External Beam Radiotherapy Dose Research Articles

Biochemical control in intermediate- and high-risk prostate cancer after EBRT with and without brachytherapy boost.

External beam radiotherapy (EBRT) with or without brachytherapy boost (BTB) has not been compared in prospective studies using guideline-recommended radiation dose and recommended androgen-deprivation therapy (ADT). In this multicenter retrospective analysis, we compared modern-day EBRT with BTB in terms of biochemical control (BC) for intermediate-risk (IR) and high-risk (HR) prostate cancer. Patients were treated for primary IR or HR prostate cancer during 1999-2019 at three high-volume centers. Inclusion criteria were prescribed ≥ 76 Gy EQD2 (α/β = 1.5 Gy) for IR and ≥ 78 Gy EQD2 (α/β = 1.5 Gy) for HR as EBRT alone or with BTB. All HR patients received ADT and pelvic irradiation, which were optional in IR cases. BC between therapies was compared in survival analyses. Of 2769 initial patients, 1176 met inclusion criteria: 468 HR (260 EBRT, 208 BTB) and 708 IR (539 EBRT, 169 BTB). Median follow-up was 49and 51months for HR and IR, respectively. BTB patients with ≥ 113 Gy EQD2Gy experienced astable, good BC outcome compared with BTB at lower doses. Patients treated with ≥ 113 Gy EQD2Gy also experienced significantly improved BC compared with EBRT (10-year BC failure rates after ≥ 113 Gy BTB and EBRT: respectively 20.4 and 41.8% for HR and 7.5and 20.8% for IR). In patients with IR and HR prostate cancer, BTB with ≥ 113 Gy EQD2Gy offered aBC advantage compared with dose-escalated EBRT and lower BTB doses.

Success of Ultra-low Dose Radiation Therapy for Primary Cutaneous B-cell Lymphoma.

Primary cutaneous B-cell lymphoma (PCBCL) is a relatively rare disease, associated with 5-year overall survival of nearly 95% when treated with external beam radiation therapy (EBRT) alone. However, standard EBRT doses yield acute skin toxicity in more than 70% of patients and grade 3 to 4 acute skin toxicity in nearly 10% of patients. Consequently, the PCBCL treatment paradigm is shifting towards lower EBRT doses. This study evaluates our early experience with ultra-low dose EBRT (total dose of 4 Gy in 2 fractions) for PCBCL. Four biopsy-confirmed PCBCL lesions (1 anterior thigh and 3 chest) in 2 male patients were treated with 2 Gy×2 fraction EBRT using electrons through a clinical setup. The anterior thigh lesion was treated using a clamshell to protect the scrotum from scatter dose. Treatment was achieved using 9 MeV electrons to the 85% isodose line using no bolus, with follow-up every 4 months and potential retreatment if no visible response at 8 to 9 months. All lesions demonstrated a response to EBRT by 4 months, visibly manifesting as flattening with changes in pigmentation. At the last follow-up (20, 20, 16.5, and 4 mo, respectively), all lesions had flattened with no evidence of local recurrence and no skin toxicity. Treatment of PCBCL with ultra-low dose EBRT to 4 Gy total dose in 2 fractions provides durable local control with zero skin toxicity. These results are encouraging for both the success of treatment and the potential to use similarly low doses for retreatment should patients exhibit local recurrence.

The prognostic effect of tumor volume, reduction ratio, and cumulative doses on external beam radiotherapy with central-shielding method and image-guided adaptive brachytherapy for cervical cancer.

To evaluate the prognostic effect of tumor volume at diagnosis, tumor reduction ratio during external beam radiotherapy (EBRT) with central-shielding method, and cumulative minimal dose to 90% of the high-risk clinical target volume (CTVHR D90) on combined EBRT and image-guided adaptive brachytherapy (IGABT) for cervical cancer. Consecutive patients who underwent definitive radiotherapy or concurrent chemoradiotherapy for cervical cancer at Gunma University Hospital between January 2010 and December 2019 were retrospectively reviewed. Tumor volume at diagnosis and reduction ratio were calculated using magnetic resonance imaging at diagnosis and before the first IGABT session. The cumulative dose of EBRT and IGABT was calculated as an equivalent dose in 2 Gy fractions (EQD2). Optimal cutoff values were determined according to a receiver operating characteristic curve. Treatment outcomes were evaluated using the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression. A total of 254 patients were included in the analysis. The median follow-up for all patients was 57 (2-134) months. The 5-year overall survival (OS) was 81.9%, progression-free survival (PFS) was 71.3%, and local control (LC) was 94.5%. The patients were divided into four groups according to tumor volume at diagnosis and reduction ratio. The group with tumor volume at diagnosis ≥ 34.1 cm3 and reduction ratio < 68.8% showed significantly worse OS, PFS, and LC than the other three groups (All p < 0.05). In this group, the patients with a cumulative CTVHR D90 < 69.6 GyEQD2 showed significantly worse PFS and LC (p = 0.042 and p = 0.027, respectively). In the multivariate analysis of OS, adenocarcinoma/adenosquamous carcinoma, International Federation of Gynecology and Obstetrics 2009 stage III/IV, and a reduction ratio of < 68.8% were independent significant poor prognostic factors (p = 0.045, p = 0.009 and p = 0.001, respectively). In the univariate analysis of LC, a reduction ratio of < 68.8% was the only poor prognostic factor (p = 0.041). The patients with large and poorly responding tumors had significantly worse prognoses in terms of OS, PFS, and LC, suggesting that dose escalation should be considered for such tumors.

