Protocollo di studio: ipam-0

Version 30.07.2008
STUDY PROTOCOL
BREAST CANCER WITH LOW RISK OF LOCAL RECURRENCE: PARTIAL AND
ACCELERATED RADIATION WITH THREE-DIMENSIONAL CONFORMAL
RADIOTHERAPY (3DCRT) VS. STANDARD RADIOTHERAPY AFTER CONSERVING
SURGERY (PHASE III STUDY)
PROPOSING OPERATIVE UNITS: RADIOTHERAPY OPERATIVE UNITS OF ANCONA,
BOLOGNA AOSP (HOSPITAL), BOLOGNA AUSL (LOCAL HEALTH UNIT), FERRARA,
FORLÌ, MODENA, PARMA, PIACENZA, RAVENNA, REGGIO EMILIA, RIMINI
INVESTIGATORS: L. ARMAROLI, E. BARBIERI, F. BERTONI, L. BUSUTTI, M.
CARDINALI, F. CARTEI, E. EMILIANI , G. FREZZA, M. FUMAGALLI , M. GIANNINI, F.
PERINI, M. VANZO
PROTOCOL AUTHORS : G.FREZZA, F.BERTONI
DATA CENTER OFFICE
Clinical Trials Office, Integrated Department of Oncology and Hematology,
Polyclinic Hospital, University of Modena and Reggio Emilia
R. D’Amico, G. Jovic, R. Vicini
Tel. 059 4223865
[email protected]
COORDINATING CENTER:
Oncological Radiotherapy Operative Unit - Clinical Trials Office, Integrated
Department of Oncology and Hematology, Modena University Hospital.
MEMBERS OF THE STEERING COMMITTEE, THE SCIENTIFIC COMMITTEE AND THE
MONITORING COMMITTEE
Steering Committee:
G. Frezza
Α.MartoniM. TaffurelliR. D’AmicoM. PajuscoP. ChiovatiV. Eusebi Scientific Committee:
L. Armaroli
E. Barbieri
F. Bertoni
L. Busutti
M. Cardinali
F. Cartei
E. Emiliani
G. Frezza
M. Fumagalli
M. Giannini
F. Perini
M.Vanzo
A. Liberati
D. Amadori
G. Natalini
Monitoring Committee:
B. Gallo and
OUTLINE AND SYNOPSIS
SURGERY
Conservative surgery (including large breast resection and lumpectomy + biopsy of
the sentinel lymph node and/or axil ary dissection)
EVALUATION OF ELIGIBILITY CRITERIA (Chapter 4)
RECRUITMENT AND INFORMED CONSENT (Appendix II)
STRATIFICATION for T and N
RANDOMIZATION (Chapter 10)
TREATMENT
RADIOTHERAPY:
•Trial arm 38.5 Gy total in 10 fractions (3.85 Gy per fraction), twice a day
with an interval of at least 6 hours between the two fractions, for five
consecutive working days.
• Control arm 45 Gy/18 fractions, or 50 Gy/25 fractions, or 50,4 Gy/28
fractions , 1 fraction/day, 5 fractions/week +/- 10 – 16 Gy boost in 5-8
fractions, according to the institutional policy of each participating center.
MEDICAL TREATMENT
For patients treated with chemotherapy the radiotherapy must start at least two weeks after the last chemotherapy cycle and no longer than five weeks after the end of chemotherapy. Hormonal therapy (tamoxifen, aromatase inhibitors) can be administered at the same time as the radiotherapy.
FOLLOW-UP
SYNOPSIS OF THE STUDY
Title of the Protocol
IRMA study protocol: breast cancer with low risk of local recurrence: Partial and
accelerated irradiation with three-dimensional conformal radiotherapy (3dcrt) vs. standard
radiotherapy after conserving surgery (phase III study)
Study Sponsor
This study was designed and developed in the Emilia Romagna research and innovation
program (PRI ER). The study does not have commercial sponsors and comes under the
independent studies provided for by Ministerial Decree 17.12.2005. The PRI ER program
wil guarantee a contribution to the study for the first three years of recruitment through the
regional Innovation Fund, to cover the costs of coordination and data management
sustained by the Coordinating Center.
Primary Objectives
The study proposes to evaluate whether partial hypofractionated and accelerated
irradiation of the sole surgical cavity, in patients suffering from breast cancer with low risk
of local recurrence and who undergo conservative surgery, is not inferior to postoperative
irradiation with conventional fractionation of the entire breast as regards local control
(incidence of ipsilateral recurrences as prime event).
Secondary Objectives
Comparison of the global survivals, freedom from locoregional recurrences (with exception
for contralateral tumors and second tumors), distant relapse-free (except for local or
regional relapses or in the contralateral breast) in patients treated with conventional
radiotherapy and accelerated partial radiation.
To evaluate whether accelerated partial irradiation offers cosmetic results, acute toxicity
comparable with conventional irradiation.
The study also provides for the initiation of two subsidiary projects concerning the
economic and organizational impact of the treatment and its influence on the quality of life
and psychosocial sphere of the patient (see subsidiary projects).
Possible connection with other national and international studies
Similar studies which nonetheless evaluate different methods of partial irradiation are
currently underway.
Study Design
Multicenter phase III controlled randomized, unblinded study of non-inferiority.
Number of centers and cases
14 Italian radiotherapy centers are participating in the study and recruitment of 3302
patients is planned.
Target Population of the Study
Women aged = > 49, ECOG 0-2, undergoing conservative breast surgery for invasive breast cancer, pT 1-2 (< 3 cm in diameter) pN0-N1 M0, unifocal, resection margins histological y negative (≥ 2 mm) at first intervention or after subsequent widening.
