Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Recurrence

Breast Diseases

Skin Diseases

The experimental policy is to give targeted intra-operative radiotherapy (TARGIT-Boost) in a single dose to substitute for the usual boost dose, in addition to whole breast external beam radiotherapy delivered according to local treatment guidelines.

The conventional policy is to receive radiation boost to the tumour bed delivered by external beam radiotherapy (EBRT) in addition to whole breast external beam radiotherapy delivered according to local treatment guidelines.

Boost to the tumour bed, with whole breast EBRT delivered according to local policy.

Boost to the tumour bed

Norman R Williams, PhD

Nick Roberts

Alexandra Banks

Dennis R Holmes, MD

Blerina Pople

Nayana Dekhne, MD

Pamela Stephenson

Benjamin T Gielda

Pond Kelemen, MD

Courtney Yanda

Stephanie Valente

Cortney Montgomery

Geraldine Jacobson

Corinne Zipperer, RN

William Owens

Xinguang Wang

Tao Ouyang

Christel Breton-Callu, MD

Boly Ann

Serge Danhier, MD

Etienne Martin, MD

Christelle Faure, MD

Didier Cowen, MD

Magali Le Blanc, MD

Francoise Izar, MD

Samuele Massarut, MD

Fabiana Gregucci

Fernando Bozza

Sung Gwe Ahn

Joon Jeong

Zarinah Abdul Rahman

Nur Aishah Mohd Taib

Maha Abdel Hadi

Kyara Bergstrom

Carol Benn

Yastira Ramdas

Montse Ventura

Evelyn Martínez Pérez

Pedro C Lara, MD

Bärbel Papassotiropoulos

Sikrit Denariyakoon

Adhisabandh Chulakadabba

Julian Singer, MD

Jayant S Vaidya, MBBS FRCS

Mo Keshtgar, MB BS

Sweta Sethi

Michael Douek

Nathan Coombs, MB BS

Elizabeth Happle

Sanjay Raj

TARGIT-Boost is an international randomised clinical trial designed to test the hypothesis that the tumour bed boost delivered as a single dose of targeted intraoperative radiotherapy (TARGIT-B) is superior to the conventional course of external beam radiotherapy boost (EBRT-Boost), especially in women with high risk of local recurrence. It is a pragmatic trial in which each participating centre can use the local predefined inclusion/exclusion criteria for entry into the trial. Only centres with access to the Intrabeam® (Carl Zeiss) are eligible to enter patients into the trial.

Eligible patients are those with a higher risk of local recurrence after breast conserving surgery.

After giving consent patients are randomised to either TARGIT Boost or EBRT Boost. All patients will receive whole breast EBRT. They may receive any other adjuvant treatments as deemed necessary. The protocol recommends that patients be followed at six monthly intervals for three years and then annually.

The primary endpoint is ipsilateral breast recurrence rate. Secondary endpoints are relapse-free survival, site of recurrence, overall survival (breast-cancer specific and non-breast cancer deaths) patient satisfaction and quality of life.

DESIGN: A pragmatic multi-centre randomised clinical trial to test whether TARGeted Intraoperative radioTherapy as a tumour bed Boost (TARGIT-B) is superior in terms of local relapse within the treated breast compared with standard post-operative external beam radiotherapy boost in women undergoing breast conserving therapy who have a higher risk of local recurrence. Patients can be entered before the primary surgery or in a smaller proportion of cases, post-pathology. SETTING: Specialist breast units in UK, USA, Canada, Australia and Europe; 31 centres currently recruiting in the TARGIT-A trial and several are ready to join. TARGET POPULATION: Breast cancer patients suitable for breast conserving surgery, but with a high risk of local recurrence. Details of inclusion and exclusion are given in part 2. Briefly the patients should be either younger than 45 or if older, need to have certain pathological features that confer a high risk of local recurrence of breast cancer. HEALTH TECHNOLOGIES BEING ASSESSED. The TARGIT Technique: The Intrabeam® (Carl Zeiss, FDA approved and CE marked) is a miniature electron beam-driven source which provides a point source of low energy X-rays (50kV maximum) at the tip of a 3.2mm diameter tube. The radiation source is inserted into the tumour bed immediately after excision of the tumour and switched on for 20-35 minutes to provide intra-operative radiotherapy accurately targeted to the tissues that are at highest risk of local recurrence. The physics, dosimetry and early clinical applications of this soft x-ray device have been well studied. For use in the breast, the technique was first developed and piloted at University College London. The radiation source is surrounded by a spherical applicator, specially designed (and available in various sizes) to produce a uniform field of radiation at its surface, enabling delivery of an accurately calculated dose to a prescribed depth. It is inserted in the tumour bed and apposed to it with surgical sutures and/or other means. As the x-rays rapidly attenuate the dose to more distant tissues is reduced; this also allows it to be used in standard operating theatres. 20 Gy is delivered to the tumour bed surface in 20-35 minutes, after which the radiation is switched off, the applicator removed, and the wound closed in the normal way. This simple technique has potentially several advantages over convential external beam radiotherapy, interstitial implantation of radioactive wires or conformal external beam radiotherapy. The first pilot of twenty-five cases was at performed at UCL using TARGIT technique as a replacement for the boost dose of radiotherapy; full dose external beam treatment was subsequently given. The phase II study of 300 patients was published and recently updated with long term data along with favourable toxicity and cosmetic outcome results of individual cohorts. A mathematical model of TARGIT developed recently (funded by Cancer Research UK) suggests that it could be superior to conventional radiotherapy. Translational research has found that TARGIT impairs the surgical-trauma-stimulated proliferation and invasiveness of breast cancer cells. This effect of radiotherapy may act synergistically with its tumouricidal effect yielding a superior result. MEASUREMENT OF COST AND OUTCOME: Patient assessments will be clinical examination (6 monthly x 3 years then yearly x 10 years) and mammography (yearly). with ulstrasound (if needed) . Primary outcome: histologically/cytologically proven local recurrence. Secondary: site of relapse in the breast, overall survival, local toxicity (RTOG and LENT SOMA criteria), cosmesis, quality of life, patient satisfaction and health economics. The cost and cost-effectiveness of TARGIT versus EBRT, both as boost, will be calculated from a NHS and personal social services (PSS) perspective. Costs directly incurred by patients will also be assesed, since EBRT as a boost is likely to impose additional time and travel expense to patients and families.