A Comparative Study of Clinical Outcomes in Locally Advanced Cervical Cancer: External Beam Radiotherapy (EBRT) and Sequential High Dose Rate Intracavitary Brachytherapy (HDRICBT) with or without Concurrent Cisplatin on the Day of ICBT Insertion - A Tertiary Care Center Randomized Controlled Trial in India.

The current study aimed to delve into the comparative clinical outcomes between external beam radiation therapy (EBRT) and sequential High Dose Rate Intracavitary Brachytherapy (HDRICBT) with or without concurrent cisplatin administration on the day of intracavitary brachytherapy (ICBT) insertion in women with locally advanced cervical cancer. In this study, conducted between January 2017 and July 2018 at a leading institute in India, diagnosed and untreated patients of locally advanced carcinoma cervix were randomized into two groups. Arm 1 received concurrent cisplatin before each course of brachytherapy, while Arm 2 underwent brachytherapy alone. The outcomes were compared in terms of acute and late toxicities, treatment response, and follow-up. Data analysis was performed using SPSS 16, with statistical significance set at p < 0.05. Both study arms showed similar complete response (CR) rates of 73.3%, with no significant advantage of concurrent cisplatin before brachytherapy. However, a noteworthy trend emerged during follow-up. In the concurrent cisplatin group, the CR rate increased from 73.3% post 1 month of brachytherapy to 86.7% at 3 months and 83.3% at 6 months. Contrastingly, the control group showed CR rates of 73.3% post 1 month, 80% at 3 months, and 76.6% at 6 months. While not statistically significant, this observation suggests a possible enhancement in response rates with concurrent cisplatin and ICBT. Future studies focusing on the optimal drug, dosage, scheduling, and combining cisplatin with other agents are recommended to further explore the potential benefits observed in this study.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial

Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Interstitial needles versus intracavitary applicators only for locally advanced cervical cancer: results from real-life dosimetric comparisons.

Image-guided adapted brachytherapy (IGABT) is superior to other radiotherapy techniques in the treatment of locally advanced cervical cancer (LACC). We aimed to investigate the benefit of interstitial needles (IN) for a combined intracavitary/interstitial (IC/IS) approach using IGABT over the intracavitary approach (IC) alone in patients with LACC after concomitant external beam radiotherapy (EBRT) and chemotherapy. We included consecutive patients with LACC who were treated with IC/IS IGABT after radiochemotherapy (RCT) in our retrospective, observational study. Dosimetric gain and sparing of organs at risk (OAR) were investigated by comparing the IC/IS IGABT plan with a simulated plan without needle use (IC IGABT plan) and the impact of other clinical factors on the benefit of IC/IS IGABT. Ninety-nine patients were analyzed, with a mean EBRT dose of 45.5 ± 1.7 Gy; 97 patients received concurrent chemotherapy. A significant increase in median D90% High Risk Clinical target volume (HR-CTV) was found for IC/IS (82.8 Gy) vs IC (76.2 Gy) (p < 10-4). A significant decrease of the delivered dose for all OAR was found for IC/IS vs IC for median D2cc to the bladder (77.2 Gy), rectum (68 Gy), sigmoid (53.2 Gy), and small bowel (47 Gy) (all p < 10-4). HR-CTV coverage was higher with IC/IS IGABT than with IC IGABT, with lower doses to the OAR in patients managed for LACC after RCT. Interstitial brachytherapy in the management of LACC after radiotherapy provides better coverage of the target volumes, this could contribute to better local control and improved survival of patients.

