A randomized patient education trial investigating treatment-related distress and satisfaction with the use of an at-home gynecologic brachytherapy educational video.

BACKGROUND: Physician explanation of gynecologic brachytherapy can be overwhelming or induce patient anxiety, and may be time-constrained given clinical limitations. We report the first randomized trial of an educational video intervention in gynecologic brachytherapy on patient-reported outcomes. METHODS: Between February 2020 and January 2022, 80 gynecologic cancer patients prescribed brachytherapy were randomly assigned to either standard informed consent (Arm A) or a supplemental 16 min brachytherapy educational video (https://vimeo.com/403385455/d0716e3cc8) via the internet (Arm B). Primary outcome was treatment-related distress (National Comprehensive Cancer Network (NCCN) distress scale scored 0 (no distress) to 10 (maximum distress)). Secondary outcome was patient satisfaction (summated Likert-scale scored 11-55). Surveys were administered at baseline, after first treatment, and prior to brachytherapy completion. RESULTS: All patients completed the prescribed brachytherapy. In Arm B, 19/40 (48%) patients and 10/40 (25%) patients' family/friends viewed the video. For patients that completed all surveys (Arm A n=29, Arm B n=28), there was no difference between arms in the sociodemographic, clinical, or treatment variables. Distress scores were low at baseline (Arm A median 4, Arm B median 4, p=0.65) and there was no detectable change in distress between arms on surveys 1 and 2 (ß 0.36, p=0.67) or surveys 1 and 3 (ß -1.02, p=0.29) in multivariable analysis. Satisfaction scores were high at baseline (Arm A median 54, Arm B median 54.5, p=0.64) and there was no detectable change in satisfaction between arms on surveys 1 and 2 (ß 0.22, p=0.93) or surveys 1 and 3 (ß 0.63, p=0.85) in multivariable analysis. CONCLUSIONS: Among patients randomized to an educational video tool for gynecologic brachytherapy, approximately 50% of the cohort and 25% of the cohort's family/friends used the video. Overall, patients had low distress scores and high satisfaction scores with no significant differences between the standard and video intervention arms. Further work is needed to understand factors contributing to gynecologic brachytherapy anxiety. TRIAL REGISTRATION NUMBER: NCT04363957.

Three-Fraction Accelerated Partial Breast Irradiation (APBI) Delivered With Interstitial Brachytherapy Is Safe: First Results From the Tri-fraction Radiation Therapy Used to Minimize Patient Hospital Trips (TRIUMPH-T) Trial.

PURPOSE: Shorter courses of breast radiotherapy are offered as an alternative to 4 weeks of whole-breast irradiation after lumpectomy, including brachytherapy. A prospective phase 2multi-institution clinical trial to study 3-fraction accelerated partial breast irradiation delivered by brachytherapy was conducted. METHODS AND MATERIALS: The trial treated selected breast cancers after breast-conserving surgery with brachytherapy applicators that delivered 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 2 cm beyond the surgical cavity. Eligible women were age ≥45 years with unicentric invasive or in situ tumors ≤3 cm excised with negative margins and with positive estrogen or progesterone receptors and no metastases to axillary nodes. Strict dosimetric parameters were required to be met and follow up information was collected from the participating sites. RESULTS: Two hundred patients were prospectively enrolled; however, a total of 185 patients who were enrolled were followed for a median of 3.63 years. Three-fraction brachytherapy was associated with low chronic toxicity. There was excellent or good cosmesis in 94% of patients. There were no grade 4 toxicities. Grade 3 fibrosis at the treatment site was present in 1.7% and 32% percent had grades 1 or 2 fibrosis at the treatment site. There was 1 rib fracture. Other late toxicities included 7.4% grade 1 hyperpigmentation, 2% grade 1 telangiectasias, 1.7% symptomatic seromas, 1.7% abscessed cavities, and 1.1% symptomatic fat necrosis. There were 2 (1.1%) ipsilateral local recurrences, 2 (1.1%) nodal recurrences and no distant recurrences. Other incidents included one contralateral breast cancer and 2 second malignancies (lung). CONCLUSIONS: Ultra-short breast brachytherapy is feasible and has excellent toxicity and could be an alternative to standard 5-day, 10 fraction accelerated partial breast irradiation in eligible patients. Patients from this prospective trial will continue to be followed to evaluate long-term outcomes.

AAPM medical physics practice guideline 13.a: HDR brachytherapy, part A.

