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

ABSTRACT: 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.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.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.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.

SUBMITTER: Horton JK

PROVIDER: S-EPMC4481883 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Horton Janet K JK Blitzblau Rachel C RC Yoo Sua S Geradts Joseph J Chang Zheng Z Baker Jay A JA Georgiade Gregory S GS Chen Wei W Siamakpour-Reihani Sharareh S Wang Chunhao C Broadwater Gloria G Groth Jeff J Palta Manisha M Dewhirst Mark M Barry William T WT Duffy Eileen A EA Chi Jen-Tsan A JT Hwang E Shelley ES

International journal of radiation oncology, biology, physics 20150314 4

<h4>Purpose</h4>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) eval ...[more]

PMID: 26104938

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Project description:BackgroundBreast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients.MethodsThis is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate.DiscussionThe study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale.Trial registrationThe study was prospectively registered at clinicaltrials.gov ( NCT04679454 ).

Project description:INTRODUCTION:Preoperative radiotherapy followed by total mesorectal excision with adjuvant chemotherapy has been recommended as the preferred treatment method for locally advanced rectal cancer (LARC). Similar rates of local control, survival and toxicity were observed in preoperative long-course chemoradiotherapy (LCRT) (45-50.4 Gy in 25-28 fractions) and in short-course radiotherapy (SCRT) with 25 Gy over five fractions. Both regimens lower the local recurrence rates compared with that of surgery followed by postoperative radiotherapy. With the simplicity and lower cost of SCRT, a growing number of patients have been receiving SCRT as preoperative radiotherapy. However, the currently established SCRT (25 Gy over five fractions) followed immediately by surgery resulted in poor downstaging and sphincter preservation rate. The pathological complete response (pCR) rate is also markedly lower with SCRT than with LCRT (0.7%vs16%). Several studies recommended SCRT with delayed surgery for more than 4 weeks with expectation of improved pathological outcomes and fewer postoperative complications. While a number of clinical trials demonstrated a persistently better overall local control with SCRT than with LCRT, overall survival advantage has not been observed. Since survival is mainly depended on distant metastases, efforts should be made towards more effective pathological response and systemic treatment. Given the apparent advantages of SCRT, we aimed to establish a dose escalation of SCRT and sequential modified FOLFOX6 (mFOLFOX6) as preoperative therapy for LARC with objectives of achieving an optimal balance of safety, cost effectiveness and clinical outcome, and to support further investigation of this regimen in a phase II/III setting. METHODS:In this phase I study, three dose levels (6Gy×5F, 7Gy×5F, 8Gy×5F to gross tumour volume, while keeping the rest of irradiated volume at 5Gy×5) of SCRT followed by four cycles of mFOLFOX6 chemotherapy as neoadjuvant therapy will be tested by using the traditional 3+3 design. The pCR rate, R0 resection rate, sphincter preservation rate and treatment related toxicity will be assessed. ETHICS AND DISSEMINATION:The study protocol was approved by the Ethics Committee of Fujian Medical University Union Hospital (No. 2017YF020-02) and all participants provided written informed consent. Results from our study will be disseminated in international peer-reviewed journals. All study procedures were developed in order to assure data protection and confidentiality. TRIAL REGISTRATION NUMBER:NCT03466424; Pre-results.

Project description:IntroductionChildren with disorders of consciousness (DOC) represent the highest end of the acquired brain injury (ABI) severity spectrum for survivors and experience a multitude of functional impairments. Current clinical management in DOC uses behavioural evaluation measures and interventions that fail to (1) describe the physiological consequences of ABI and (2) elicit functional gains. In paediatric DOC, there is a critical need to develop evidence-based interventions to promote recovery of basic responses to improve rehabilitation and aid decision-making for medical teams and caregivers. The purpose of this investigation is to examine the safety, tolerability and feasibility of transcranial direct current stimulation (tDCS) in children with DOC.Methods and analysisThis study is an open-label dose escalation trial evaluating the safety, tolerability and feasibility of tDCS in 10 children (5-17 years) receiving inpatient rehabilitation for DOC. This study will follow a modified rule-based design, allowing for intrapatient escalation, where a cohort of patients will be assigned to an initial tDCS current of 0.5 or 1 mA based on participant's head circumference and according to the safety data available in other paediatric populations. The subsequent assignment of increased current (1 or 2 mA) according to the prespecified rules will be based on the clinical observation of adverse events in the patients. The study will include up to three, 20 min sessions of anodal tDCS (sham, 0.5 or 1 mA, 1 or 2 mA) applied over the dorsolateral prefrontal cortex. The primary outcomes are adverse events, pain associated with tDCS and intolerable disruption of inpatient care. Secondary outcomes are changes in electroencephalography (EEG) phase-locking and event-related potential components and the Coma Recovery Scale-Revised total score from prestimulation to poststimulation.Ethics and disseminationThe Johns Hopkins IRB (#IRB00174966) approved this study. Trial results will be disseminated through journals and conferences.Registration numberNCT03618849.

Dataset Information

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

Publications

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

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