A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy

Purpose/ObjectivesTo compare health-related Quality of Life (QoL) in urinary, bowel and sexual domains after combined external beam radiotherapy (EBRT) and either low dose rate (LDR) or high dose rate (HDR) prostate brachytherapy (BT). Materials/MethodsEligible men with intermediate or high-risk prostate cancer, treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score (IPSS), Index of Erectile Function (IIEF), Expanded Prostate Cancer Composite (EPIC-26) were collected at baseline, 1,3,6 and 12 months, q6 months to 3 years and then annually along with PSA/testosterone. Fisher's exact test compared categorical variables and the Mann Whitney U test EPIC domain scores. ResultsFrom 01/2014 to 12/2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89/88 for GU and 92/93 for GI. EPIC urinary scores decreased at one month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained > the MCID out to 5 years. ConclusionsPatient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms.

TRImodal DEfinitive invasive vagiNal carcinoma Treatment (TRIDENT protocol): how a standardized approach may change prognostic outcomes

ObjectiveVaginal carcinoma is a rare malignancy accounting for 1–2% of all gynecological cancers. Surgery has a limited role, while definitive radiotherapy–chemotherapy followed by interventional radiotherapy is considered a valid alternative....

Practice and principles of stereotactic body radiation therapy for spine and non-spine bone metastases

Radiotherapy is the dominant treatment modality for painful spine and non-spine bone metastases (NSBM). Historically, this was achieved with conventional low dose external beam radiotherapy, however, stereotactic body radiotherapy (SBRT) is increasingly applied for these indications. Meta-analyses and randomized clinical trials have demonstrated improved pain response and more durable tumor control with SBRT for spine metastases. However, in the setting of NSBM, there is limited evidence supporting global adoption and large scale randomized clinical trials are in need. SBRT is technically demanding requiring careful consideration of organ at risk tolerance, and strict adherence to technical requirements including immobilization, simulation, contouring and image-guidance procedures. Additional considerations include follow up practices after SBRT, with appropriate imaging playing a critical role in response assessment. Finally, there is renewed research into promising new technologies that may further refine the use of SBRT in both spinal and NSBM in the years to come.

Online Adaptive Magnetic Resonance-guided Radiation Therapy for Gynaecological Cancers: Preliminary Results of Feasibility and Outcome

AimsTo present the preliminary results on the clinical utilisation of an online daily adaptive magnetic resonance-guided radiation therapy (MRgRT) for various gynaecological cancers. Materials and methodsTwelve patients treated between September 2018 and June 2022 were included. Six patients (50%) were treated with pelvic radiation therapy followed by MRgRT boost as brachytherapy boost was ineligible or unavailable, three patients (25%) were treated with pelvic MRgRT followed by high dose rate brachytherapy, two patients (16.7%) were treated with only MRgRT, one patient (8.3%) was treated with linear accelerator-based radiation therapy followed by MRgRT boost for bulky iliac lymph nodes. ResultsThe median age was 56.5 years (range 31–86 years). Eight patients (66.7%) had a complete response, three patients (25%) had a partial response and one patient (8.3%) died due to acute renal failure. The mean follow-up time was 11.2 months (range 3.1–42.6 months). The estimated 1-year overall survival was 88.9%. The median treatment time was 47 days (range 10–87 days). During external beam radiation therapy, 10 (83.3%) patients had concomitant chemoradiotherapy. Pelvic external beam radiation therapy doses for all cohorts were 45–50.4 Gy with a fraction dose of 1.8 Gy. The median magnetic resonance-guided boost dose was 32 Gy (range 20–50 Gy) and fraction doses ranged between 4 and 10 Gy. Three patients were treated with intracavitary high dose rate brachytherapy (26–28 Gy in four to five fractions). None of the patients had grade >3 late genitourinary toxicities. ConclusionMRgRT is reliable and clinically feasible for treating patients with gynaecological cancers alone or in combination with brachytherapy with an acceptable toxicity and outcome. MRgRT boost could be an option when brachytherapy is not available or ineligible.

Spatially Fractionated Radiation Therapy in Sarcomas: A Large Single-Institution Experience

