Intra-Operative Electron Boost and Hypofractionated Whole-Breast Irradiation During Breast-conserving Treatment (BCT) - Full Text View

Purpose

Title:

HIOB - Hypofractionated Whole-Breast Irradiation preceded by Intra-Operative Radiotherapy with Electrons as anticipated Boost ISIORT- 01

HIOB is defined as hypofractionated WBRT (40,5 Gy in 2,7 Gy per fraction) preceded by an Intra-Operative Boost to the tumor bed ( 90 % reference dose of 10 Gy, 11,1 Gy Dmax IOERT).

Primary endpoint is the proof of superiority of a new treatment regimen.

The HIOB study concept is supposed to test the hypothesis whether such a combined schedule is superior (or iso-effective) towards "standard" RT in terms of local control and cosmetic outcome.

In the vast majority of all publications, annual and 5 year in-breast recurrence rates following BCT showed a clear dependency on patient age within the following boundaries (primary references):

Age > 50: Bartelink (standard): 0,7% (annual) 3,5% (5y) START B (best): 0,4 %(annual) 2,0% (5y)

Age 41-50: Bartelink (standard) 1,2% (annual) 6,0% (5y) Whelan (best) 0,72%(annual) 3,6% (5y)

Age ≥ 35-40 Bartelink (standard) 2% (annual) 10% (5y) Whelan (best) 0,72% (annual) 3,6% (5y)

long these three different age groups, benchmarking will be performed against the best published results following `Golden Standard`RT, usually defined as conventionally fractionated WBRT with 50 Gy (25 x2) plus external tumor bed boost with 10-16 Gy electrons (5-8x2Gy).

Superiority is defined as going below the lower limit of the estimated 5 year local recurrence rate within the respective age group Inferiority is defined as crossing the respective upper limit .

Secondary endpoint:

Disease free survival

Tertiary endpoint: toxicity assessment (acute and late) including long term cosmetic evaluation

Study design and statistics:

Prospective multi-center single-armed
Sequential probability ratio test (SPRT)
Separate analysis within three different age groups

Estimated Accrual time: strongly dependent on recruitment per year within the respective age group . Due to the statistical estimation of Szenario A and B the study will close after max. Time-period of 10 years in case of A or 6,4 years in case of B..

Principal investigators and study coordinators:

UC of Radiotherapy and Radio-Oncology UC of Special Gynecology and Breast Cancer Center Landeskrankenhaus Salzburg, Paracelsus University Clinics

Condition	Intervention	Phase
Local Neoplasm Recurrence Toxicity	Radiation: HIOB	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Hypofractionated Whole-Breast Irradiation Preceded by Intra-Operative Radiotherapy With Electrons as Anticipated Boost HIOB A New Option in Breast-Conserving Treatment for Operated Breast Cancer Stages I and II

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

U.S. FDA Resources

Further study details as provided by Paracelsus Medical University:

Primary Outcome Measures:

5 year local recurrence rate: Sequential Probability Ratio Test [ Time Frame: 10 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Acute toxicity: CTC-toxicity Scoring-system;Late toxicity: LENT-SOMA scoring-systems [ Time Frame: 10 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	1000
Study Start Date:	January 2011
Estimated Study Completion Date:	May 2021
Estimated Primary Completion Date:	March 2021 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Hypofractionated WBRT with IOERT Boost	Radiation: HIOB IOERT IOERT is performed on mobile or fixed linacs Reference dose: 11 Gy specified as maximum dose, with a minimum target volume dose of 90% encompassing the PTV (i.e. 10 Gy). WBRT must start within day 36- 56 postoperatively (week 6 - 8 p.o.) in case of adjuvant hormonal treatment (or no further tumor specific medication) In case of adjuvant chemotherapy, a time - gap between IOERT and WBRT up to 6 months is allowed. Single reference dose per fraction: 2,7 Gy (ICRU) Number of fractions: 15, Number of fractions per week: 5 Total WBRT dose: 40,5 Gy

Arms

Assigned Interventions

Experimental: Hypofractionated WBRT with IOERT Boost

Radiation: HIOB

IOERT

IOERT is performed on mobile or fixed linacs
Reference dose: 11 Gy specified as maximum dose, with a minimum target volume dose of 90% encompassing the PTV (i.e. 10 Gy).

