Pharmacokinetic Drug-Drug Interaction Studies Between Trilaciclib and Midazolam, Metformin, Rifampin, Itraconazole, and Topotecan in Healthy Volunteers and Patients with Extensive-Stage Small-Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression in patients with extensive-stage small-cell lung cancer. Trilaciclib is a substrate and time-dependent inhibitor of cytochrome P450 3A4 and an inhibitor of multidrug and toxin extrusion 1, multidrug and toxin extrusion 2-K, organic cation transporter 1, and organic cation transporter 2. Here, we investigate the pharmacokinetic drug-drug interaction potential of trilaciclib. METHODS: Two phase I studies were conducted as prospective, open-label, fixed-sequence drug-drug interaction studies in healthy subjects (n = 57, n = 20) to investigate potential interactions between intravenously administered trilaciclib (200 or 240 mg/m2) and orally administered midazolam (5 mg), metformin (1000 mg), itraconazole (200 mg), and rifampin (600 mg). A population pharmacokinetic model was fit to phase Ib/IIa data in patients with extensive-stage small-cell lung cancer (n = 114) to assess the impact of trilaciclib dose and exposure (area under the plasma concentration-time curve) on topotecan clearance. RESULTS: Coadministration with trilaciclib had minimal effects on the exposure (area under the plasma concentration-time curve from time 0 to infinity) of midazolam (geometric least-square mean ratio [GMR] vs midazolam alone 1.065; 90% confidence interval [CI] 0.984-1.154) but statistically significantly increased plasma exposure (GMR 1.654; 90% CI 1.472-1.858) and decreased renal clearance (GMR 0.633; 90% CI 0.572-0.701) of metformin. Coadministration of trilaciclib with rifampin or itraconazole decreased trilaciclib area under the plasma concentration-time curve from time 0 to infinity by 17.3% (GMR 0.827; 90% CI 0.785-0.871) and 14.0% (GMR 0.860; 0.820-0.902), respectively, vs trilaciclib alone. Population pharmacokinetic modeling showed no significant effect of trilaciclib on topotecan clearance. CONCLUSIONS: Overall, the drug-drug interaction and safety profiles of trilaciclib in these studies support its continued use in patients with extensive-stage small-cell lung cancer. CLINICAL TRIAL REGISTRATION: Study 106: EudraCT number: 2019-002303-18; Study 114: not applicable; Study 03: Clinicaltrials.org: NCT02514447; August 2015.

Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline.

PURPOSE: To provide recommendations on the best strategies for the management and on the best timing and treatment (surgical and radiotherapeutic) of the axilla for patients with early-stage breast cancer. METHODS: Ontario Health (Cancer Care Ontario) and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature. RESULTS: This guideline endorsed two recommendations of the ASCO 2017 guideline for the use of sentinel lymph node biopsy in patients with early-stage breast cancer and expanded on that guideline with recommendations for radiotherapy interventions, timing of staging after neoadjuvant chemotherapy (NAC), and mapping modalities. Overall, the ASCO 2017 guideline, seven high-quality systematic reviews, 54 unique studies, and 65 corollary trials formed the evidentiary basis of this guideline. RECOMMENDATIONS: Recommendations are issued for each of the objectives of this guideline: (1) To determine which patients with early-stage breast cancer require axillary staging, (2) to determine whether any further axillary treatment is indicated for women with early-stage breast cancer who did not receive NAC and are sentinel lymph node-negative at diagnosis, (3) to determine which axillary strategy is indicated for women with early-stage breast cancer who did not receive NAC and are pathologically sentinel lymph node-positive at diagnosis (after a clinically node-negative presentation), (4) to determine what axillary treatment is indicated and what the best timing of axillary treatment for women with early-stage breast cancer is when NAC is used, and (5) to determine which are the best methods for identifying sentinel nodes.Additional information is available at www.asco.org/breast-cancer-guidelines.

Exploratory composite endpoint demonstrates benefit of trilaciclib across multiple clinically meaningful components of myeloprotection in patients with small cell lung cancer.

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after Week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared to placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after Week 5 were significantly reduced with trilaciclib vs placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared to placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC.