ObjectiveSpatially fractionated radiation therapy (SFRT) is a recognized technique for enhancing tumor response in radioresistant and bulky tumors. We analyzed clinical and treatment outcomes in patients with bone and soft tissue sarcomas treated with modern SFRT techniques. MethodsPatients with metastatic and/or unresectable sarcoma treated with brass collimator, volumetric modulated arc therapy (VMAT) lattice, or proton SFRT from December 2019-June 2022 were retrospectively reviewed. Consolidative external beam radiation therapy (EBRT) was delivered at the physician's discretion. Patient and treatment characteristics, treatment response (symptom improvement, local control, and imaging response), and toxicity data were collected. ResultsThe cohort consisted of 53 patients treated with 61 SFRT treatments. Median age at treatment was 60.0 years. The primary location was soft tissue in 46 courses (75%) and bone in 15 (25%). Fifty-three courses (87%) were treated for symptom relief. The most utilized SFRT technique was VMAT lattice (n=52, 85%) to a dose of 20 Gy (n=48, 79%, range: 16-20 Gy). EBRT was delivered post-SFRT in 55 (90%) treatment courses with a median time interval from SFRT to EBRT of 5 days (range: 0-14 days). Median physical EBRT dose and fractionation was 40 Gy (range: 9-73.5 Gy) and 10 fractions (range: 3-33 fractions). Median follow up was 7.4 months (range: 0.2-30 months). One-year overall survival and local control rates were 53% and 82%. Symptom relief was documented with 32 treatment courses (60%). Stable or partial response was observed with 47 treatment courses (90%). Four grade 3-4 acute and subacute toxicities were attributable to SFRT (8%). ConclusionsThe current series is the largest to date documenting outcomes for SFRT in sarcomas. Our results suggest combined SFRT with EBRT is associated with a favorable toxicity profile and high rates of symptomatic and radiographic responses for metastatic and/or unresectable sarcomas.

Early Clinical Outcomes in Patients of Carcinoma Cervix Treated With Volumetric Modulated Arc Therapy.

Objective Carcinoma cervix is one of the major cancers affecting Indian women. Concurrent chemo-radiotherapy is the standard of care in the treatment of carcinoma cervix. We aimed to study the outcomes and toxicity profile of volumetric modulated arc therapy (VMAT), an advanced modality of radiation delivery when used to treat patients with carcinoma cervix. Materials and methods Patients of carcinoma cervix belonging to FIGO (The International Federation of Gynecology and Obstetrics) stages IB2- IVA were recruited into the study. The patients were treated with VMAT to an EBRT (External Beam Radiation Therapy) dose of 50.4Gy in 28 fractions, which was followed by a brachytherapy schedule of 8Gy for each fraction to point A for three fractions. Toxicities were monitored weekly during the course of treatment and thereafter at every follow-up visit. A response assessment CECT (Contrast Enhanced Computed Tomography) scan was done three months after treatment and the response was recorded using RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Results Sixty-four patients were available for analysis and most of the patients belonged to stage IIB (50.3%) followed by stage IIIB (28.5%). The complete response rate was 90.6% at three months and at a median follow-up of 12 months, the overall survival was 100% and disease-free survival was 89.1%. An analysis of clinically significant toxicities (grade 2 or worse) showed that diarrhea was the most common (20.3%) followed by proctitis (14%) and anemia (9.3%). Conclusion The results of the study established that volumetric modulated arc therapy is an acceptable modality of treatment of carcinoma cervix with an attractive toxicity profile. However, longer follow-ups will provide valuable information regarding the long-term disease control and late toxicities of the treatment.

MR-Guided HDR Brachytherapy Boost in Localized Prostate Cancer - Results of a Phase II Trial.

Dose escalation in localized prostate cancer using brachytherapy combined with external beam radiation (EBRT) has demonstrated improved biochemical control compared to EBRT alone. However, ultrasound guided LDR brachytherapy might be associated with increased GU toxicity. We report the results of a prospective study of MR-guided HDR brachytherapy (MRgHDR) in combination with EBRT for localized prostate cancer. Intermediate- (IR) and high-risk (HR) prostate cancer patients were eligible. Patients received either 15Gy single fraction or 10Gy x 2 fractions using MRgHDR technique, followed by EBRT (37.5 Gy, [prostate only] -IR or 45-46 Gy - [prostate + pelvic nodes] -HR). Toxicity (CTCAE v4) and HRQoL (EPIC) were recorded at 1, 3 and 6 months, then at 1, 2, 3, and 5 years. Androgen deprivation therapy (ADT) was used according to the appropriate disease risk category. Biochemical failure was defined according to Phoenix definition (nadir+2). From 2010-2018, 120 patients were enrolled, 53 (44%) had IR and 67 (56%) had HR disease. Median age was 69 years (range, 46-78), median PSA was 12.1 ng/ml (3.2-148). ADT was used in 84 (70%) of patients, of whom 51 (60%) patients received <1 year and 33 (40%) received >1 year of ADT. A single fraction of 15Gy was given to 94 patients (78%) and the remaining 26 patients (22%) received 10Gy x 2 fractions. EBRT dose was 37.5Gy in 52 (43%) patients while 67 (56%) received 45-46Gy. One patient received only the first fraction of 10Gy, declined the second fraction and subsequently received 60Gy EBRT to the prostate. The median follow up was 58 months (11-134). Overall, 5-year biochemical control was 90% while it was 95% and 86% for IR and HR, respectively. At 5 years 7% patient had nodal or distant relapse or both. While the 5-yr distant control rates were 95% and 91% in the IR, HR, respectively. Acute grade ≥2 GU and GI toxicity was 6.7% and 5% respectively. Acute toxicity trended back to baseline by 6 months in all patients except one. Late grade ≥ 2 GU and GI worst toxicity was seen in 10% and 4.2%, respectively. As with acute toxicity, late toxicity tended to improve over time. Only one patient experienced severe toxicity (Grade 3 GU - frequency) at 6 months but subsequently this resolved. HRQol will be reported separately. MRgHDR brachytherapy boost in conjunction with EBRT provides comparable biochemical outcomes compared to the literature. Severe toxicity rates were minimal. Further follow-up will determine if these outcomes are sustained.

