patients with rectal >66.37–74.18 GyEQD2 should be closely observed for grade2–4 LRC.

The Case Selection for Vaginal Cuff Brachytherapy in Cervical Cancer Patients After Radical Hysterectomy and External Beam Radiation Therapy.

ObjectiveTo explore the suitable cases for vaginal cuff brachytherapy (VCB) combined with external beam radiation therapy (EBRT) in the postoperative treatment of cervical cancer.MethodsWe retrospectively analyzed the clinical data of 214 postoperative cervical cancer patients who received radiotherapy from January 2008 to December 2015. Among them, 146 patients received postoperative EBRT, 68 received EBRT plus VCB. There was no statistical difference in clinical and pathological characteristics between these two groups. Those who with negative vaginal cuff underwent supplemented 12–18 Gy/2–3 Fx VCB. Survival analyses were performed using Kaplan–Meier method, and Cox model was used to analyze prognostic factors.ResultsThe median follow-up was 52 months (9–136 months), and 4-year RFS (recurrence-free survival) was 77%. Among them, 58 patients (27.10%) had local or distant recurrences, 29 (13.55%) in pelvis, six (2.80%) with metastases to para-aortic, 19 (8.88%) with distant metastases (including inguinal lymph nodes) and four (1.87%) with both local and distant recurrences. The postoperative brachytherapy boost did not improve RFS or OS (overall survival) among the investigated subjects, P = 0.77, P = 0.99, respectively. Neither it decreased the local relapse in the pelvis or vaginal cuff, P = 0.56, P = 0.59. Subgroup analyses showed that brachytherapy boost improved RFS in patients who had bulky mass (>4 cm) as well as 1) with deep stromal invasion (>50% stromal invasion), P = 0.012 or 2) received low EBRT dose (≤45 Gy), P = 0.033, and in patients with deep stromal invasion as well as received low EBRT dose (P = 0.018).ConclusionsWe first proposed the case selection model for postoperative EBRT plus VCB. Brachytherapy boost were considered in the setting of postoperative radiotherapy if the patients had at least two out of these following factors: bulky mass, deep stromal invasion and low EBRT dose.

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy

IntroductionThe biological consequences of absorbed radiation doses are ill-defined for radiopharmaceuticals, unlike for external beam radiotherapy (EBRT). A reliable assay that assesses the biological consequences of any radionuclide is much needed. Here, we evaluated the cell-free plasmid DNA assay to determine the relative biological effects of radionuclides such as Auger electron-emitting [67Ga]GaCl3 or [111In]InCl3 compared to EBRT. MethodsSupercoiled pBR322 plasmid DNA (1.25 or 5 ng/μL) was incubated with 0.5 or 1 MBq [67Ga]GaCl3 or [111In]InCl3 for up to 73 h or was exposed to EBRT (137Cs; 5 Gy/min; 0–40 Gy). The induction of relaxed and linear plasmid DNA, representing single and double strand breaks, respectively, was assessed by gel electrophoresis. Chelated forms of 67Ga were also investigated using DOTA and THP. Topological conversion rates for supercoiled-to-relaxed (ksrx) or relaxed-to-linear (krlx) DNA were obtained by fitting a kinetic model. ResultsDNA damage increased both with EBRT dose and incubation time for [67Ga]GaCl3 and [111In]InCl3. Damage caused by [67Ga]GaCl3 decreased when chelated. [67Ga]GaCl3 proved more damaging than [111In]InCl3; 1.25 ng/μL DNA incubated with 0.5 MBq [67Ga]GaCl3 for 2 h led to a 70% decrease of intact plasmid DNA as opposed to only a 19% decrease for [111In]InCl3. For both EBRT and radionuclides, conversion rates were slower for 5 ng/μL than 1.25 ng/μL plasmid DNA. DNA damage caused by 1 Gy EBRT was the equivalent to damage caused by 0.5 MBq unchelated [67Ga]GaCl3 and [111In]InCl3 after 2.05 ± 0.36 and 9.3 ± 0.77 h of incubation, respectively. ConclusionsThis work has highlighted the power of the plasmid DNA assay for a rapid determination of the relative biological effects of radionuclides compared to external beam radiotherapy. It is envisaged this approach will enable the systematic assessment of imaging and therapeutic radionuclides, including Auger electron-emitters, to further inform radiopharmaceutical design and application.

Hydrogel spacer shrinkage during external-beam radiation therapy following low-dose-rate brachytherapy for high-risk prostate cancer: a case series\xa0

BackgroundFew studies have assessed hydrogel spacer shrinkage during external-beam radiation therapy following brachytherapy for localized high-risk prostate cancer. This case presentation evaluated the changes in hydrogel spacer appearance by magnetic resonance imaging during external-beam radiation therapy after brachytherapy for prostate cancer and analyzed the effect of this shrinkage on the dose distribution in four cases.Case presentationIn all cases, we implanted 125I sources using a modified peripheral loading pattern for seed placement. The prescribed dose for each implant was 110 Gy. After delivering the sources, a hydrogel spacer was injected. All cases underwent external-beam radiation therapy approximately 1–2 months after brachytherapy. The prescribed dose of external-beam radiation therapy was 45 Gy in 1.8-Gy fractions. Magnetic resonance imaging was performed for evaluation on the day following seed implantation (baseline), at external-beam radiation therapy planning, and during external-beam radiation therapy. The median hydrogel spacer volume was 16.2 (range 10.9–17.7) cc at baseline, 14.4 (range, 9.4–16.1) cc at external-beam radiation therapy planning, and 7.1 (range, 2.0–11.4) cc during external-beam radiation therapy. The hydrogel spacer volume during external-beam radiation therapy was significantly lower than that at external-beam radiation therapy planning. The rectum V60–80 (rectal volume receiving at least 60–80% of the prescribed dose of external-beam radiation therapy) during external-beam radiation therapy was significantly higher than that at external-beam radiation therapy planning.ConclusionsThe potential reduction in hydrogel spacer size during external-beam radiation therapy following brachytherapy can lead to unexpected irradiation to the rectum. This case presentation would be helpful for similar cases.