A Comparison of Intra-operative Radiotherapy Boost With External Beam Radiotherapy Boost in Early Breast Cancer.

An International Randomised Controlled Trial to Compare Targeted Intra-operative Radiotherapy Boost With Conventional External Beam Radiotherapy Boost After Lumpectomy for Breast Cancer in Women With a High Risk of Local Recurrence.

To evaluate whether a tumour bed boost in the form of a single fraction of radiotherapy given intra-operatively and targeted to the tissues at the highest risk of local recurrence is superior (in terms of local tumour control) to standard post-operative external beam radiotherapy boost, after breast conserving surgery in women undergoing breast conserving therapy who have a higher risk of local recurrence.

Site of relapse within the breast will be recorded in order to assess whether the recurrence is at the site of the initial tumour or at a new site and whether it has occurred within the treated field (TARGIT or EBRT boost).

Relapse-free survival will be recorded as the time interval between randomisation and the date of confirmation of recurrence. The actual date to be used is the clinic day on which the investigations that led to a confirmed diagnosis of the recurrence were requested. Relapse-free survival will include any recurrence of breast cancer or death without a prior report of relapse.

Overall survival will be the time interval between randomisation and death.

Local toxicity and morbidity will be recorded as adverse events related to the primary treatment of the breast cancer. Quality of life will be assessed though validated patient-completed questionnaires.

The primary patient reported outcome endpoint for quality of life will be the FACT-B+4 trial outcome index (TOI) score. The TOI score (0-180) is a sum of the scores of the 27 items included in the physical well-being, functional well-being and breast cancer subscales of the FACT-B+4. A change of at least 5 points in TOI is considered to be clinically relevant or a minimally important difference (Eton et al. 2004). Secondary endpoints will be: 1) the five item arm functioning subscale score (0-20) 2) The 40 item FACT B+4 score (0-160), which reflects global quality of life including social and emotional well-being.

National Institute for Health Research, United Kingdom

University College, London

Behaviors and Mental Disorders

Quality of Life

All Drugs and Chemicals

Hormones

IORT (20Gy) as intervention will be given during breast conserving surgery. If risk factors (Tumor \> 3.5 cm, lobular cancer, resection margin \< 2 mm\*, L1, pN+ mulitfocal/multicentric, EIC, negative hormone receptors) are present, external beam radiotherapy will be added.

\* In case of positive margins (\<2 mm resection margin) a re-resection should be done

The surgeon and radiation oncologist should choose the largest possible suitable applicator in order to ensure that the highest possible dose is delivered to the tumor bed tissue. A dose of 20 Gy at the surface of the applicator (in water) is prescribed by the radiation oncologist and delivered to the breast tissue. This takes approximately 20-50 minutes, depending on the size of the applicator.

To minimize radiation dependent side effects the skin-applicator surface distance should be more than 5 mm.

Intraoperative radiotherapy (IORT)

Elena Sperk, MD

This prospective, multicentric single arm phase IV study is based on the protocol of the international TARGIT-A and TARGIT-E study.