External Beam Radiotherapy Interdigitated with High Dose Rate(HDR) Intracavitary Brachytherapy versus External Beam Radiotherapy followed by Sequential HDR Intracavitary Brachytherapy for Locally Advanced Carcinoma Cervix-Randomized Control Study.

In cervical cancer treatment, overall treatment time (OTT) is an important prognostic factor. This study compares the clinical outcomes when High-Dose-Rate Intracavitary-Brachytherapy(HDR-ICRT) is interdigitated with external beam radiotherapy(EBRT) versus sequential HDR-ICRT after EBRT in the treatment of locally advanced carcinoma cervix. Histologically confirmed carcinoma cervix patients [FIGO Stage IIB-IVA (except IIIC-2)] were included and randomized into two groups. The study group received EBRT 50Gy in 25 fractions with interdigitated HDR-ICRT 7Gy per fraction weekly for three fractions starting after completion of 3 weeks of EBRT or as soon as cervical os became negotiable thereafter. Patients in the control group received EBRT 50Gy in 25 fractions with sequential HDR-ICRT 7Gy per fraction weekly for three fractions starting one week after completion of EBRT. All patients were regularly followed up during and after radiotherapy for local toxicity and disease control. This study enrolled 102 patients; 51 in each arm. Median OTT in study and control arm were 46 and 60 days, respectively. Median follow-up duration was 24 months (two years). Loco-regional control after two years of follow-up was 84.31 % and 72.54% of patients in study arm control arm respectively (p-value 0.148). Two (3.92%) patients from study arm and eight (15.68%) from control arm had residual disease. Two patients in study arm and one from control arm had local recurrence. Two patients from study arm three patients from control arm developed distant metastases. RTOG mucosal grade III acute mucosal toxicity in either arm. Cervical-os negotiability was limiting factor for interdigitated HDR-ICRT. Interdigitated HDR-ICRT with EBRT may give local control with manageable toxicities as compared to sequential HDR-ICRT, with the advantage of significant reduction in OTT.<br />.

Initial Clinical Outcomes of a Phase II Trial of Focal Salvage LDR Brachytherapy for Local Recurrence of Prostate Cancer after External Beam Radiation Therapy.

To evaluate the clinical outcomes of focal salvage low dose rate brachytherapy (FSB) for biopsy proven local recurrence of prostate cancer after definitive external beam radiation therapy (EBRT). Patients with a Phoenix definition PSA recurrence (nadir + 2.0ng/dL) after definitive EBRT for localized prostate cancer and a negative metastatic work up were enrolled in a Phase II clinical trial. Patients first underwent MR-guided transperineal mapping biopsy of the prostate using a template grid. Patients with a pathologically confirmed recurrence underwent FSB using iodine-125 seeds to a prescription dose of 145 Gy. The brachytherapy planning target volume (PTV) was defined by the positions of the pathologically negative core biopsies adjacent to the positive core biopsies as recorded on the template grid during the biopsy procedure. An intraoperative treatment plan was then developed to cover the PTV with the 145 Gy isodose line. Follow up included assessment of genitourinary (GU) and gastrointestinal (GI) toxicities using Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03), patient reported outcomes using the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index-26 (EPIC-26) forms, and serial PSA blood draws. Ten patients underwent FSB. The median prior EBRT dose was 7805 cGy (interquartile range IQR 7560-7920) and the median time from completion of EBRT to FSB was 81 months (IQR 68-134). The median PSA prior to FSB was 3.2 ng/dL (IQR 2.3 - 4.5). The median follow up after FSB was 32 months (IQR 18-57). Eight patients were free of Phoenix definition PSA failure at last follow up. Of the two patients who experienced a PSA failure, one developed distant metastases 5 months after FSB and the other a biopsy proven seminal vesicle recurrence 3 years after FSB. The median change in post FSB IPSS score compared to the pre-FSB IPSS score was an increase of 1.5 (IQR -1.5 to 8) at 3 month follow up and an increase of 3.5 (IQR 0.5 to 5.5) at last follow up (≥1 year). The median change in post FSB EPIC-26 urinary domain score compared to the pre-FSB score was -1 (IQR -26 to +14.5) at 3 month follow up and +2 (IQR -12.5 to +14.5) at last follow up (≥1 year). The median change in post FSB EPIC-26 bowel domain score compared to the pre-FSB score was -2 (IQR -9.5 to 0.0) at 3 month follow up and 0 (IQR -6.0 to +3.0) at last follow up (≥1 year). No patients experienced post FSB Grade 3 or higher GU or GI toxicities. High dose FSB for a local recurrence of prostate cancer after EBRT can be delivered with good biochemical control and a favorable toxicity profile. Further clinical trial enrollment and longer follow up will be needed to better assess long term outcomes.