Accuracy and efficiency of image-guided radiation therapy (IGRT) for preoperative partial breast radiosurgery.

OBJECTIVE: To analyze and evaluate accuracy and efficiency of IGRT process for preoperative partial breast radiosurgery. METHODS: Patients were initially setup with skin marks and 5 steps were performed: (1) Initial orthogonal 2D kV images, (2) pre-treatment 3D CBCT images, (3) verification orthogonal 2D kV images, (4) treatment including mid-treatment 2D kV images (for the final 15 patients only), and (5) post-treatment orthogonal 2D kV or 3D CBCT images. Patient position was corrected at each step to align the biopsy clip and to verify surrounding soft tissue positioning. RESULTS: The mean combined vector magnitude shifts and standard deviations at the 5 imaging steps were (1) 0.96 ± 0.69, (2) 0.33 ± 0.40, (3) 0.05 ± 0.12, (4) 0.15 ± 0.17, and (5) 0.27 ± 0.24 in cm. The mean total IGRT time was 40.2 ± 13.2 minutes. Each step was shortened by 2 to 5 minutes with improvements implemented. Overall, improvements in the IGRT process reduced the mean total IGRT time by approximately 20 minutes. Clip visibility was improved by implementing oblique orthogonal images. CONCLUSION: Multiple imaging steps confirmed accurate patient positioning. Appropriate planning and imaging strategies improved the effectiveness and efficiency of the IGRT process for preoperative partial breast radiosurgery.

Automatic Planning of Whole Breast Radiation Therapy Using Machine Learning Models.

Purpose: To develop an automatic treatment planning system for whole breast radiation therapy (WBRT) based on two intensity-modulated tangential fields, enabling near-real-time planning. Methods and Materials: A total of 40 WBRT plans from a single institution were included in this study under IRB approval. Twenty WBRT plans, 10 with single energy (SE, 6MV) and 10 with mixed energy (ME, 6/15MV), were randomly selected as training dataset to develop the methodology for automatic planning. The rest 10 SE cases and 10 ME cases served as validation. The auto-planning process consists of three steps. First, an energy prediction model was developed to automate energy selection. This model establishes an anatomy-energy relationship based on principle component analysis (PCA) of the gray level histograms from training cases' digitally reconstructed radiographs (DRRs). Second, a random forest (RF) model generates an initial fluence map using the selected energies. Third, the balance of overall dose contribution throughout the breast tissue is realized by automatically selecting anchor points and applying centrality correction. The proposed method was tested on the validation dataset. Non-parametric equivalence test was performed for plan quality metrics using one-sided Wilcoxon Signed-Rank test. Results: For validation, the auto-planning system suggested same energy choices as clinical-plans in 19 out of 20 cases. The mean (standard deviation, SD) of percent target volume covered by 100% prescription dose was 82.5% (4.2%) for auto-plans, and 79.3% (4.8%) for clinical-plans (p > 0.999). Mean (SD) volume receiving 105% Rx were 95.2 cc (90.7 cc) for auto-plans and 83.9 cc (87.2 cc) for clinical-plans (p = 0.108). Optimization time for auto-plan was <20 s while clinical manual planning takes between 30 min and 4 h. Conclusions: We developed an automatic treatment planning system that generates WBRT plans with optimal energy selection, clinically comparable plan quality, and significant reduction in planning time, allowing for near-real-time planning.

Lessons Learned From Hurricane Maria in Puerto Rico: Practical Measures to Mitigate the Impact of a Catastrophic Natural Disaster on Radiation Oncology Patients.