WBRT

must start within day 36- 56 postoperatively (week 6 - 8 p.o.) in case of adjuvant hormonal treatment (or no further tumor specific medication)
In case of adjuvant chemotherapy, a time - gap between IOERT and WBRT up to 6 months is allowed.
Single reference dose per fraction: 2,7 Gy (ICRU)
Number of fractions: 15, Number of fractions per week: 5
Total WBRT dose: 40,5 Gy

Detailed Description:

Study population:

See Points 4.1 und 4.2 Inclusion/Exclusion criteria of the entire protocol

Operation:

Lumpectomy / segmentectomy / tumorectomy with sufficient safety margins (see above). Lymph node assessment must follow a sentinel node concept.
Perioperative antibiotic prophylaxis is mandatory
After IORT, radio-opaque clips have to be fixed at the tumorbed.

Chemotherapy:

neoadjuvant: not allowed adjuvant: allowed.

There are no limitations towards special chemotherapeutic schemes and schedules.

Radiotherapy:

IOERT

IOERT is performed on mobile or fixed linacs
Reference dose: 11 Gy specified as maximum dose, with a minimum target volume dose of 90% encompassing the PTV (i.e. 10 Gy).

WBRT

must start within day 36- 56 postoperatively (week 6 - 8 p.o.) in case of adjuvant hormonal treatment (or no further tumor specific medication)
In case of adjuvant chemotherapy, a time - gap between IOERT and WBRT up to 6 months is allowed.
Single reference dose per fraction: 2,7 Gy (ICRU)
Number of fractions: 15, Number of fractions per week: 5
Total WBRT dose: 40,5 Gy

RT of regional lymphatics: exclusion criterion

Diagnostics of Local recurrence:

yearly mammographies,
optional breast sonography, MRI
LR has to be histologically confirmed

Follow-up screening for detection of metastases (minimum requirements):

Chest X-Ray,
abdominal sonography,
lab tests incl. tumor markers.

Assessment of acute toxicity of WBRT according to CTC-toxicity Scoring-systems:

Assessment of late toxicity according to LENT-SOMA scoring-systems

Assessment of cosmetic outcome according to 5-point- Scoring System (vanLimbergen) starting before WBRT, including photodocumentation in standardized positions

Eligibility

Ages Eligible for Study:	35 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histological proven invasive breast carcinoma
Age: ≥ 35 years
Tumor stage T1-2
nodal status: N0-1
Freedom of surgical margins: R0; ≥ 2 mm (both invasive and in situ component). Exception: In dorsal direction it could be below 2 mm margin if the pectoralis fascia was additional removed; also in ventral direction it could be < 2mm if skin was a part of resection and second resection is not possible.
Also multifocal disease within the same quadrant with a maximum distance of < 5 cm
all grades G1-G3
Hormonal receptor and Her-2 status: no limitations
Informed and undersigned consent

Exclusion Criteria:

In-situ Carcinoma without invasive component
Age < 35
Tumor stage T3,4
Nodal status >N1
if irradiation of regional lymphatics is required
surgical margins/ histological clearance < 2mm
Re-excision after IOERT
Immediately secondary mastectomy (not due to recurrence).
Multicentricity according to international definition: > 5 cm distance to each other
previous radiotherapy to the involved breast
Karnofsky Index < 70%
Mixed connective tissue diseases including rheumatoid Polyarthritis, Thrombangitis obliterans
Chronic pre-existent lung disease (Lungfibrosis, Pneumokoniosis, late-type Allergies like Farmer lung; Asthma bronchiale, severe Emphysema, COPD III *)
Cardiac Co-Morbidity: clinically positive coronary vessel disease, St.p. myocardial infarction, pacemakers and/or defibrillators)
neoadjuvant CT
Distant metastases
breast size (PTV) -≥ 1800 ml
missing written consent
observed pregnancy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01343459

Contacts

Contact: Felix Sedlmayer, Prof. MD	0043/662/4482/3915	f.sedlmayer@salk.at
Contact: Gerd Fastner, MD	0043/662/4482/58918	g.fastner@salk.at

Locations

Austria
Paracelsus private university; University Clinic of Radio-Oncology	Recruiting
Salzburg, Austria, 5020
Contact: Felix Sedlmayer, chairman Prof. MD 0043/662/4482/3915 f.sedlmayer@salk.at
Contact: Gerd Fastner, MD 0043/662/4482/58918 g.fastner@salk.at
Principal Investigator: Felix Sedlmayer, chairman Prof. MD

Sponsors and Collaborators

Paracelsus Medical University

LKH Klagenfurt

Poznan University of Medical Sciences

San Filippo Neri General Hospital

RWTH Aachen University

Investigators

Principal Investigator:

Felix Sedlmayer, Prof. MD

Paracelsus private university; University Clinic of Radio-Oncology, Müllnerhaupstraße 48 5020 Salzburg/Austria/Europe

More Information

Publications:

Bartelink H, Horiot JC, Poortmans P, Struikmans H, Van den Bogaert W, Barillot I, Fourquet A, Borger J, Jager J, Hoogenraad W, Collette L, Pierart M; European Organization for Research and Treatment of Cancer Radiotherapy and Breast Cancer Groups. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med. 2001 Nov 8;345(19):1378-87.