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines (MPPGs) will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: (1) Must and must not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. (2) Should and should not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances. Approved by AAPM's Executive Committee April 28, 2022.

Outcomes from a 3-fraction high-dose-rate brachytherapy regimen for patients with cervical cancer.

PURPOSE: To estimate local control, survival, and toxicity associated with a 3-fraction (3F) image-guided brachytherapy (IGBT) regimen compared to longer fraction (LF) for cervical cancer. METHODS: 150 patients treated between 2015-2020 with 3F (24Gy in 3 fractions) or LF (28...30 Gy in 4-5 fractions) were reviewed. The primary outcome was 2-year local failure. We compared overall survival (OS), disease-free survival (DFS), hospitalizations, and toxicity. RESULTS: There were 32 patients in the 3F group and 118 in the LF group, with a median follow up of 22 months. The 3F had worse performance status (p = 0.01) but otherwise similar characteristics. The 2-year local failure rate was 3.6% (95% CI 0%, 10.6%) for 3F, and 7.5% (95% CI 2.4%, 12.6%) for LF. The univariable hazard ratio (HR) for local failure for 3F was 0.43 (0.05, 3.43; p = 0.43). Moreover, 2 of 32 (6.3%) 3F patients experienced Grade ...3 toxicity compared to 7 of 118 (5.9%) LF patients (p = 1.0), with no difference in hospitalization within 2 years (p = 0.66) and no treatment-related deaths. CONCLUSIONS: Local control was excellent, with long term survival and toxicity similar between the groups. These findings support consideration of 3F.

Partial breast irradiation: An updated consensus statement from the American brachytherapy society.

PURPOSE: In recent years, results with mature follow-up have been reported for several Phase III trials randomizing women to receive whole breast irradiation (WBI) versus varying modalities of partial breast irradiation (PBI). It is important to recognize that these methods vary in terms of volume of breast tissue treated, dose per fraction, and duration of therapy. As such, clinical and technical guidelines may vary among the various PBI techniques. METHODS: Members of the American Brachytherapy Society with expertise in PBI performed an extensive literature review focusing on the highest quality data available for the numerous PBI options offered in the modern era. Data were evaluated for strength of evidence and published outcomes were assessed. RESULTS: The majority of women enrolled on randomized trials of WBI versus PBI have been age >45 years with tumor size <3 cm, negative margins, and negative lymph nodes. The panel also concluded that PBI can be offered to selected women with estrogen receptor negative and/or Her2 amplified breast cancer, as well as ductal carcinoma in situ, and should generally be avoided in women with extensive lymphovascular space invasion. CONCLUSIONS: This updated guideline summarizes published clinical trials of PBI methods. The panel also highlights the role of PBI for women facing special circumstances, such as history of cosmetic breast augmentation or prior breast irradiation, and discusses promising novel modalities that are currently under study, such as ultrashort and preoperative PBI. Updated consensus guidelines are also provided to inform patient selection for PBI and to characterize the strength of evidence to support varying PBI modalities.

Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy.

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control.

Retrospective review of three-fractioned accelerated partial breast irradiation.

METHODS: This retrospective study evaluated patients who received three-fraction accelerated partial breast irradiation (APBI) via brachytherapy for breast cancer between January 2016 and April 2020. Inclusion criteria included age ≥18 years and early-stage unilateral breast cancer with negative lymph nodes. We evaluated acute toxicity (<6 weeks), late toxicity (≥6 weeks), and cosmetic outcomes. Frequencies of each variable were calculated. Cancer-specific outcomes were determined via the Kaplan-Meier method. RESULTS: Thirty consecutive patients received three-fraction APBI of 2,250 cGy over 2 d. All cancers were stage T2 or less. Median time to last follow-up was 22 months. Local recurrence-free survival was 95.8% at 22 months. Seventeen (56.7%) patients reported an acute toxicity event. All were grade 1 except one patient with grade 2 (fatigue). No patient experienced ≥ grade 3 acute toxicity. One (3.3%) patient reported grade 3 late toxicity (tissue fibrosis). No patients had breast edema, fat necrosis, or non-healing wounds. There were no ≥ grade 3 cosmetic events. DISCUSSION: Three-fraction APBI via brachytherapy was successful in preventing disease recurrence and death in this study, with still limited follow-up. Although acute and late toxicities or adverse cosmetic outcomes were seen, very few were grade 2 or higher and compare favorably to those reported in prior 10-fraction APBI studies. CONCLUSIONS: This study provides early single institutional evidence that three-fraction APBI may become a feasible treatment alternative.