PURPOSE: Although the wind, rain, and flooding of Hurricane Maria in Puerto Rico abated shortly after its landfall on September 20, 2017, the disruption of the electrical, communications, transportation, and medical infrastructure of the island was unprecedented in scope and caused lasting harm for many months afterward. A compilation of recommendations from radiation oncologists who were in Puerto Rico during the disaster, and from a panel of American Society for Radiation Oncology (ASTRO) cancer experts was created. METHODS AND MATERIALS: Radiation oncologists throughout Puerto Rico collaborated and improvised to continue treating patients in the immediate aftermath of the storm and as routine clinical operations were restored gradually. Empirical lessons from the experience of radiation therapy administration in this profoundly altered context of limited resources, impaired communication, and inadequate transportation were organized into a recommended template, applicable to any radiation oncology practice. ASTRO disease-site experts provided evidence-guidelines for mitigating the impact of a 2- to 3-week interruption in radiation therapy. RESULTS: Practical measures to mitigate the medical impact of a disaster are summarized within the framework of "Prepare, Communicate, Operate, Compensate." Specific measures include the development of an emergency operations plan tailored to specific circumstances, prospective coordination with other radiation oncology clinics before a disaster, ongoing communications with emergency management organizations, and routine practice of alternate methods to disseminate information among providers and patients. CONCLUSIONS: These recommendations serve as a starting point to assist any radiation oncology practice in becoming more resiliently prepared for a local or regional disruption from any cause. Disease-site experts provide evidence-based guidelines on how to mitigate the impact of a 2- to 3-week interruption in radiation therapy for lung, head and neck, uterine cervix, breast, and prostate cancers through altered fractionation or dose escalation.

Findings on Surveillance Imaging After Preoperative Partial Breast Irradiation for Early Stage Breast Cancer.

PURPOSE: To evaluate the mammographic sequelae of preoperative accelerated partial breast irradiation (APBI) delivered via either stereotactic radiosurgery or a conventionally fractionated regimen. METHODS AND MATERIALS: This multicenter, retrospective study evaluated surveillance mammograms from patients enrolled in 2 prospective, preoperative APBI clinical trials. At 1 site, 31 patients with cT1N0 invasive carcinomas or low- or intermediate-grade ductal carcinoma in situ (<2 cm) received preoperative stereotactic radiosurgery and had a total of 186 mammograms available for review. At the second site, 180 mammograms from 25 patients with cT1-2 (<3 cm) unifocal invasive carcinomas treated with conventionally fractionated, preoperative APBI were reviewed. Findings were compared with those of 26 early stage breast cancers treated with conventional postoperative whole breast radiation therapy. RESULTS: At a median follow-up of 61 months, 17 patients (55%) treated with single-dose APBI exhibited exuberant fat necrosis at the lumpectomy site. Fat necrosis was believed to be clinically palpable in 5 (16%) of these patients within the first 3 years of follow-up. Exuberant fat necrosis developed in 5 patients (20%) treated with fractionated APBI over a median 68-month follow-up period but only 2 of those patients (8%) who underwent conventional whole breast radiation therapy. CONCLUSIONS: In situ tumor targeting in the preoperative setting allows relative sparing of normal tissue but results in a larger and more vigorous area of change on surveillance imaging, potentially reflecting the interaction of surgical resection with an irradiated tissue bed. High-dose stereotactic radiosurgery in particular increases the risk of developing a uniquely robust and well-demarcated pattern of fat necrosis on mammogram that may also present clinically. With many ongoing studies evaluating the preoperative treatment approach, defining the landscape of expected imaging sequelae will provide useful anticipatory guidance for clinicians and patients.

Concurrent Veliparib With Chest Wall and Nodal Radiotherapy in Patients With Inflammatory or Locoregionally Recurrent Breast Cancer: The TBCRC 024 Phase I Multicenter Study.

Purpose Locoregional control for inflammatory breast cancers and chest wall recurrences is suboptimal, which has motivated interest in radiosensitization to intensify therapy. Preclinical studies have suggested a favorable therapeutic index when poly (ADP-ribose) polymerase inhibitors are used as radiosensitizers; clinical investigation is necessary to establish appropriate dosing and confirm safety. Patients and Methods We conducted a multi-institutional phase I study of veliparib and concurrent radiotherapy (RT) to the chest wall and regional lymph nodes in 30 patients with inflammatory or locally recurrent breast cancer after complete surgical resection. RT consisted of 50 Gy to the chest wall and regional lymph nodes plus a 10-Gy boost. A Bayesian time-to-event continual reassessment method escalated dose through four levels, with a 30% targeted rate of dose-limiting toxicity (DLT) measured during the 6 weeks of treatment plus 4 weeks of follow-up. DLTs were defined as confluent moist desquamation > 100 cm2, nonhematologic toxicity grade ≥ 3, toxicity that requires an RT dose delay > 1 week, absolute neutrophil count < 1,000/mm3, platelet count < 50,000/mm3, or hemoglobin < 8.0 g/dL if possibly, probably, or definitely related to study treatment. Results Five DLTs occurred: Four were moist desquamation (two each at 100 and 150 mg twice a day), and one was neutropenia (at 200 mg twice a day). The crude rate of any grade 3 toxicity (regardless of attribution) was 10% at year 1, 16.7% at year 2, and 46.7% at year 3. At year 3, six of 15 surviving patients had severe fibrosis in the treatment field. Conclusion Although severe acute toxicity did not exceed 30% even at the highest tested dose, nearly half of surviving patients demonstrated grade 3 adverse events at 3 years, which underscores the importance of long-term monitoring of toxicity in trials of radiosensitizing agents.

