Title:

HIOB - Hypofractionated Whole-Breast Irradiation preceded by Intraoperative 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 Intraoperative 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 multicenter 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

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 tumor bed.

Histology: R0-Resection is mandatory

Chemotherapy:

neoadjuvant: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 9 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, optional
• abdominal sonography, optional
• lab tests incl. tumor markers, optional

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 photo documentation in standardized positions

Inclusion Criteria:

• Histological proven invasive breast carcinoma
• Age: ≥ 35 years
• Tumor stage T1-2
• nodal status: N0-1
• Freedom of surgical margins: R0 (both invasive and in situ component), that means no ink on tumors (invasive or in situ) (ago-online.de) .
• 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
• R1
• 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 (Lung fibrosis, 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)
• Distant metastases
• breast size (PTV) > 2500 ml
• missing written consent
• observed pregnancy