Trial Information

Radiotherapy After Primary CHEMotherapy for cT1-2cN1M0 Breast Cancer.: a Multicentre Prospective Registration Study.

Background: Neoadjuvant chemotherapy for breast cancer patients used to be given only to
patients with locally advanced disease. Although until now no studies have been reported
that neoadjuvant chemotherapy leads to a superior survival compared to adjuvant
chemotherapy, current practice have been showing an increase in the use of neoadjuvant
chemotherapy over the last years, including for patients with earlier stage breast cancer.
The suggested advantages of this policy are 1) that neoadjuvant chemotherapy allows for
monitoring of the response on the treatment, such that the type of chemotherapy can be
modified in case of no response, and 2) that neoadjuvant chemotherapy may shrink the tumour
volume, allowing for a higher percentage of breast conserving therapy. Since the indications
for post-operative radiotherapy are based upon studies where loco-regional recurrences were
correlated to the pathological T and N stage and neoadjuvant chemotherapy is affecting the
pathological T and N stage, a major disadvantage of neoadjuvant chemotherapy is that the
indications for post-operative radiotherapy have become uncertain in these patients. This
holds also true for predictive factors for locoregional recurrence such as ngioinvasion,
grade of the tumour etc. These uncertainties may lead to over- and/or under treatment.

Objective: The primary aim of the study is to evaluate the 5 yr locoregional recurrence rate
(LRR) in cT1-2cN1(cytology/histology and/or positive SN, excluding patients with > 3
pathologic axillary nodes on ultrasound or MRI) breast cancer patients, treated with
neo-adjuvant chemotherapy, breast surgery, and radiotherapy that is protocolised based on
the pathology findings after chemotherapy and definitive surgery (ypTNM stage). The
secondary aim is to develop a risk model based on risk factors, that can be used to predict
which of the patients with a cT1-2cN1 breast carcinoma, treated with neoadjuvant
chemotherapy and surgery, have a 5 yr LRR > 8 % if radiotherapy is withheld. Study design:
This study is a multicentre prospective cohort study.

Study population: In total 710 patients with cT1-2pN+, excluding ≥cN2 and patients with > 3
pathologic axillary nodes on ultrasound or MRI) breast cancer, treated with at least three
cycles of chemotherapy followed by breast and axillary surgery are eligible for the study.

During 5 years (2011-2015) patients diagnosed for primary breast cancer and eligible
according to the criteria will be registered by the National Cancer Registry in this
project. Radiotherapy will be given based on the post-operative pathological T and N status
(ypTN-stage):

- Group I: ypT0-2N0 (N = 237)

- no after MRM: no radiotherapy

- after BCT: radiation treatment of the breast with boost

- Group II: ypT0-2N1 (N = 237):

- after MRM: radiation treatment of the thoracic wall

- after BCT: radiation treatment of the breast with boost

- Group III: ypT0-2N2-3, ypT3-4N0-1, and ypT3-4N0-3 (N = 237):

- after MRM: radiation treatment of the thoracic wall and supraclavicular nodes

- after BCT: radiation treatment of the breast with boost, and supraclavicular nodes

RT of the axillary and internal mammary chain nodes is optional for group III, based on the
local protocol. In case of a positive sentinel node in the internal mammary chain prior to
chemotherapy, internal mammary chain irradiation is strongly recommended.

Main study parameters/endpoints:

The primary endpoint is the 5 yr locoregional recurrence rate (LRR). Secondary endpoints are
10 year LRR, and 5, 10, and 15 yr overall survival rates. In addition, analyses will be
performed to investigate whether preradiotherapy factors (e.g. like age < 40 yr, response to
chemotherapy, tumor size) can be identified that correlate with a high LRR.

Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: Currently no clear data are present in literature showing the indications for
radiotherapy in this patient group. Based on literature that is available for patients
treated with chemotherapy after surgery we have chosen what we think might be the optimal
treatment from a benefit/risk perspective. The study focuses on adequate registration of all
risk factors, treatment, and outcome.