Breast Cancer Biology: Clinical Implications for Breast Radiation Therapy.

Historically, prognosis and treatment decision making for breast cancer patients have been dictated by the anatomic extent of tumor spread. However, in recent years, "breast cancer" has proven to be a collection of unique phenotypes with distinct prognoses, patterns of failure, and treatment responses. Recent advances in biologically based assays and targeted therapies designed to exploit these unique phenotypes have profoundly altered systemic therapy practice patterns and treatment outcomes. Data associating locoregional outcomes with tumor biology are emerging. However, the likelihood of obtaining level I evidence for fundamental radiation therapy questions within each of the specific subtypes in the immediate future is low. As such, this review aims to summarize the existing data and provide practical context for the incorporation of breast tumor biology into clinical practice.

Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer.

Breast cancer is the most common malignancy diagnosed among women and represents a heterogeneous group of subtypes. Radiation therapy is a critical component of treatment for breast cancer patients. However, little is known about radiation response among these intrinsic subtypes. In previous studies, we identified a significant induction of FAS after irradiation in biologically favorable breast cancer patients and breast cancer cell lines. Here, we expanded our study and investigated radiation response in a mouse model of breast cancer. MCF7 (luminal), HCC1954 (HER2+) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of nude mice. These mice were then treated with different doses of radiation to assess tumor growth control. We further investigated the therapeutic effect of FAS modulation by silencing FAS in radiation-responsive tumors and injecting FAS agonist antibody into radiation-resistant tumors. Exposure to radiation inhibited MCF7, and to a lesser extent HCC1954 tumor growth in a dose-dependent manner. In contrast, SUM159 tumors were resistant to radiation. The estimated TCD50 values were 19.3 Gy for MCF7 and 44.9 Gy for SUM159. Radiation induced FAS expression in MCF7 tumors, but not SUM159 tumors. We found that silencing of FAS did not negatively impact radiation response in MCF7 tumors, possibly due to compensation by other apoptotic pathways. On the other hand, FAS activating antibody in combination with radiation treatment delayed SUM159 and HCC1954 tumor growth. However, it did not reach statistical significance compared to radiation treatment alone. Our results suggest that there is intrinsic variation in radiation response among breast cancer subtypes. FAS activation concurrent with radiation slows tumor growth in the radiation-resistant subtypes, but the effect was not significant. Alternative subtype-specific modulators of radiation response are under investigation.

Treatment constraints for single dose external beam preoperative partial breast irradiation in early-stage breast cancer.

BACKGROUND: Following breast-conserving surgery and post-operative 3D-conformal accelerated partial breast irradiation (APBI), suboptimal cosmetic results have been reported. Preoperative radiation delivery to the intact tumor enables better target visualization and treatment volume reduction. Single dose preoperative APBI has the potential to improve toxicity profiles, reduce treatment burden and enable in vivo exploration of breast cancer radiogenomics. PURPOSE: Develop practical guidelines for single dose external beam preoperative APBI. METHODS: Recommended dose constraints were derived from pooled dosimetry estimates from 2 clinical trials. In an American dose escalation trial, a uniform 15, 18 or 21 Gy dose has previously been evaluated for non-lobular cT1N0 or low/intermediate grade DCIS <2 cm in prone position (n = 32). In the Netherlands, the feasibility of ablative APBI (20 Gy to GTV, 15 Gy to CTV) to non-lobular cT1N0 in supine position, is currently being explored (n = 15). The dosimetric adherence to the developed constraints was evaluated in new APBI plans with a 21 Gy uniform dose but an extended CTV margin (n = 32). RESULTS: Dosimetric data pooling enabled the development of practical guidelines for single dose preoperative APBI. CONCLUSION: The developed guidelines will allow further explorations in the promising field of single dose preoperative external beam APBI for breast cancer treatment.

