Home For Patients Outline Centers Links Login
   
 

EUROPEAN BRACHYTHERAPY BREAST CANCER
GEC-ESTRO WORKING GROUP

PHASE III MULTICENTER TRIAL

INTERSTITIAL BRACHYTHERAPY ALONE VERSUS EXTERNAL BEAM RADIATION THERAPY AFTER BREAST CONSERVING SURGERY FOR LOW RISK INVASIVE CARCINOMA AND LOW RISK DUCT CARCINOMA IN-SITU (DCIS) OF THE FEMALE BREAST

 
Study chairmen: V. Strnad (Erlangen)
C. Polgár (Budapest)
Study coordinator: O.J. Ott (Erlangen)
Responsible Physicists: T. Major (Budapest)
M. Lotter (Erlangen)
Randomisation and
Monitoring:

W. Uter (Erlangen)
O. Gefeller (Erlangen)
Institute for Medical Informatics, Biometry and Epidemiology
University Erlangen-Nuremberg
Tel.: +49 9131 8522720
Fax: +49 9131 8522721
Email: apbi.study -at -imbe.med.uni-erlangen.de

Rationale

Accelerated partial breast irradiation (APBI) leads to a equivalent local control rate with lower toxicity as external beam irradiation (EBI) after breast conserving surgery (BCS) in a highly selected subgroup of patients with low risk invasive carcinoma and low risk duct carcinoma in-situ (DCIS).

End Points

Primary objective

To assess the role of brachytherapy alone compared to whole breast irradiation in a defined low-risk group of invasive breast cancer or ductal carcinoma in situ concerning local failure (all ipsilateral local recurrences) to affirm the hypothesis that local control rates in each arm are equivalent.
Secondary objectives
  • To assess incidence and severity of acute and late side effects of brachytherapy alone compared to whole breast irradiation.
  • To assess the differences in cosmetic results of brachytherapy alone compared to whole breast irradiation.
  • To assess distant metastases free survival (DMFS).
  • To assess survival rates (Overall Survival: OS, Disease-free Survival: DFS).
  • To assess the contralateral breast cancer rate.
  • To assess QoL (Quality-of-Life) of patients treated with BT alone compared with WBRT.
End Criteria
Inclusion criteria
  • Stage 0, I or II breast cancer.
  • Invasive ductal, papillary, mucinous, tubular, medullary or lobular carcinoma.
  • Ductal carcinoma in situ (DCIS) alone.
  • No lymph invasion (L0) and no hemangiosis (V0).
  • Lesions of <= 3 cm diameter, histopathologically assured.
  • pN0/pNmi (a minimum of 6 nodes in specimen, or a negative sentinel node is acceptable); in the case of DCIS alone axillary staging (e.g. sentinel lymph node biopsy ) is optional.
  • M0.
  • Clear resection margins at least 2 mm in any direction; by lobular histology or DCIS histology only the resection margins must be clear at least 5 mm.
  • For DCIS only: lesions must be classified as low or intermediate risk group (Van Nuys Prognostic Index <8, see Appendix XIV).
  • Unifocal and unicentric DCIS or breast cancer.
  • Age >= 40 years.
  • Time interval from final definitive breast surgical procedure to the start of external beam therapy or to brachytherapy is less than 12 weeks (84 days). If patients receive chemotherapy the radiotherapy can be started before systemic treatment (within 12 weeks). The radiation therapy can be also given in the interval between the chemotherapy courses. It is also possible to start radiation therapy after chemotherapy is completed according local protocols as soon as possible within 4 weeks after chemotherapy.
  • Signed study-specific consent form prior to randomization.
Exclusion criteria
  • Stage III or IV breast cancer.
  • Surgical margins that cannot be microscopically assessed.
  • Extensive intraductal component (EIC).
  • Paget's disease or pathological skin involvement.
  • Synchronous or previous breast cancer.
  • Prior malignancy (<= 5 years prior to enrollment in study) except non-melanoma skin cancer or cervical carcinoma FIGO 0 and I if patient is continuously disease-free.
  • Pregnant or lactating women.
  • Collagen vascular disease.
  • The presence of congenital diseases with increased radiation sensitivity, for example Ataxia telangiectatica or similar.
  • Psychiatric disorders.
  • Patient with breast deemed technically unsatisfactory for brachytherapy.
Projected accrual
Based on the assumed scenario 530 patients per group are required in the final analysis. To account for dropout (non-valid cases) estimated to be 10%, altogether 1170 patients should be recruited for the study.
Outline
The comparative therapeutic study is designed as a prospective, randomized, multicentric phase III-trial. The primary outcome is local recurrence. Randomization of patients will be stratified (balanced) with respect to center, invasive vs. non-invasive disease, and pre- vs. post-menopausal status.
Patients are randomized to one of two treatment arms:
Arm I (Standard treatment): Whole breast radiotherapy (WBRT)
Arm II (Investigational Treatment): Accelerated partial breast irradiation (APBI)
Treatment Modalities

Accelerated partial breast irradiation (APBI)

The target volume of the brachytherapy arm consists of the tumor bed with a safety margin of 2-3 cm in all directions. Minimal distance between implant and underlying ribs should be >= 5 mm and between implant and skin >= 5-7 mm to protect the skin from teleangiectasia. The volume enclosed by the reference isodose surface (calculated analogue Paris-System, see protocol for details) depends on the tumor size and on the size of the resection margins (size of the PTV) - mostly about 40-150 cm³. A volume over 150 cm³ should be exceeded only in justified cases. The dose distribution is seen as sufficiently homogeneous, if the DNR is < 0.35 (preferably < 0.30).

Following dose concepts are recommended (Dref):
HDR:
32.0 Gy/8 fractions (8 x 4 Gy, 2 x daily) or
30.3 Gy/7 fractions (7 x 4.3 Gy, 2 x daily)
PDR:
0.60 - 0.80 Gy/hour to 50 Gy (1 pulse/hour, 24 hours/day)

Notice: The dose distribution is seen as sufficiently homogeneous, if the DNR is < 0.35 (preferably < 0.30).

Whole breast radiotherapy (WBRT)

All patients randomized to the external radiation treatment arm shall receive a total dose of 50.4 Gy to the entire breast in 1.8 Gy fractions x 28 fractions and afterwards a dose of 10 Gy in 2 Gy fractions x 5 fractions to the tumor bed as boost with appropriate electron beam, OR a total dose of 50.0 Gy in 2 Gy fractions x 25 fractions and afterwards a dose of 10 Gy in 2 Gy fractions x 5 fractions to the tumor bed as boost with appropriate electron beam.

Radiation treatment will be delivered in uniform daily doses through standard tangent photon and electron boost fields from Monday to Friday for 6-7 weeks.

Notice: In the WBRT-arm interstitial brachytherapy boost is not allowed.

Treatment Schedule
Time interval from final definitive breast surgical procedure to the start of external beam therapy or to brachytherapy is less than 12 weeks (84 days). If patients receive chemotherapy the radiotherapy can be started before systemic treatment (within 12 weeks). The radiation therapy can be also given in the interval between the chemotherapy courses. It is also possible to start radiation therapy after chemotherapy is completed according local protocols as soon as possible within 4 weeks after chemotherapy.
Follow-up
Patients are followed as shown in the table below: