PURPOSE:Brachytherapy (BT) is an increasingly used modality for delivering highly conformal, surface-weighted radiation to cancers involving the skin with excellent cosmetic outcomes. Its applications span nonmelanoma skin cancers and cutaneous manifestations of hematologic and other malignancies, and are useful in the definitive or palliative settings. Currently, there is no standardized framework for training radiation oncologists in delivering cutaneous BT. This review outlines current evidence and principles to guide patient selection, proper setup, planning, and treatment delivery in accordance with the recent ABS/GEC-ESTRO Consensus Statement on Objectives for BT training. METHODS AND MATERIALS:A narrative review was conducted, synthesizing consensus guidelines, key clinical series, historical planning systems, and contemporary recommendations from experts and professional societies. RESULTS:Both electronic and radionuclide-based high-dose-rate BT offer flexible, conformal treatment options for diverse anatomical sites with respective advantages and limitations. Optimal application depends on risk stratification, evaluating locoregional involvement and pathologic features. High-quality delivery requires precise imaging and target delineation, matching anatomic complexity with the appropriate applicator selection and placement, appropriate planning, and rigorous quality assurance. Fractionation schedules range from conventional to ultra-hypofractionated, with prescription depth and applicator type guiding dose. CONCLUSIONS:The clinical and technical evidence summarized within establishes a practical framework for the core competencies necessary to perform high-quality skin brachytherapy.

The goal of this report is to assist the clinical medical physicist in assuring that key quality standards and practice considerations are met to ensure safe, reliable, and reproducible high dose rate (HDR) brachytherapy (BT) treatment. This guideline has been developed to provide appropriate minimum standards for such services. The secondary goal is to provide recommendations to the regulatory community from the experts to guide the adoption of regulations in the future. This MPPG is limited to iridium-192-based HDR brachytherapy and will not discuss electronic, low-dose rate, pulsed dose rate brachytherapy, or any alternative radionuclide. SCOPE: This MPPG 13a report is divided into two parts. Part A has been previously published1 and describes the infrastructure and program design in the creation of an afterloader-based HDR brachytherapy program. This publication, Part B, describes the clinical treatment processes including site-specific imaging, planning, and treatment delivery. MPPG 13a Part B starts with the arrival of the patient to the clinic and concludes with emergency procedures and error mitigation. DISCLAIMER: It is the responsibility of all healthcare staff to be familiar with state and federal guidelines that may take precedence over AAPM recommendations that are provided in this report. Each health care facility may have site-specific or state-mandated needs and requirements that may modify their usage of these recommendations.

The most effective treatments for locally advanced cancers rely on non-targeted chemotherapies given with radiotherapy. Advances in cancer biology have identified vulnerabilities amenable to precision oncology approaches including antibody drug conjugates (ADCs). In theory, ADCs combine specificity of cancer cell receptor antibody targeting with potent cytotoxins. However, toxicities and resistance limit ADC clinical efficacy. Delivering ADCs with radiotherapy can improve their therapeutic index. Here, the combination of ADC payloads (anti-tubulin monomethyl auristatin E (MMAE) or topoisomerase I inhibitors DXd and SN-38) with radiotherapy is reported in immune-competent murine models. To directly compare ADC payload effects and remove targeting bias, the payloads are tested as free drugs and as tumor-targeted ADC or peptide-drug conjugates in combination with ionizing radiation. Both DXd and MMAE induce anti-tumor immune response that block re-challenge tumor growth. As monotherapy, DXd is more potent than MMAE at inhibiting tumor formation. In contrast when combined with ionizing radiation at subtherapeutic doses, MMAE but not DXd radiosensitizes resulting in improved tumor control and greater immune activation with MMAE. The differential effects of anti-tubulin versus topoisomerase I inhibitors when combined with ionizing radiation and immunotherapies can inform and optimize clinical development of ADC based chemo-radio-immunotherapy combinations for cancer patients.

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.

HCT-116 tumor xenografts have b3 integrin expression.

It is clinically feasible to obviate the need for IS needles by incorporating the DMBT tandem-and-ovoids while producing lower OAR D2cc doses and maintaining equivalent target coverage.

MMAF anti-HER2 antibody conjugates increase tumor G2/M fraction.

Purpose There are no standard guidelines for optimal needle insertion/placement during high dose-rate (HDR) intracavitary-interstitial (IC-IS) brachytherapy of the cervix. Therefore, sophisticated technical skillset must be acquired through repeated practice of inserting IS needles next to IC applicators to enhance dosimetry of improving target coverage while limiting dose to organs at risk (OARs). This study sought to evaluate potential of nine direction modulated brachytherapy (DMBT) tandem applicator models of unique designs to effectively removing the need for IS needles in a range of IC-IS cases found in multi-institutional clinics via achieving equivalent or better dosimetry. Materials and Methods A cohort of 33 retrospective clinical 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. The average high-risk clinical target volume (HRCTV) was 36.0±17.4 [range 9.8-69.6] cm3. Nine unique DMBT tandem models of varying physical dimensions were integrated for the first time into the BV-TPS, with thicknesses comparable to those tandems used clinically and ranged between 4-8 mm. During re-planning, the conventional tandems and all of the needles were replaced by one of the 9 DMBT tandem models while leaving the ovoids/rings in place. A two-step inverse optimization process was performed such that the lowest possible OAR D2cc doses could be achieved while 1) keeping equivalent target coverage (ΔHRCTV-D90 to within ±0.5%) and, at the same time, 2) maintaining the general pear-shape dose distribution of the original plans. For all plans, this process was repeated using each of the 9 DMBT tandem models for a total re-planning of (33×9=) 297 cases. Results Average ΔHRCTV-D90 was +2.8±3.1 cGy. Reductions in D2cc for the OARs for most of the plans were achieved by all 9 DMBT tandem models, which are shown in Figure 1A, with the magnitude increasing with the DMBT tandem thickness (from #1-9). The performance of the thickest DMBT model (#9, with 8 mm) was the best in terms of achieving the lowest D2cc for all OARs. For this particular model, 31 out of 33 plans (94%) had achieved lower D2cc doses for all three OARs. The two cases where the D2cc doses could not be lowered, compared to the original plans, had HRCTV volumes of about 50 cm3 and 60 cm3 (Figure 1b-c). Additionally, D2cc reductions in terms of EQD2 [Gy] were calculated assuming each re-plan was delivered throughout the course of treatment (Figure 1C), which includes the external beam radiotherapy dose of 45 Gy, and 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, for the DMBT model #9. These reductions were achieved with an average net increase in total dwell times of 173.8±58.5 seconds (i.e., 3-4 minutes) at the luxury of avoiding IS needles to insert. Conclusions We have successfully incorporated 9 DMBT tandem models into a commercial TPS and re-planned 33 cases, to a total of 297 plans. 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 IS needles. There are no standard guidelines for optimal needle insertion/placement during high dose-rate (HDR) intracavitary-interstitial (IC-IS) brachytherapy of the cervix. Therefore, sophisticated technical skillset must be acquired through repeated practice of inserting IS needles next to IC applicators to enhance dosimetry of improving target coverage while limiting dose to organs at risk (OARs). This study sought to evaluate potential of nine direction modulated brachytherapy (DMBT) tandem applicator models of unique designs to effectively removing the need for IS needles in a range of IC-IS cases found in multi-institutional clinics via achieving equivalent or better dosimetry. A cohort of 33 retrospective clinical 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. The average high-risk clinical target volume (HRCTV) was 36.0±17.4 [range 9.8-69.6] cm3. Nine unique DMBT tandem models of varying physical dimensions were integrated for the first time into the BV-TPS, with thicknesses comparable to those tandems used clinically and ranged between 4-8 mm. During re-planning, the conventional tandems and all of the needles were replaced by one of the 9 DMBT tandem models while leaving the ovoids/rings in place. A two-step inverse optimization process was performed such that the lowest possible OAR D2cc doses could be achieved while 1) keeping equivalent target coverage (ΔHRCTV-D90 to within ±0.5%) and, at the same time, 2) maintaining the general pear-shape dose distribution of the original plans. For all plans, this process was repeated using each of the 9 DMBT tandem models for a total re-planning of (33×9=) 297 cases. Average ΔHRCTV-D90 was +2.8±3.1 cGy. Reductions in D2cc for the OARs for most of the plans were achieved by all 9 DMBT tandem models, which are shown in Figure 1A, with the magnitude increasing with the DMBT tandem thickness (from #1-9). The performance of the thickest DMBT model (#9, with 8 mm) was the best in terms of achieving the lowest D2cc for all OARs. For this particular model, 31 out of 33 plans (94%) had achieved lower D2cc doses for all three OARs. The two cases where the D2cc doses could not be lowered, compared to the original plans, had HRCTV volumes of about 50 cm3 and 60 cm3 (Figure 1b-c). Additionally, D2cc reductions in terms of EQD2 [Gy] were calculated assuming each re-plan was delivered throughout the course of treatment (Figure 1C), which includes the external beam radiotherapy dose of 45 Gy, and 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, for the DMBT model #9. These reductions were achieved with an average net increase in total dwell times of 173.8±58.5 seconds (i.e., 3-4 minutes) at the luxury of avoiding IS needles to insert. We have successfully incorporated 9 DMBT tandem models into a commercial TPS and re-planned 33 cases, to a total of 297 plans. 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 IS needles.

Antibody conjugation to drug and Cy5.

Cell line HER2 expression and Anti-HER2 antibody drug conjugate binding.

Purpose To propose a generalization of the known relationship between total reference air Kerma (TRAK) and isodose surface volumes for intracavitary, hybrid and interstitial applicators used for treating cervical cancer with high dose rate (HDR) brachytherapy (BT). Materials and Methods A single institution cohort of 123 retrospective clinical HDR BT plans from 34 patients treated for cervical cancer were evaluated. The cohort consisted of 71 intracavitary (tandem and ring - T&R - and tandem and ovoid - T&O), 32 hybrid (T&R or T&O with the addition of stainless steel and/or flexi needles) and 20 interstitial plans. Patients received 45Gy external beam radiotherapy (EBRT), followed by one of three fractionation schemes delivered with BT: 600cGy x 4 fractions (4 patients for a total of 16 fractions), 700cGy x 4 fractions (21 patients for a total of 80 fractions) and 800cGy x 3 fractions (9 patients for a total of 27 fractions). The average dose per fraction was 708.9±58.5cGy considering all 123 plans. For each plan the isodose surface volumes (TPSvol) were evaluated considering the accumulated EBRT and BT dose. Because three different fractionation schemes were used, the radiobiological equivalent doses in 2Gy fractions (EQD2) were estimated considering the EBRT and BT contributions. We have considered α/β ratio = 10Gy for tumor repair and repair half time T1/2 = 1.5 hour. In this work we have considered three reference dose levels (dref): 60Gy, 75Gy and 85Gy. Figure 1A-C illustrates the isodose surface volumes for the different fractionation schemes. The TRAK of each plan was also recorded. The relationship between TRAK/dref and TPSvol for the different applicators was evaluated by applying a second degree polynomial linear regression considering the two variables for each case. Results The linear regressions showed correlation coefficients R2 of 0.998, 0.997, 0.995 and 0.997 for the data obtained from treatments using intracavitary (Fig. 1D), hybrid (Fig. 1E), interstitials (Fig. 1F) and all applicators together (Fig. 1G), respectively. The linear regressions were not found to be affected by the different fractionation schemes. The quadratic, linear coefficients and the curve intercepts ranged from 0.621 to 0.739, 11.29 to 12.64 and -16.9 to -12.32, respectively. The fitted equation for the hybrid implants (Fig. 1E) showed the largest differences for the quadratic coefficient and curve intercept when compared to the equation fitted for intracavitary and interstitial applicators. The equation resulting from all applicators (Fig. 1G) showed the smallest differences for quadratic and linear coefficients when compared to the equation resulting intracavitary applicators. Conclusions We have shown that TRAK might be useful to predict volumes of isodose surfaces independently of the applicator and fractionation scheme used for treating cervical cancer with BT. The potential to use the correlation between TRAK and volumes of isodose surfaces to predict patients’ outcomes and toxicities should be evaluated in a further study. To propose a generalization of the known relationship between total reference air Kerma (TRAK) and isodose surface volumes for intracavitary, hybrid and interstitial applicators used for treating cervical cancer with high dose rate (HDR) brachytherapy (BT). A single institution cohort