Patients ≥ 50 years with small, low-risk breast cancer who are operated but not irradiated show local relapse rates around 6% after 5 years. With adjuvant whole breast radiotherapy (WBRT) the local relapse rate drops to under 1% after 5 years under Tamoxifen (4).

It has been demonstrated (6, 9, 10) that the efficacy of radiation of the tumor bed only in a selected group can be non-inferior to WBRT.

The TARGIT C study should confirm the efficacy of a single dose of intraoperative radiotherapy (IORT) in a well selected group of patients with small breast cancer and absence of risk factors. In presence of risk factors postoperative WBRT will be added to complete the radiotherapeutic treatment according to international guidelines.

Endpoints are the local relapse rate (within 2 cm of the tumor bed), ipsilateral relapse, cancer-specific and overall survival and contralateral breast cancer as well as documentation of quality of life and cosmetic outcome.

The expected local relapse rates are 0.825/1.375% after 3/5 years, respectively. Discontinuation of the trial is scheduled if rates of local relapse rates rise to 1.55/2.4/4% after 1/3/5 years. Power calculations result in 387 patients with a calculated dropout and loss to follow-up rate of 10%, an alpha of 0.05 and a beta of 0.10. There will be only a pre-pathology stratum.

It is a pragmatic trial in which each participating centre has the option to modify entry criteria and criteria for WBRT according to this core protocol after consultation with the steering committee and local ethics committee (e.g. size, free margins). Only centers with access to the Intrabeam® system (Carl Zeiss) can recruit patients into the trial.

1. Introduction

   Randomized studies provide evidence that concerning the overall survival breast conserving surgery (BCS) combined with postoperative radiotherapy is equally effective as modified mastectomy (1, 2, 3). Postoperative radiation decreases the local relapse rate (1, 2) highly significantly in comparison to BCS alone (3). The recent metaanalysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG (3)) show that the avoidance of 4 local relapses after 5 years can prevent one death in 15 years (4 to 1 rule).

   Several studies in the past demonstrated that complete omission of radiotherapy failed in terms of local tumor control. Fyles et al. (4) showed local relapse rates of 8% within a low risk group of patients with tumors of pathological stage T1/T2 and \>50 years of age treated with BCS and antihormonal treatment (AHT). By adding postoperative whole breast radiation (WBRT) the rate of local relapse was reduced to 1% after 5 years. This effect was also seen in elderly patients with small tumors. Hughes et al. (5) observed low local relapse rates of 4% for patients treated with AHT only after BCS vs. 1% for patients with additional WBRT after 4 years, evaluating a low-risk group of patients with tumors \< 2 cm and \> 70 years of age. Apparently, all patients benefit from postoperative WBRT. However, due to the fact that 90% of all local relapses after breast conserving therapy are localized very close to the primary tumor, it might be possible to treat a selected group of patients with a relatively low risk of local recurrence with tumor bed irradiation only. Polgar et al. (6) provided evidence of the non-inferiority of accelerated partial breast irradiation (APBI) in comparison to WBRT in a small randomized trial. Very recently the TARGIT-A data (9, 10) reported a non-inferior efficacy of tumor bed irradiation with single dose intraoperative radiation (Intrabeam System, Carl Zeiss Oberkochen) compared to WBRT regarding local relapse.

   By using the Intrabeam System, the intraoperative radiotherapy (IORT) can be given during surgery with protection of the surrounding tissue while applying a biologically highly effective dose to the tissue adjacent to the tumor.

   Advantages of IORT are its high precision regarding beam application, its possibility of protection of the skin and the prevention of tumor cell proliferation during the time interval between breast conserving surgery and adjuvant WBRT as well as during fractionated WBRT.

   By manually positioning of the applicator in the tumor bed geographic miss is excluded and radiation of risk structures like the heart and lung can be avoided. Therefore, it is possible to give a high single fraction to the target and minimize relevant side effects.
2. Aim

The objective of this single armed phase IV study is to further investigate the efficacy of a single intraoperative radiotherapy treatment within low risk patients (≥ 50 years, cT1 and small cT2 (\< 3.5 cm), cN0, cM0, invasive-ductal, hormone receptor positive) which is followed by WBRT only when risk factors are present.

The primary endpoint is the rate of local relapse (within 2 cm of the initial tumor); secondary endpoints are ipsi- or contralateral breast cancer, cancer specific and overall survival. Of further interest is the cosmetic outcome and Quality of Life.

Therefore, patients ≥ 50 years with small, histologically verified and hormone receptor positive invasive-ductal breast cancer (clinically cT1 or small T2 ≤ 3.5 cm) without risk factors (multifocality/- centricity, extensive intraductal component (EIC), lymph vessel invasion (L1), clinically positive lymph nodes) who receive BCS will be recruited.