Health-Related Quality of Life after Combined External Beam and Either High Dose Rate (HDR) or Low Dose Rate (LDR) Brachytherapy: Does the Rectal Dose from the LDR Brachytherapy Make a Difference?

The recently reported randomized Phase III trial comparing health related quality of life (HRQOL) after combined external beam radiation therapy (EBRT) and either HDR or LDR brachytherapy (BT) found a significant decline in the EPIC Bowel domain HRQOL score at 24- 48 months after treatment in the LDR arm of the trial. As all patients in the trial received the same EBRT dose, and HDR rectal dose was strictly controlled to be <9.5 Gy to 1cc of rectal wall (RD1cc), we investigated whether the variable rectal dose from the LDR component of treatment was related to the decline in Bowel HRQOL for these patients. A total of 195 men with upper tier intermediate or high-risk prostate cancer were assigned by a random number generator to receive either an HDR (15 Gy, n = 108) or LDR (110Gy, n = 87) brachytherapy boost combined with 46Gy/23 fractions EBRT. All LDR patients had 1 month post implant quality assurance using CT-MRI fusion. The Expanded Prostate Cancer Composite (EPIC) questionnaire was used to evaluate HRQOL at baseline, q3 mo for 1 year, q6mo for 3 yr and then annually. A multivariate linear regression model was used to investigate the dose-response relationship between EPIC bowel domain score at 24- 48 months and RD1cc. With a median follow up of 48 months, the previous analysis confirmed the expected time course of acute bowel/urinary symptoms, with LDR showing more prolonged decline in HRQOL bowel domain at 3 and 6 months, but equivalence to HDR by 12 months. HRQOL urinary domain remained equivalent from 12-60 mo. The decline in the HRQOL bowel domain observed for LDR patients from 24-48 mo was analyzed for the 79 patients with sufficient data. The mean baseline HRQOL bowel domain score was 92 and fell on average to 85 at 24-48 mo. Mean RD1cc for the LDR patients was 82Gy (SD 22 Gy), with a maximum value of 129 Gy. In this range of rectal doses, a 20Gy increase in RD1cc, was associated on average with a 1.5-point decrease in EPIC HRQOL bowel domain score (p = 0.21). The rectal dose received by the LDR patients showed a non-significant dose-response with the EPIC Bowel domain HRQOL score. This confirms the accepted rectal dose constraints for LDR brachytherapy but does not explain the observed decline in bowel scores from 24-48 months.

Single Institute Experience with MRI-Guided Adaptive Brachytherapy for Locally Advanced Cervix Cancer: Long Term Outcomes and Toxicity Analysis