of 123 retrospective clinical HDR BT plans from 34 patients treated for cervical cancer were evaluated. The cohort consisted of 71 intracavitary (tandem and ring - T&R - and tandem and ovoid - T&O), 32 hybrid (T&R or T&O with the addition of stainless steel and/or flexi needles) and 20 interstitial plans. Patients received 45Gy external beam radiotherapy (EBRT), followed by one of three fractionation schemes delivered with BT: 600cGy x 4 fractions (4 patients for a total of 16 fractions), 700cGy x 4 fractions (21 patients for a total of 80 fractions) and 800cGy x 3 fractions (9 patients for a total of 27 fractions). The average dose per fraction was 708.9±58.5cGy considering all 123 plans. For each plan the isodose surface volumes (TPSvol) were evaluated considering the accumulated EBRT and BT dose. Because three different fractionation schemes were used, the radiobiological equivalent doses in 2Gy fractions (EQD2) were estimated considering the EBRT and BT contributions. We have considered α/β ratio = 10Gy for tumor repair and repair half time T1/2 = 1.5 hour. In this work we have considered three reference dose levels (dref): 60Gy, 75Gy and 85Gy. Figure 1A-C illustrates the isodose surface volumes for the different fractionation schemes. The TRAK of each plan was also recorded. The relationship between TRAK/dref and TPSvol for the different applicators was evaluated by applying a second degree polynomial linear regression considering the two variables for each case. The linear regressions showed correlation coefficients R2 of 0.998, 0.997, 0.995 and 0.997 for the data obtained from treatments using intracavitary (Fig. 1D), hybrid (Fig. 1E), interstitials (Fig. 1F) and all applicators together (Fig. 1G), respectively. The linear regressions were not found to be affected by the different fractionation schemes. The quadratic, linear coefficients and the curve intercepts ranged from 0.621 to 0.739, 11.29 to 12.64 and -16.9 to -12.32, respectively. The fitted equation for the hybrid implants (Fig. 1E) showed the largest differences for the quadratic coefficient and curve intercept when compared to the equation fitted for intracavitary and interstitial applicators. The equation resulting from all applicators (Fig. 1G) showed the smallest differences for quadratic and linear coefficients when compared to the equation resulting intracavitary applicators. We have shown that TRAK might be useful to predict volumes of isodose surfaces independently of the applicator and fractionation scheme used for treating cervical cancer with BT. The potential to use the correlation between TRAK and volumes of isodose surfaces to predict patients’ outcomes and toxicities should be evaluated in a further study.

Tumor xenografts show cleavage dependent tumor contrast with radiometric ACPP.

Schematic model of therapeutic strategy utilizing tumor targeted MMAE delivery with ACPP.

Polycation conjugated MMAE is cytotoxic to tumor cells.

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 be-tween the groups. These findings support consideration of 3F. (c) 2023 Published by Elsevier Inc. on behalf of American Brachytherapy Society.

MMAE enhances comet tail length following irradiation in pancreatic tumor cell lines.

Combination of increased delivery of ACPP-cRGD-MMAE with IR significantly improved tumor regression.

MMAE enhances γH2Ax foci formation following irradiation.

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.