Evaluation of dose differences between intracavitary applicators for cervical brachytherapy using knowledge-based models.

PURPOSE: Currently, there is a lack of patient-specific tools to guide brachytherapy planning and applicator choice for cervical cancer. The purpose of this study is to evaluate the accuracy of organ-at-risk (OAR) dose predictions using knowledge-based intracavitary models, and the use of these models and clinical data to determine the dosimetric differences of tandem-and-ring (T&R) and tandem-and-ovoids (T&O) applicators. MATERIALS AND METHODS: Knowledge-based models, which predict organ D2cc, were trained on 77/75 cases and validated on 32/38 for T&R/T&O applicators. Model performance was quantified using ΔD2cc=D2cc,actual-D2cc,predicted, with standard deviation (σ(ΔD2cc)) representing precision. Model-predicted applicator dose differences were determined by applying T&O models to T&R cases, and vice versa, and compared to clinically-achieved D2cc differences. Applicator differences were assessed using a Student's t-test (p < 0.05 significant). RESULTS: Validation T&O/T&R model precision was 0.65/0.55 Gy, 0.55/0.38 Gy, and 0.43/0.60 Gy for bladder, rectum and sigmoid, respectively, and similar to training. When applying T&O/T&R models to T&R/T&O cases, bladder, rectum and sigmoid D2cc values in EQD2 were on average 5.69/2.62 Gy, 7.31/6.15 Gy and 3.65/0.69 Gy lower for T&R, with similar HRCTV volume and coverage. Clinical data also showed lower T&R OAR doses, with mean EQD2 D2cc deviations of 0.61 Gy, 7.96 Gy (p < 0.01) and 5.86 Gy (p < 0.01) for bladder, rectum and sigmoid. CONCLUSIONS: Accurate knowledge-based dose prediction models were developed for two common intracavitary applicators. These models could be beneficial for standardizing and improving the quality of brachytherapy plans. Both models and clinical data suggest that significant OAR sparing can be achieved with T&R over T&O applicators, particularly for the rectum.

Knowledge-based dose prediction models to inform gynecologic brachytherapy needle supplementation for locally advanced cervical cancer.

PURPOSE: The use of interstitial needles, combined with intracavitary applicators, enables customized dose distributions and is beneficial for complex cases, but increases procedure time. Overall, applicator selection is not standardized and depends on physician expertise and preference. The purpose of this study is to determine whether dose prediction models can guide needle supplementation decision-making for cervical cancer. MATERIALS AND METHODS: Intracavitary knowledge-based models for organ-at-risk (OAR) dose estimation were trained and validated for tandem-and-ring/ovoids (T&R/T&O) implants. Models were applied to hybrid cases with 1-3 implanted needles to predict OAR dose without needles. As a reference, 70/67 hybrid T&R/T&O cases were replanned without needles, following a standardized procedure guided by dose predictions. If a replanned dose exceeded the dose objective, the case was categorized as requiring needles. Receiver operating characteristic (ROC) curves of needle classification accuracy were generated. Optimal classification thresholds were determined from the Youden Index. RESULTS: Needle supplementation reduced dose to OARs. However, 67%/39% of replans for T&R/T&O met all dose constraints without needles. The ROC for T&R/T&O models had an area-under-curve of 0.89/0.86, proving high classification accuracy. The optimal threshold of 99%/101% of the dose limit for T&R/T&O resulted in classification sensitivity and specificity of 78%/86% and 85%/78%. CONCLUSIONS: Needle supplementation reduced OAR dose for most cases but was not always required to meet standard dose objectives, particularly for T&R cases. Our knowledge-based dose prediction model accurately identified cases that could have met constraints without needle supplementation, suggesting that such models may be beneficial for applicator selection.

Hyper-dense foreign bodies found in the bowel during IGRT following brachytherapy.

A 28-year-old female with locally advanced adenocarcinoma of the cervix was undergoing treatment with external beam radiation therapy (EBRT), concurrent chemotherapy and high dose rate brachytherapy (BT). On-board imaging obtained prior to one of her external beam treatments revealed four radiopaque foreign bodies in her abdomen. The patient's treatment was delayed for further work-up of this new finding. Upon further investigation, it was discovered that the patient had recently started taking bismuth subsalicylate tablets (brand name: Pepto-Bismol, Procter & Gamble Co., Cincinnati, OH). A computed tomography (CT) scan of the tablets confirmed the size and Hounsfield Unit (HU) values coincided with the foreign object properties seen on the patient's scan. This unexpected finding is important to recognize as it consequently lead to a delay in treatment, additional imaging, and patient anxiety.

Development, implementation, and associated challenges of a new HDR brachytherapy program.

Developing any new radiation oncology program requires planning and analysis of the current state of the facility and its capacity to take on another program. Staff must consider a large number of factors to establish a feasible, safe, and sustainable program. We present a simple and generic outline that lays out the process for developing and implementing a new HDR brachytherapy program in any setting, but with particular emphasis on challenges associated with starting the program in a limited resource setting. The sections include feasibility of a program, starting cases, machine and equipment selection, and quality and safety.

A knowledge-based organ dose prediction tool for brachytherapy treatment planning of patients with cervical cancer.

PURPOSE: The purpose of this study is to explore knowledge-based organ-at-risk dose estimation for intracavitary brachytherapy planning for cervical cancer. Using established external-beam knowledge-based dose-volume histogram (DVH) estimation methods, we sought to predict bladder, rectum, and sigmoid D2cc for tandem and ovoid treatments. METHODS AND MATERIALS: A total of 136 patients with loco-regionally advanced cervical cancer treated with 456 (356:100 training:validation ratio) CT-based tandem and ovoid brachytherapy fractions were analyzed. Single fraction prescription doses were 5.5-8 Gy with dose criteria for the high-risk clinical target volume, bladder, rectum, and sigmoid. DVH estimations were obtained by subdividing training set organs-at-risk into high-risk clinical target volume boundary distance subvolumes and computing cohort-averaged differential DVHs. Full DVH estimation was then performed on the training and validation sets. Model performance was quantified by ΔD2cc = D2cc(actual)-D2cc(predicted) (mean and standard deviation). ΔD2cc between training and validation sets were compared with a Student's t test (p < 0.01 significant). Categorical variables (physician, fraction-number, total fractions, and case complexity) that might explain model variance were examined using an analysis of variance test (Bonferroni-corrected p < 0.01 threshold). RESULTS: Training set deviations were bladder ΔD2cc = -0.04 ± 0.61 Gy, rectum ΔD2cc = 0.02 ± 0.57 Gy, and sigmoid ΔD2cc = -0.05 ± 0.52 Gy. Model predictions on validation set did not statistically differ: bladder ΔD2cc = -0.02 ± 0.46 Gy (p = 0.80), rectum ΔD2cc = -0.007 ± 0.47 Gy (p = 0.53), and sigmoid ΔD2cc = -0.07 ± 0.47 Gy (p = 0.70). The only significant categorical variable was the attending physician for bladder and rectum ΔD2cc. CONCLUSION: A simple boundary distance-driven knowledge-based DVH estimation exhibited promising results in predicting critical brachytherapy dose metrics. Future work will examine the utility of these predictions for quality control and automated brachytherapy planning.

Implementation of peer-review quality rounds for gynecologic brachytherapy in a high-volume academic center.

PURPOSE: While peer review is critical for quality and safety in radiotherapy, there are neither formal guidelines nor format examples for brachytherapy (BT) peer review. We report on a gynecologic BT peer-review method implemented at a high-volume academic center. METHODS AND MATERIALS: We analyzed discussions at bimonthly gynecologic BT peer-review rounds between July and December 2018. Rounds consisted of 2-5 attending physicians with gynecologic BT expertise, 1-2 BT physicists, and trainees. Peer-review targets included clinical case review, contours, implant technique, dose/fractionation, and target/organ-at-risk (OAR) dosimetry. The projected/final target and OAR dosimetry were analyzed. RESULTS: 55 separate implants from 44 patients were reviewed. Implants were mostly reviewed after the first BT fraction (n = 16, 29%) or at another time point during BT (n = 20, 36%). One (2%) implant was presented prospectively. The applicator type and BT technique were reviewed for all implants. Dose/fractionation was evaluated for 46 implants (84%); contours were discussed for 21 (38%). Target and OAR dosimetry were reviewed for 54 (98%) and 28 implants (51%), respectively. Six cases (11%) underwent minor changes to the applicator type to improve target and/or OAR dosimetry. One case (2%) had a major change recommended to the dose/fractionation. CONCLUSIONS: Gynecologic BT peer review may enhance BT quality by allowing for implant optimization and formal review of challenging cases, ultimately improving medical decision-making and team communication. Peer review should be implemented in centers offering gynecologic BT.

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability.

The most successful therapeutic strategies for locally advanced cancers continue to combine decades-old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor-specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor-selective radiosensitization, we synthesized and tested anti-HER2 antibody-drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However, when attached to trastuzumab or pertuzumab, MMAF was as efficacious as MMAE in blocking HER2-expressing tumor cells in G2-M. Moreover, MMAF anti-HER2 conjugates selectively killed and radiosensitized HER2-rich tumor cells. Importantly, when conjugated to targeting antibody, MMAF had the advantage of decreased bystander and off-target effects compared with MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulated in the normal tissue surrounding tumors compared with MMAE. Therapeutically, systemically injected MMAF anti-HER2 conjugates combined with focal ionizing radiation increased tumor control and improved survival of mice with HER2-rich tumor xenografts. In summary, our results demonstrate the potential of cell-impermeable radiosensitizing warheads to improve the therapeutic ratio of radiotherapy by leveraging antibody-drug conjugate technology.

Compendium of fractionation choices for gynecologic HDR brachytherapy-An American Brachytherapy Society Task Group Report.

PURPOSE: The purpose of this study was to report a list of accepted fractionation schemes for high-dose-rate (HDR) brachytherapy for gynecological cancers in a definitive, neoadjuvant, or adjuvant setting. METHODS AND MATERIALS: Members of the American Brachytherapy Society (ABS) Task Force with expertise in gynecological brachytherapy reviewed the literature and existing ABS guidelines regarding various dose-fractionation schedules for HDR brachytherapy to create this compendium. Other resources include current guidelines published by medical societies, clinical trials, the published medical literature, and the clinical experience of the ABS Task Force members. The ABS consensus statements for HDR brachytherapy practice were reviewed for these fractionation schemes and form the major source for this report. Specific recommendations for therapy and recommendations for further investigations were made when there was agreement. RESULTS: A variety of dose-fractionation schedules for HDR brachytherapy alone or integrating brachytherapy with external-beam radiation exist. The choice of a given fractionation schedule may be appropriate depending on the practice situation for the patient and the resources available. While there is no single optimal dose-fractionation scheme for any disease site or clinical situation, higher doses per fraction with fewer fractions per regimen have been known to increase toxicity. The corresponding 2-Gray (Gy) per fraction radiobiologic equivalent doses have been provided (normalized therapy dose) to compare the various regimens where indicated and can be used to estimate isoeffective schedules. CONCLUSIONS: This compendium of HDR brachytherapy fractionation schedules provides various options to the gynecologic brachytherapist and a ready reference for clinical use in the management of gynecological cancer treatments.

Direction Modulated Brachytherapy for Treatment of Cervical Cancer. II: Comparative Planning Study With Intracavitary and Intracavitary-Interstitial Techniques.

PURPOSE: To perform a comprehensive comparative planning study evaluating the utility of the proposed direction modulated brachytherapy (DMBT) tandem applicator against standard applicators, in the setting of image guided adaptive brachytherapy of cervical cancer. METHODS AND MATERIALS: A detailed conceptual article was published in 2014. The proposed DMBT tandem applicator has 6 peripheral grooves of 1.3-mm width, along a 5.4-mm-thick nonmagnetic tungsten alloy rod of density 18.0 g/cm(3), capable of generating directional dose profiles. We performed a comparative planning study with 45 cervical cancer patients enrolled consecutively in the prospective observational EMBRACE study. In all patients, MRI-based planning was performed while utilizing various tandem-ring (27 patients) and tandem-ring-needles (18 patients) applicators, in accordance with the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology recommendations. For unbiased comparisons, all cases were replanned with an in-house-developed inverse optimization code while enforcing a uniform set of constraints that are reflective of the clinical practice. All plans were normalized to the same high-risk clinical target volume D90 values achieved in the original clinical plans. RESULTS: In general, if the standard tandem was replaced with the DMBT tandem while maintaining all other planning conditions the same, there was consistent improvement in the plan quality. For example, among the 18 tandem-ring-needles cases, the average D2cm(3) reductions achieved were -2.48% ± 11.03%, -4.45% ± 5.24%, and -5.66% ± 6.43% for the bladder, rectum, and sigmoid, respectively. An opportunity may also exist in avoiding use of needles altogether for when the total number of needles required is small (approximately 2 to 3 needles or less), if DMBT tandem is used. CONCLUSIONS: Integrating the novel DMBT tandem onto both intracavitary and intracavitary-interstitial applicator assembly enabled consistent improvement in the sparing of the OARs, over a standard "single-channel" tandem, though individual variations in benefit were considerable. Although at an early stage of development, the DMBT concept design is demonstrated to be useful and pragmatic for potential clinical translation.

Strut-based accelerated partial breast irradiation: Report of treatment results for 250 consecutive patients at 5 years from a multicenter retrospective study.

PURPOSE: This registry trial studied the long-term outcomes of women receiving accelerated partial breast irradiation (APBI) using strut-based applicators and reports on the local control, toxicity, and survival for the first 250 patients treated with this device. METHODS AND MATERIALS: Patients were treated using the strut-based brachytherapy device with conventional dose and fractionation of 34 Gy in 10 twice-daily fractions. Planning goals for the planning target volume were V90 > 90%, V150 < 50 cc, and V200 < 20 cc. Toxicity was graded based on the Common Terminology Criteria for Adverse Events v3.0. Recurrence rates were also calculated. RESULTS: Median followup was 59.5 months for the 250 patients. Grade 2 or higher adverse events at any time for hyperpigmentation, induration, erythema, telangiectasia, breast pain, seroma, and fat necrosis were 0.4%, 3.0%, 3.0%, 3.0%, 3.9%, 4.8%, and 1.3%, respectively. The median V90 was 97%, V95 was 95.1%, V150 was 28.7 cc, and V200 was 14.2 cc. For those patients with a less than a 5-mm or 3-mm-skin bridge, the median skin max doses were 272 and 289 cGy, respectively. The 4-year actuarial recurrence rates for true recurrence/marginal miss and ipsilateral breast tumor recurrence were 2.3% and 3.6%, respectively. The 4-year actuarial rates for overall survival, cause-specific survival, and disease-free survival were 97%, 98%, and 92%, respectively. CONCLUSIONS: The strut-based applicator was designed to simplify APBI compared to interstitial brachytherapy. This report confirms excellent tumor control and survival with low toxicity and supports the evidence that brachytherapy has less normal tissue toxicity than APBI with external beam irradiation.

A consensus-based, process commissioning template for high-dose-rate gynecologic treatments.

PURPOSE: There is a lack of prescriptive, practical information for those doing the work of commissioning high-dose-rate (HDR) gynecologic (GYN) treatment equipment. The purpose of this work is to develop a vendor-neutral, consensus-based, commissioning template to improve standardization of the commissioning process. METHODS AND MATERIALS: A series of commissioning procedures and tests specific to HDR GYN treatments were compiled within one institution. The list of procedures and tests was then sent to five external reviewers at clinics engaged in HDR GYN treatments. External reviewers were asked to (1) suggest deletions, additions, and improvements/modifications to descriptions, (2) link the procedures and tests to common, severe failure modes based on their effectiveness at mitigating those failure modes, and (3) rank the procedures and tests based on perceived level of importance. RESULTS: External reviewers suggested the addition of 14 procedures and tests. The final template consists of 67 procedures and tests. "Treatment process" and "staff training" sections were identified as mitigating the highest number of commonly reported failure modes. The mean perceived importance for all procedures and tests was 4.4 of 5, and the mean for each section ranged from 3.6 to 4.8. Sections of the template that were identified as mitigating the highest number of commonly reported failure modes were not assigned the highest perceived importance. CONCLUSION: The commissioning template developed here provides a standardized approach to process and equipment commissioning. The discord between perceived importance and mitigation of the highest number of failure modes suggests that increased focus should be placed on procedures and tests in "treatment process" and "staff training" sections.

Clinical Outcomes of Computed Tomography-Based Volumetric Brachytherapy Planning for Cervical Cancer.

PURPOSE/OBJECTIVES: A report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer. METHODS AND MATERIALS: Seventy-six women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV. RESULTS: The median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm(3) of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval [CI]: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥ 2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥ 4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥ 3 events were observed. CONCLUSIONS: This is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment.

Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery.

Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor-targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell-penetrating peptide targeting matrix metalloproteinases and RGD-binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low-passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule- and dose-dependent manner, correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double-strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with nontargeted free MMAE or tumor-targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor-targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell-penetrating peptides.