Assessment of Treatment Response With Diffusion-Weighted MRI and Dynamic Contrast-Enhanced MRI in Patients With Early-Stage Breast Cancer Treated With Single-Dose Preoperative Radiotherapy: Initial Results.

Single-dose preoperative stereotactic body radiotherapy is a novel radiotherapy technique for the early-stage breast cancer, and the treatment response pattern of this technique needs to be investigated on a quantitative basis. In this work, dynamic contrast-enhanced magnetic resonance imaging and diffusion-weighted magnetic resonance imaging were used to study the treatment response pattern in a unique cohort of patients with early-stage breast cancer treated with preoperative radiation. Fifteen female qualified patients received single-dose preoperative radiotherapy with 1 of the 3 prescription doses: 15 Gy, 18 Gy, and 21 Gy. Magnetic resonance imaging scans including both diffusion-weighted magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging were acquired before radiotherapy for planning and after radiotherapy but before surgical resection. In diffusion-weighted magnetic resonance imaging, the regional averaged apparent diffusion coefficient was calculated. In dynamic contrast-enhanced magnetic resonance imaging, quantitative parameters K (trans) and v e were evaluated using the standard Tofts model based on the average contrast agent concentration within the region of interest, and the semiquantitative initial area under the concentration curve (iAUC6min) was also recorded. These parameters' relative changes after radiotherapy were calculated for gross tumor volume, clinical target volume, and planning target volume. The initial results showed that after radiotherapy, initial area under the concentration curve significantly increased in planning target volume (P < .006) and clinical target volume (P < .006), and v e significantly increased in planning target volume (P < .05) and clinical target volume (P < .05). Statistical studies suggested that linear correlations between treatment dose and the observed parameter changes exist in most examined tests, and among these tests, the change in gross tumor volume regional averaged apparent diffusion coefficient (P < .012) and between treatment dose and planning target volume K (trans) (P < .029) were found to be statistically significant. Although it is still preliminary, this pilot study may be useful to provide insights for future works.

FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target.

Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in radioresistant basal cell lines. Our findings suggest that cell-type-specific, radiation-induced FAS contributes to subtype-specific breast cancer radiation response and that activation of FAS pathways may be exploited for biologically tailored radiotherapy.

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.

OBJECTIVES: To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). METHODS: 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. RESULTS: Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. CONCLUSIONS: Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.

PURPOSE: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. METHODS AND MATERIALS: Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. RESULTS: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. CONCLUSIONS: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.

A phase 1 trial of preoperative partial breast radiation therapy: Patient selection, target delineation, and dose delivery.

PURPOSE: Diffusion of accelerated partial breast irradiation into clinical practice is limited by the need for specialized equipment and training. The accessible external beam technique yields unacceptable complication rates, likely from large postoperative target volumes. We designed a phase 1 trial evaluating preoperative radiation therapy to the intact tumor using widely available technology. METHODS AND MATERIALS: Patients received 15, 18, or 21 Gy in a single fraction to the breast tumor plus margin. Magnetic resonance imaging (MRI) was used in conjunction with standard computed tomography (CT)-based planning to identify contrast enhancing tumor. Skin markers and an intratumor biopsy marker were used for verification during treatment. RESULTS: MRI imaging was critical for target delineation because not all breast tumors were reliably identified on CT scan. Breast shape differences were consistently seen between CT and MRI but did not impede image registration or tumor identification. Target volumes were markedly smaller than historical postoperative volumes, and normal tissue constraints were easily met. A biopsy marker within the breast proved sufficient for setup localization. CONCLUSIONS: This single fraction linear accelerator-based partial breast irradiation approach can be easily incorporated at most treatment centers. In vivo targeting may improve accuracy and can reduce the dose to normal tissues.