The impact of demographics and Medicare payments on quality of external beam radiotherapy for bone metastases in U.S. hospitals.

e18504 Background: External Beam Radiotherapy (EBRT) has a well-established role in palliation of metastatic bone disease, yet the adherence to evidence based palliative EBRT doses and fractionation schemes is not universal across United States outpatient treatment facilities. We aimed to explore potential disparities in palliative EBRT quality in relation to Medicare visit payments and population demographics. Methods: Centers for Medicare &amp; Medicaid Services (CMS) EBRT for Bone Metastases process measure score for 2018 included in the Hospital Outpatient Quality Reporting Program (Hospital OQR) was available for a total of 824 facilities across the US. The score represents the percentage of evaluated patients that received an acceptable palliative dose/fractionation regimen. Radiation Oncology Office Visit Costs per zip code for new and established patients were obtained from CMS. Demographics (percentage of total population representing males, females, 5 years or younger, under 18 years, 65 or older, white, black or African American, Latino) were obtained from US census. Linear regression analysis was carried out with score representing the dependent variable. Results: The median score was 95% (range 5-100%), average 88.86%. In the final multivariate model, the score was significantly positively associated with the percentage of white population (p = 0.04) and negatively associated with the percentage of population under 18 (p = 0.03), and there was a trend toward association with the mode of Medicare pricing for a new patient visit (p = 0.06). Of note, the percentage of population under 18 was positively correlated with percentage of Latino population (p = 3.155e-09) but not black population (p = 0.9.) There was no association with gender, or with the percentage of those patients who were very young (under 5) or over the age of 65 years. Conclusions: The quality of palliative EBRT in US outpatient facilities is associated with demographic diversity of a given area, with predominantly nondiverse neighborhoods generally receiving higher quality EBRT-based palliative care. Additionally, it appears to be negatively affected by Medicare payments. This data suggests that disparities in healthcare quality are directly mediated by race and partially by geography.

Time to review the role of intraluminal brachytherapy for dose escalation after concurrent chemoradiation in cancer esophagus: A retrospective audit.

e16054 Background: Intraluminal brachytherapy (ILBT) for dose escalation after concurrent chemoradiation (CRT) in cancer esophagus is not routinely practiced. This is particularly attributable to radiotherapy toxicity in terms of strictures and fistulas. Cancer esophagus has poor locoregional control and overall survival rates in comparison to head and neck cancers. Dose escalation may be an option to counteract the high failure rates. Methods: A retrospective analysis was conducted for esophageal cancer patients treated between 2008 to 2016 planned for radical CRT to a minimum dose of 59.4 Gy in 33 fractions along with concurrent cisplatin 35 mg/m2 and 5 FU 375 mg/m2 on weekly basis. Further, the patients who received dose escalation after external beam radiotherapy (EBRT) completion by ILBT to a dose of 6 Gy in a single fraction to the pre EBRT volume were also analysed. The patient, tumor, treatment characteristics along with response rates, survival outcomes, and toxicities were evaluated and compared between the two groups - the patients who received ILBT and those who did not. Statistical significance between variables was analysed with the Chi-Square or Fischer’s exact test and t-test. Survival analysis was done by Log-Rank test. The analysis was done on a worst-case scenario basis where the patients lost to follow-up were considered dead. Results: The total number of patients treated by CRT was 69, out of which 13 patients received ILBT for dose escalation. The median age was 60 years (Range - 40 to 80 years) and the male: female ratio was 1.09, mean tumor length was 6.4 ± 2.4 cms (Range-1.5-12 cms). The commonest tumor site was the middle third observed in 58% patients. The median EBRT dose was 59.4 Gy (Range- 9 to 63 Gy). The median concurrent chemotherapy cycles were 5. The median follow-up period was 15 months (range 1-100 months). In terms of complete response rates, there was a trend towards significant improvement in patients receiving ILBT compared to those receiving EBRT alone (84.61% versus 57.49%, p=0.07). Also, the overall survival (OS) was significantly higher in the ILBT group (45.31 months versus 19.20 months; p = 0.005). The other patient, tumor, and treatment characteristics analyzed showed no significant impact on OS. There was no significant difference in the incidence of strictures (p=0.206) and severity (p=0.764) of strictures amongst both the groups. Grade ≥3 late toxicity was reported in 10 patients (17.85%) receiving EBRT alone and in 3 patients (23.07%) receiving ILBT. None of the patients receiving ILBT developed a fistula. Conclusions: The present study reveals a dramatic increase in OS by dose escalation with ILBT. The limitations of the present study were a small sample size and a lesser number of patients in the ILBT group. Recapitulating the concept of ILBT to increase the local tumoricidal dose may improve the survival rates.