START Trialists' Group; Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, Bentzen SM, Bliss JM, Brown J, Dewar JA, Dobbs HJ, Haviland JS, Hoskin PJ, Hopwood P, Lawton PA, Magee BJ, Mills J, Morgan DA, Owen JR, Simmons S, Sumo G, Sydenham MA, Venables K, Yarnold JR. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008 Mar 29;371(9618):1098-107. Epub 2008 Mar 19.

Whelan TJ, Kim DH, Sussman J. Clinical experience using hypofractionated radiation schedules in breast cancer. Semin Radiat Oncol. 2008 Oct;18(4):257-64.

Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, Shelley W, Grimard L, Bowen J, Lukka H, Perera F, Fyles A, Schneider K, Gulavita S, Freeman C. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010 Feb 11;362(6):513-20.

Ivaldi GB, Leonardi MC, Orecchia R, Zerini D, Morra A, Galimberti V, Gatti G, Luini A, Veronesi P, Ciocca M, Sangalli C, Fodor C, Veronesi U. Preliminary results of electron intraoperative therapy boost and hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal women. Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):485-93. Epub 2008 Apr 11.

START Trialists' Group; Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, Bliss JM, Brown J, Dewar JA, Dobbs HJ, Haviland JS, Hoskin PJ, Hopwood P, Lawton PA, Magee BJ, Mills J, Morgan DA, Owen JR, Simmons S, Sumo G, Sydenham MA, Venables K, Yarnold JR. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008 Apr;9(4):331-41. Epub 2008 Mar 19.

Owen JR, Ashton A, Bliss JM, Homewood J, Harper C, Hanson J, Haviland J, Bentzen SM, Yarnold JR. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006 Jun;7(6):467-71. Erratum in: Lancet Oncol. 2006 Aug;7(8):620.

Yarnold J, Ashton A, Bliss J, Homewood J, Harper C, Hanson J, Haviland J, Bentzen S, Owen R. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol. 2005 Apr;75(1):9-17. Epub 2005 Mar 16.

Reitsamer R, Sedlmayer F, Kopp M, Kametriser G, Menzel C, Deutschmann H, Nairz O, Hitzl W, Peintinger F. The Salzburg concept of intraoperative radiotherapy for breast cancer: results and considerations. Int J Cancer. 2006 Jun 1;118(11):2882-7.

Reitsamer R, Peintinger F, Sedlmayer F, Kopp M, Menzel C, Cimpoca W, Glueck S, Rahim H, Kopp P, Deutschmann H, Merz F, Brandis M, Kogelnik H. Intraoperative radiotherapy given as a boost after breast-conserving surgery in breast cancer patients. Eur J Cancer. 2002 Aug;38(12):1607-10.

Sedlmayer F, Fastner G, Merz F, Deutschmann H, Reitsamer R, Menzel C, Ciabattoni A, Petrucci A, Hager E, Willich N, Orecchia R, Valentini V; International Society of Intraoperative Radiotherapy. IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: results of an ISIORT pooled analysis. Strahlenther Onkol. 2007 Dec;183 Spec No 2:32-4. No abstract available.

Whelan T, MacKenzie R, Julian J, Levine M, Shelley W, Grimard L, Lada B, Lukka H, Perera F, Fyles A, Laukkanen E, Gulavita S, Benk V, Szechtman B. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002 Aug 7;94(15):1143-50.

Responsible Party:	Sedlmayer, Paracelsus medical university
ClinicalTrials.gov Identifier:	NCT01343459 History of Changes
Other Study ID Numbers:	ISIORT - 01, ISIORT 01
Study First Received:	April 26, 2011
Last Updated:	April 27, 2011
Health Authority:	Austria: Ethikkommission

Keywords provided by Paracelsus Medical University:

Hypofractionated Whole breast irradiation
Hypofractionated Whole breast irradiation long term results
Breast conserving therapy

IORT with electrons in breast cancer
IOERT as anticipated Boost
IOERT and hypofractionated whole breast irradiation

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasms
Neoplasm Recurrence, Local
Recurrence
Neoplasms by Site

Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Disease Attributes

ClinicalTrials.gov processed this record on May 22, 2013

Intra-Operative Electron Boost and Hypofractionated Whole-Breast Irradiation During Breast-conserving Treatment (BCT) (HIOB)