Protocollo di studio: ipam-0

Version 6.12.2009
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, R D'AMICO
DATA CENTER OFFICE
Clinical Trials Office, Department of Oncology, Hematology and Pulmonary
Diseases.
Polyclinic Hospital, University of Modena and Reggio Emilia
R. D'Amico, C. Del Giovane, R. Vicini
Tel. +39 059 4223865
roberto.vicini@unimore.it
COORDINATING CENTER:
Oncological Radiotherapy Operative Unit - Data Center Office, Clinical Trials
Office, Integrated Department of Oncology, Hematology and Pulmonary
Disease, Modena University Hospital.
MEMBERS OF THE STEERING COMMITTEE, THE SCIENTIFIC COMMITTEE AND THE
MONITORING COMMITTEE
Steering Committee:
G. Frezza
A.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
Independent Data Monitoring Committee:
B. Gal o and
←V. Torri←R. Fossati←R. Orecchia←M. Valli OUTLINE AND SYNOPSIS
SURGERY
Conservative surgery (including large breast resection and lumpectomy + biopsy of
the sentinel lymph node and/or axillary dissection).
←EVALUATION OF ELIGIBILITY CRITERIA (Chapter 4)
RECRUITMENT AND INFORMED CONSENT (Appendix II)
STRATIFICATION for: 1) size of T; 2) lymph nodes (N0 and N1); and 3)
chemotherapy (Yes, No).
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, or isoeffective fraction schemes, once a day for 5 days a week. A
10 - 16 Gy boost is allowed in centers where it is part of the standard
treatment.
←MEDICAL TREATMENT
←In patients who have not been previously treated with chemotherapy the
radiotherapy must begin within 12 weeks from surgery. Whereas, for those who
have been treated with chemotherapy the radiotherapy must start at least 2
weeks after the last chemotherapy cycle and no longer than 5 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 within the Emilia Romagna Research and
Innovation Program (PRI ER). The study does not have any commercial sponsor. It is
considered an independent study according to the Ministerial Decree 17.12.2005. The PRI
ER program guarantees a contribution to the study for the first three years of recruitment
through the Regional Innovation Fund, which wil cover the costs of coordination and data
management sustained by the Coordinating Center.
Primary Objectives
The main aim of the study is 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 undergoing conservative surgery, is not inferior to postoperative
irradiation with conventional fractionation of the entire breast as regards local control,
measured in terms of incidence of ipsilateral recurrences as first event.
Secondary Objectives
To compare the two methods of irradiation in terms of:
a) overall survival;
b) locoregional recurrence free survival (with exception of contralateral tumors and second
c) distant relapse-free survival (except for local or regional relapses or in the contralateral d) cosmetic results;e) acute toxicity.
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) will also be carried out.
Possible connection with other national and international studies
Similar studies are currently underway, however they evaluate different methods of partial
irradiation.
Study Design
Multicenter, unblinded phase III, non-inferiority randomized controlled trial.
Number of centers and cases
At the moment 22 radiotherapy centers are participating 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, histological y negative
resection margins (≥ 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 follow-up period of 5 years for an overall
duration of the study of 8 years.
Eligibility criteria (inclusion)
.Histologically confirmed invasive breast cancer.pT 1-2 (< 3 cm in diameter) pN0-N1 M0 according to TNM classification.Unifocal disease (confirmed radiologically and histological y).Eligible histotypes: al except for non-epithelial histotypes (lymphoma, sarcoma).Hormonal receptor status: indifferent.Patients undergoing conservative breast surgery for neoplasms with a diameter < 3 cm and with biopsy of the sentinel lymph node or first instance axillary dissection.Breast resection margins histological y negative (≥ 2 mm) at first intervention or after subsequent widening.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 surgery.Positioning of 3-6 metallic clips, or in any case of an appropriate number to delineate the area of surgical exeresis (tumor bed).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.
.No chemotherapy must be carried out during or at least two weeks after completion of the radiotherapy.Treatment with tamoxifen or aromatase inhibitors is allowed at the same time.Age ≥ 49.Gender: female.Menopause status: unspecified.Performance status: 0-2 according to ECOG.Life expectation: at least five years.INFORMED consent: yes.Non-hormonal contraception in patients of childbearing age.Patients technically eligible for radiotherapy (see paragraph 7.2) Exclusion criteria
.In situ carcinoma (CLIS and DCIS ).Non-epithelial breast neoplasms (sarcoma, lymphoma etc.).Micro/macrometastases in > 3 axillary lymph nodes; micro/macrometastases in the internal mammary and/or supraclavicular or subclavicular lymph nodes.Multicentric carcinomas (lesions in different quadrants of the breast or in the same quadrant but separated by at least 4 cm) or clinical y or radiologically suspected lesions in the ipsilateral breast, unless their tumoral nature was excluded through biopsy or fine needle sample.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).Treatments for previous contralateral or ipsilateral breast cancers.Paget's disease of the nipple.Cutaneous involvement, independently of the tumor diameter.Distant metastases.Previous radiotherapy on the thoracic region.Previous neoadjuvant chemotherapy.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 will be randomized to receive one of the following 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 45 Gy/18 fractions, or 50 Gy/25 fractions, or 50,4 Gy/28 fractions, or
iso-effective fraction schemes, once a day for 5 days a week. A 10 - 16 Gy
boost is al owed in centers where it is part of the standard treatment.
Endpoints
Primary: local ipsilateral recurrence as first event free survival
Secondary: overall survival, locoregional recurrence-free survival, distant
recurrence-free survival, acute and late toxicity (RTOG) and cosmetic result.
Evaluation and Follow-Up Program
Clinical examinations are scheduled as follows: at the end of treatment, at 6 weeks, at 3 -
6 - 12 months from the end of the radiotherapy and then once a year until the end of the
fifth year.
Data Analysis
Partial irradiation will be considered not inferior to the standard irradiation if the upper
bound of the one-sided HR 95% confidence interval does not exceed the established value
of 1.5
The study was sized assuming that the percentage of local ipsilateral breast recurrences
as first event at 5 years in the control arm is equal to 4% and setting error α and β equal
respectively to 0.05 and 0.10.
The Kaplan-Meier method wil be used to estimate the survival rates. The hazard ratio (HR), estimated by using the Cox model, will be reported as wel as its one-sided 95% confidence interval.
The independent data monitoring committee (IDMC) will periodically receive reports about patient accrual rate, number of patients, events observed and toxicity.
If necessary, the IDMC will consider the possibility of an early suspension of the study.
Ethical Aspects and Informed Consent
Before entry onto the study, each patient wil be informed about the investigational nature
of the study, and a written informed consent, which has to have been previously approved
by the institutional ethics committee, will be obtained.
The study wil be carried out according to the ethical principles of the Helsinki Declaration
and the GCP guidelines.

Source: https://servertrial.unimo.it/irma/files/synopsis_trial_IRMA_december_2009.pdf