After tumor resection with free margins \> 1 mm the applicator will be exactly positioned in the tumor bed with a minimum distance to skin of 5 mm. The prescription dose will be 20 Gy to the surface of the applicator. The treatment times depend on the diameter of the applicator and can last up to 20-50 minutes. After radiation the applicator will be removed and the operation finished as usual. The biologic effectiveness of 20 Gy prescribed during the operation is equivalent to 70 Gy normo-fractionated irradiation according to radiobiological modelling.

If the final histopathological report provides evidence of a different histology or risk factors, such as an extensive intraductal component (EIC), lymph vessel invasion (L1), multifocality/-centricity or resection margins \<2 mm, patients will receive a postoperative WBRT with 46 Gy (after a delay of at least 5 weeks). Depending on the lymph node status postoperative WBRT will be performed with 50 Gy (pN1) or WBRT including lymphatic drainage with 50 Gy (≥ pN2). A re-resection has to be performed in presence of insufficient free margins (e.g. tumor on ink, or margin \< 2mm depending on local policy) and will be followed by WBRT with 50 Gy omitting the boost.

Cosmetic outcome and toxicity evaluation will be performed by chart (CTC and LENT-SOMA score) and standardized photo documentation.

For Quality of Life assessment the patients will complete two standardized and validated questionnaires developed by the EORTC (European Organisation for Research and Treatment of Cancer). The questionnaires include 53 questions and take approximately 10 minutes and will be filled out at clinic visits.

Therefore, a patient group including patients ≥ 50 years with a low-risk tumor profile will be treated in this single-arm study by intraoperative radiotherapy of the tumor bed only, using a well established method (Intrabeam System, Carl Zeiss Surgical, Oberkochen, Germany) in order to optimize radiotherapy treatment after breast conserving surgery in terms of local relapse, toxicity, overall survival and quality of life.

Single arm study: IORT +/- EBRT (risk adapted approach).

TARGIT-C(Consolidation) Prospective Phase IV Study of IORT in Patients With Small Breast Cancer

TARGIT-C(Consolidation) Prospective Phase IV Study of Intraoperative Radiotherapy (IORT) in Patients With Small Breast Cancer

Local relapse rate within 2 cm of the tumor bed

Breast cancer related and overall survival

Cosmetic outcome, acute and late toxicity measured by CTC Score V5 and LENT SOMA scale (fibrosis, telangiectasia, edema arm, edema breast, ulceration, hyperpigmentation, pain, retraction

measured by EORTC QLQ C30 and BR23 questionnaires; longitudinal analysis

Universitätsmedizin Mannheim

Head, Clinical Trials Unit, Department of Radiation Oncology Mannheim

Boost with 20 Gy during BCS, EBRT with 46-50 Gy

Intraoperative radiotherapy with the INTRABEAM System with 20 Gy

IORT with 50 kV x-rays, 20 Gy

Quality Control Registry for IORT used as an anticipiated boost with 20 Gy at the applicator surface followed by EBRT

Quality Control Registry of a standard treatment with intraoperative radiotherapy during breast conserving surgery with 20 Gy at the applicator surface as an advanced boost followed by a shortened external beam radiotherapy. This is a prospective phase IV study to evaluate real life data of IORT Boost. Study runs in Germany with 13 active centers recruiting. Due to the nature of the study (registry) there is no need for randomization. Inclusion of n = \>1000 patients is planned.

TARGeted Intraoperative radioTherapy With INTRABEAM as a Boost for Breast Cancer - A Quality Control Registry

TARGeted Intraoperative radioTherapy With the INTRABEAM-System as an Advanced Boost in Patients With Breast Cancer - A Quality Control Registry in Germany (TARGIT BQR)

LENT SOMA Scale for toxicity regular follow up

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Comparison of Intra-operative Radiotherapy Boost With External Beam Radiotherapy Boost in Early Breast Cancer.	NCT01792726	Early Breast Ca...	Boost to the tu...	-	University College, London
A Comparison of Intra-operative Radiotherapy Boost With External Beam Radiotherapy Boost in Early Breast Cancer.	NCT01792726	Early Breast Ca...	Boost to the tu...	-	University College, London
TARGIT-C(Consolidation) Prospective Phase IV Study of IORT in Patients With Small Breast Cancer	NCT02290782	Breast Cancer	Intraoperative ...	50 Years -	Universitätsmedizin Mannheim
TARGeted Intraoperative radioTherapy With INTRABEAM as a Boost for Breast Cancer - A Quality Control Registry	NCT01440010	Breast Cancer	IORT with 50 kV...	18 Years - 85 Years	Universitätsmedizin Mannheim

Spots Global Cancer Trial Database for targit

Every month we try and update this database with for targit cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for targit

Every month we try and update this database with for targit cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for targit cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.