We report over 10 years' experience of MRI-guided adaptive brachytherapy (MRIGABT) in locally advanced cervix cancer (LACC). A total of 162 patients with LACC FIGO stage IB-IVB were treated at our institute between 2010 and 2020. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m², 5 cycles, 1 day per cycle, 45-50.4 Gy external beam radiotherapy (EBRT) in 1·8-2 Gy fractions, followed by MRIGABT. Target volume definition and dose reporting for MRIGABT was according to GEC-ESTRO recommendations. MRIGABT dose prescription was according to our institutional practice. Overall survival (OS) and disease-free survival (DFS) were the primary endpoints. Kaplan-Meier estimates were calculated for OS and DFS at 2, 5 and 10-years. Organ-specific late toxicity grade ≥3 (≥G3) (CTCAEv5.0) was reported, alongside rates of bowel fistula, stricture, and perforation. Using logistic regression, we explored the relationship between EQD2 D2cc bladder and ≥G3 genitourinary (GU) toxicity. We compared patient proportions developing ≥ G3 GU toxicity in those who received EQD2 ≥85 Gy versus <85 Gy. We examined the following predictors of ≥G3 gastrointestinal (GI) toxicity: EQD2 dose (≥65 Gy versus <65 Gy), pre-existing bowel conditions, nodal boost, and extended field EBRT. Median follow up was 4.7 years (IQR 3.3-7.1 years). Median EBRT dose was 50.4 Gy (IQR 50.4-50.4 Gy); 91% received chemotherapy. Median high-risk clinical target volume (HRCTV) was 23.6 cm3 (IQR 16.6-31.3 cm3). Median doses were as follows; D90 HRCTV 88.9 Gy EQD210 (IQR 84.1-91.3 Gy), median D2cc bladder 81.6 (IQR 76.9-85.7 Gy), rectum 62.2 (IQR 57.9-65.3 Gy), sigmoid 67.4 (IQR 60.8-71.1 Gy), and bowel 55 (IQR 49.9-63.2 Gy), (all EQD23). The 2, 5 and-10-year OS were 98%, 80% and 75%. The 2, 5 and 10-year DFS were 98%, 75% and 60%. Late toxicity ≥G3 was 9% GU, 6% GI and 3% vaginal. There was a significant relationship between EQD2 and ≥G3 GU toxicity (OR: 1.11, 95% CI: 1.01-1.25; P = 0.04). When comparing those who received EQD2≥ 85Gy versus <85Gy, higher doses were associated with a greater proportion of ≥G3 GU toxicity (13% vs 6%). No significant predictors of ≥ G3 GI toxicity were observed. We observed excellent LC and OS. A significant relationship was found between EQD2 >85 Gy and bladder toxicity, although ≥G3 toxicity was low. We did not identify predictors of bowel toxicity. New predictors of bowel toxicity are required. Mean EBRT dose, D1.0 cc rectum, sigmoid and bowel are being investigated further.

Single Institution Experience of the Effect of Adjuvant Radiation on Outcomes for Patients with Uterine Carcinosarcoma

Uterine carcinosarcoma (UCS) is a rare but aggressive malignancy with poor outcomes. Due to its low incidence, there is no well-established optimal treatment. Standard treatment involves surgery and chemotherapy (CT) +/- adjuvant radiation therapy (RT). Our primary aim was to determine if patients who underwent adjuvant RT had improved distant metastasis free survival (DMFS) and locoregional recurrence free survival (LRRFS). Our secondary aim was to determine the effect of adjuvant RT on overall survival (OS). We performed a single institutional retrospective review of all patients with UCS who underwent primary surgical resection +/- CT and +/- RT between 2007 to 2021. Patients without at least 3 months of documented follow-up were excluded. We assessed DMFS, LRRFS, and OS between patients who did and did not receive adjuvant RT, consisting of vaginal brachytherapy (VBT), external beam radiation therapy (EBRT), or EBRT + VBT. Statistical analysis was performed with spreadsheet and statistical software. Sixty-four patients underwent primary surgical resection for FIGO stage I-IV UCS. Sixty six percent (n = 42) had early stage, FIGO I-II disease and 34% (n = 22) had late stage, FIGO III-IV disease. Eleven percent (n = 7) underwent surgery alone, 28% (n = 18) underwent surgery + CT, 6% (n = 4) underwent surgery + adjuvant RT, and 55% (n = 35) underwent surgery + CT + RT. Most patients who underwent surgery + CT + EBRT + VBT (n = 9) had worse clinicopathologic features including late stage (56%), lymphovascular invasion positive (78%) disease with 50% or greater myometrial invasion (56%). EBRT doses ranged from 45-50.4 Gray (Gy) in 1.8 Gy per fraction. VBT doses ranged from 21-25 Gy in 3-5 fractions when delivered alone and 10-15 Gy in 2-3 fractions when delivered as a boost. Median DMFS was 20.3 months, median LRRFS was 22.6 months, median DFS was 19.4 months, and median OS was 24.7 months. Rate of distant metastasis appeared to drive rate of disease-free survival (Table 1). Patients who underwent adjuvant RT had improved median DMFS (71.5 vs. 11.3 months, p = .002), median LRRFS (71.5 vs 22.5 months, p = .002), and median OS (60.7 vs. 22.5 months, p = .002) compared to those who did not receive RT. Prognosis of patients with UCS remains poor; however, adjuvant RT delivered after CT may offer potential benefit in survival outcomes despite worse clinicopathologic features in these patients.