Duration of the recruitment and of the subsequent follow-up
A recruitment of 3 years is planned and a fol ow-up period of 5 years for an overall
duration of the study of 8 years.
Eligibility criteria (inclusion)
Β.Histologically confirmed invasive breast cancerΧ.pT 1-2 (< 3 cm in diameter) pN0-N1 M0 according to TNM classification. ∆.Unifocal disease (confirmed radiologically and histological y) Ε.Eligible histotypes: all except for non-epithelial histotypes (lymphoma, sarcoma) Φ.Hormonal receptor status: indifferent Γ.Patients undergoing conservative breast surgery for neoplasms with a diameter < 3 cm and with biopsy of the sentinel lymph node or first instance axil ary dissection. Η.Breast resection margins histological y negative (≥ 2 mm) at first intervention or after subsequent wideningΙ.Radiological examination of the surgical specimen to assess the excision of the hidden lesions and/or the microcalcifications if present in the mammography carried out before surgeryϑ.Positioning of 3-6 metallic clips, or in any case of an appropriate number to delineate the area of surgical exeresis (tumor bed)Κ.At least two weeks must have elapsed from the end of the chemotherapy if this is administered before the radiotherapy. In patients who do not receive chemotherapy, radiotherapy should start < 12 weeks after surgery.
Λ.No chemotherapy must be carried out during or at least two weeks after completion of the radiotherapyΜ.Treatment with tamoxifen or aromatase inhibitors is al owed at the same timeΝ.Age ≥ 49 Ο.Gender: femaleΠ.Menopause status: unspecifiedΘ.Performance status: 0-2 according to ECOGΡ.Life expectation: at least five years Σ.INFORMED consent: yes •Non-hormonal contraception in patients of childbearing age •Patients technically eligible for radiotherapy (see paragraph 7.2) Exclusion criteria
Τ.In situ carcinoma (CLIS and DCIS ) Υ.Non-epithelial breast neoplasms (sarcoma, lymphoma etc.)ς.Micro/macrometastases in > 3 axillary lymph nodes; micro/macrometastases in the internal mammary and/or supraclavicular or subclavicular lymph nodesΩ.Multicentric carcinomas (lesions in different quadrants of the breast or in the same quadrant but separated by at least 4 cm) or clinically or radiological y suspected lesions in the ipsilateral breast, unless their tumoral nature was excluded through biopsy or fine needle sample. Ξ.Palpable radiologically suspected ipsilateral or contralateral axillary, supraclavicular or infraclavicular, internal mammary nodes ( unless their tumoral nature was excluded through biopsy or fine needle sample) Ψ.Treatments for previous contralateral or ipsilateral breast cancersΖ.Paget's disease of the nippleΑΑ.Cutaneous involvement, independently of the tumor diameterΒΒ.Distant metastases •Previous radiotherapy on the thoracic region •Collagen diseases (systemic erythematosus lupus, scleroderma, dermatomiositis) •Other pathological conditions that limit life expectancy to < 5 years •Psychiatric diseases or disorders of other nature that prevent signing of informed consent for the treatment•Other neoplasms in the last 5 years with the exception of skin tumors apart from melanoma and squamous intraepithelial lesions (SIL) of the uterine cervix•Pregnancy and breast-feeding Treatment
The patients wil be randomized to receive one of the fol owing treatments:
Trial arm 38.5 Gy total in 10 fractions (3.85 Gy per fraction), twice a day with an interval of
at least 6 hours between the two fractions, for five consecutive working days.
Control arm 50.0 Gy in 25 fractions (2 Gy per fraction), once a day for 5 days in the week.
Endpoints
Primary: survival free of local ipsilateral recurrence as prime event
Secondary: global survival, locoregional recurrence-free, distant recurrence-free, acute
and late toxicity (RTOG) and cosmetic result
Evaluation and Follow-Up Program
Controls are planned during the radiotherapy, at the end of treatment, at 6 weeks, 3-6-12
months from the end of the radiotherapy and then once a year until the end of 5 years.
Data Analysis
Partial irradiation wil be considered not inferior to the standard irradiation if the top extreme of the HR confidence interval at 95% (to endpoint) does not exceed the established value of 1.5The study was sized in relation to the rate of local ipsilateral breast recurrences as prime event at 5 years and assuming that this rate in the standard treatment group is 4%, accepting as maximum Hazard Ratio inferior to 1.5 and error α and β equal respectively to 0.05 and 0.10 and test at an endpoint.
The survivals will be calculated using the Kaplan-Meier method. The hazard ratio (HR) will be calculated using the Cox model and its confidence interval at 95% wil be reported.
An independent committee is planned (monitoring committee) for control of the data and the relative scientific evaluations. It wil meet periodically. The committee made up of independent members will receive periodic reports from the data center and will send its comments and recommendations to the study steering committee and scientific committee.
The monitoring committee wil determine based on the interim analyses concerning the events observed both in relation to the primary and secondary endpoints the early suspension of the study if necessary.
Ethical Aspects and Informed Consent
For participation in the study an informed consent is planned appropriately drawn up and
submitted to the approval of the Ethics Committees.
The clinical study wil be carried out according to the ethical principles of the Helsinki
Declaration, the GCP guidelines, the Italian laws and regulatory activities for carrying out
clinical studies.
Before formal commencement of the study its approval/sole opinion by the reference
Ethics Committee of the proposing group is stipulated. The individual investigators of the
different participating institutions are directly responsible for the submission for approval of
the protocol by their Ethics Committees.

Source: http://www.irmatrial.it/files/synopsis_trial_IRMA.pdf