Direction Modulated Brachytherapy Tandem Model Applicators for Treatment Planning of Multi-Institutional Cervical Cancer Cases

Direction Modulated Brachytherapy (DMBT) offers a means of utilizing an anisotropic source to create more conformal dose distributions when integrated with image-guided adaptive brachytherapy (IGABT). Authors sought to validate the implementation of nine unique six-channeled, MRI-compatible, novel DMBT tandem applicators of varying physical dimensions within Varian's BrachyVision® (v16.1) treatment planning system (BV-TPS). A total of 110 retrospective clinically delivered high-dose-rate (HDR) cervical cancer brachytherapy plans, from three institutions, were re-planned for each of the nine DMBT tandem models within the BV-TPS, using the latest VEGO® inverse optimization algorithm, with dose heterogeneity accounted for through AcurosBV®. Plans consisted of both intracavitary (77 plans) and interstitial (33 plans) cases with an average prescription dose and high-risk clinical target volumes (CTVHR) of 607±113 cGy and 26.96±14.95 [range 6.70-69.58] cm3, respectively. During re-planning, the conventional tandems were replaced by one of the nine DMBT tandem models while leaving ovoids or rings, and needles (if present), in place. A two-step inverse optimization process was performed such that the lowest possible organs at risk (OAR) D2cc doses could be achieved while 1) keeping equivalent target coverage (ΔCTVHR-D90 to within ±0.5%) and, at the same time, 2) maintaining the general pear-shape dose distribution of the original plans. Noteworthy improvements in plan quality were achieved by all nine DMBT tandem models, which are presented in Table 1. Irrespective of the model, about ∼50 cGy reduction in D2cc across all OARs appear feasible. There is also a general trend of D2cc reductions' magnitude becoming smaller as the CTVHR volume increased due to loss in modulation at distance. Additionally, D2cc reductions in terms of EQD2 [Gy] were calculated assuming each re-plan was delivered throughout the course of treatment, which includes the external beam radiotherapy dose of 45 Gy and showed significant reductions of -6.29±4.38 Gy, -3.80±2.06 Gy, and -4.86±3.02 Gy for the bladder, rectum, and sigmoid, respectively, for DMBT model #9 for example. We have successfully incorporated nine DMBT tandem models into a commercial TPS and re-planned 110 cases, to a total of 990 plans. All nine DMBT tandem models were each able to generate notable D2cc reductions to OARs (∼50 cGy), without compromising target coverage, across plans from multiple institutions with various clinical/optimization practices. The results indicate both a promising impact and smooth integration of DMBT tandem technology into modern clinical IGABT workflow.

Direction Modulated Brachytherapy Tandem Model Applicators for Treatment Planning of Multi-Institutional Cervical Cancer Cases: Removing Needles in Intracavitary-Interstitial Techniques

To evaluate the potential of nine direction modulated brachytherapy (DMBT) tandem applicator models of various designs to obviate the need for needles during intracavitary-interstitial (IC-IS) cervical cancer brachytherapy. A cohort of 33 retrospective clinical high dose-rate (HDR) brachytherapy plans, from three institutions, were re-planned with Varian's BrachyVision® (v16.1) treatment planning system (BV-TPS), using the latest VEGO® inverse optimization algorithm, with dose heterogeneity accounted for through the AcurosBV® model-based dose calculation algorithm. All plans consisted of IC-IS cases, with a range of 2-4 freehand-loaded needles, with an average prescription dose of 706±54 cGy and average high-risk clinical target volume (HRCTV) of 36.0±17.4 [range 9.8-69.6] cm3. Nine novel DMBT tandem models of varying physical dimensions were integrated for the first time into the BV-TPS, with thicknesses (4-8 mm). During re-planning, the conventional tandems and all of the needles were replaced by one of the nine DMBT tandem models while leaving the ovoids/rings in place. An optimization process was performed such that the lowest possible organs at risk (OAR) D2cc doses could be achieved while keeping equivalent target coverage (ΔHRCTV-D90 to within ±0.5%) and maintaining a pear-shape dose distribution. The process was repeated for each of the nine DMBT tandem models resulting in (33 × 9 =) 297 plans. Average ΔHRCTV-D90 was +0.35±0.39% (+2.8±3.1 cGy). OAR D2cc reductions were achieved by all models for all plans. The performance of the thickest DMBT model (8 mm) was the best in terms of achieving the lowest D2cc for all OARs, with 31 out of 33 plans (94%) achieving lower D2cc doses for all three OARs. The two cases in which the D2cc doses could not be reduced had HRCTV volumes ranging between 50 cm3 and 60 cm3. Additionally, D2cc reductions in terms of EQD2 [Gy] were calculated assuming each re-plan was delivered throughout the entire course of a patient's treatment, which included the external beam radiotherapy dose of 45 Gy, showed significant reductions of -2.64±2.67 Gy, -1.65±1.97 Gy, and -2.80±2.20 Gy for bladder, rectum, and sigmoid, respectively. According to the results, it is clinically feasible to replace the conventional IC-IS cases, with 2-4 freehand-loaded needles, with the DMBT tandem technology, effectively avoiding the need for needle involvement.