Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03783364 |
| Other study ID # |
EC /2018/0996 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 17, 2018 |
| Est. completion date |
November 19, 2021 |
Study information
| Verified date |
January 2023 |
| Source |
University Hospital, Ghent |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
20 non-metastasized breast cancer patients receiving neoadjuvant chemotherapy will be
randomized between preop or postop RT. Patients with clinically suspicious axillary lymph
nodes will receive a fine needle biopsy. Patients receiving postop RT will receive
neoadjuvant CT followed by surgery (21-28 days after CT) and adjuvant RT starting 28-35 days
after surgery. Patients receiving preop RT will receive RT first, followed by CT (5-8 days
after the end of RT) and surgery (21-28 days after CT). All patients will receive a clip to
locate the tumor before the start of any treatment.
Description:
In early-stage breast cancer the cornerstone of treatment is surgery. There are 2
possibilities: either mastectomy (ME, the whole breast, including the tumour, is removed) or
breast-conserving surgery (BCS, only the tumour is removed, along with a part of the
surrounding healthy tissue). After surgery, most patients also receive some kind of adjuvant
systemic therapy like hormone therapy, chemotherapy (CT), targeted therapy or a combination
of these. After BCS, adjuvant radiotherapy (RT) has shown to improve locoregional control and
overall survival rates. After ME, a benefit of adjuvant RT was observed only in node positive
patients. In recent years, adjuvant or postoperative (postop) CT is more and more replaced by
preoperative (preop) or neo-adjuvant CT in patients with large tumours since the need for
mastectomy may then be significantly decreased. Several randomized controlled trials
demonstrated that there is no difference in overall survival whether CT is given pre- or
postoperatively.
The use of breast RT in the neo-adjuvant setting is far less common. It has been proposed for
patients with inoperable or inflammatory breast cancer and a recent retrospective study in
breast cancer patients showed preop RT might improve disease free survival compared to postop
RT. In another retrospective study comparing neoadjuvant versus adjuvant radio- and
chemotherapy a possible benefit of neoadjuvant treatment was suggested for tumours larger
than 2 cm. These benefits have also been observed in other cancer sites. There is evidence
from randomized trials that preop RT is more effective than postop RT in patients with rectal
carcinoma. For soft tissue sarcoma, better local control rates have been described with preop
than with postop RT. From a radiobiological point of view, the benefits of giving RT
preoperatively are not surprising. In contrast to the postop setting, the vasculature is
still intact and less radioresistant tumour clones are present, both possibly increasing
radiosensitivity. But there are other advantages of preop RT treatment. On the postop imaging
used for RT planning, the localisation of the initial tumor is challenging, even with the aid
of surgical clips. This is especially the case in patients receiving chemotherapy which is
typically given before RT, thus increasing the interval between surgery and radiotherapy to
about 6 months. In this 6-month period, tissue distortion and seroma, which are useful to
guide the radiation oncologist when delineating the target volume for boost irradiation, have
often disappeared. In the postop setting, larger volumes are delineated and interobserver
variability is larger than in the preop setting. Preop breast irradiation has the advantage
that the tumour is still in place and easy to locate. Zones of higher doses can be better
targeted. For the latter reason, less acute side effects and a better overall breast cosmesis
is expected. There is also a possibility of downsizing the tumour which might lead to a lower
need for mastectomy. While preop breast RT clearly has some advantages, there are some
obstacles that complicate its introduction into daily practice. One of these is the fear of
delaying surgery and/or chemotherapy for too long. At Ghent University, investigators have
experience with a 5-fraction RT schedule allowing preop RT delivery in a very short time
span. Large randomized trials confirm that moderate hypofractionation schemes in 15 or 16
fractions are at least equivalent in tumor control and toxicity although the total dose is
lower than the traditional 50 Gy in 25 fractions. Further acceleration to 5 fractions is
expected to have an even greater radiobiological advantage concerning tumor control. In the
UK FAST randomized trial, a schedule of 5 times 5.7 Gy, once a week, was compared to a
normofractionation schedule of 25 times 2 Gy. Tumor control and toxicity were comparable
after 3 years of follow-up. At Ghent University Hospital (UZ Gent) a feasibility trial was
started using the FAST scheme (5 x 5.7 Gy) over 12 days (instead of 5 weeks) in patients of
65 years or older. Additionally, patients requiring a boost received a simultaneously
integrated boost to the tumor bed of 5 x 6.5 Gy. The final analysis on 95 patients shows <10%
grade 2-3 erythema, with only one case of moist desquamation, located at a skin fold(10).
With this RT schedule of 5 fractions in 12 days given preoperatively, the investigators
hypothesize that overall treatment time will not be increased.
The 3 main objectives of this project are: 1 - to prove the feasibility of preop breast RT in
5 fractions in patients also receiving neoadjuvant CT; 2 - to identify the involved cell
death mechanisms and the effect of preop breast RT on the in-situ immune micro-environment;
and 3 - to identify the markers that predict for response and toxicity.
Classically, radiotherapy is considered to mediate its effects via the direct killing of
cancer cells. It is now known that radiotherapy can induce systemic effects resulting in
tumour responses outside the irradiated regions. This phenomenon called the "abscopal"-effect
has been reported in breast and several kinds of malignancies and is nowadays considered to
be immune mediated. The hypothesis is that radiotherapy induces immunogenic cell death (ICD)
through the release of tumour-associated antigens and damage associated molecular patterns
(DAMPs), which leads to antigen uptake and dendritic cell maturation, resulting in the
priming and clonal expansion of cytotoxic T-lymphocytes (CTLs) in the lymph nodes. These CTLs
then travel back to the tumour, becoming tumour-infiltrating lymphocytes (TILs). Radiation
could increase these TILs in a clinical setting and, more importantly, a high level of
(post-therapy) TILs is associated with a good prognosis. Immunogenic cell death implicates
the release of DAMPs and tumoral antigens through a disintegrated cell plasma membrane. The
latter correlates with necrosis (regulated or secondary) instead of apoptosis, which was
considered to be the principal mechanism of radiation induced cell death for years. Distinct
cell death modalities may thus have a different (immunogenic) outcome. In this project the
investigators would like to determine the mode of cell death evoked by high-dose
pre-operative RT through measurement by immunohistochemistry (IHC) of cell death markers on
pre-treatment, post-RT (only in case of pre-operative RT) as well as tumorectomy tissue
samples. The investigators will correlate the results of the IHC stainings for cell death
markers with the presence (or increase) of tumour infiltrating lymphocytes (TILs) in the same
tissue samples and response to treatment. The number of TILs before and after radiotherapy
will be assessed according to international guidelines.
Extracellular vesicles (EVs), such as exosomes (50-150 nm) are composed of a lipid bilayer
that contains transmembrane proteins (such as receptors and adhesion molecules) derived from
the donor cell and encloses soluble hydrophilic components derived from the cytosol of the
donor cell such as signaling molecules, and nucleic acids (small RNAs such as miRNA).
Different cell types can release EVs, including immune cells (monocytes, neutrophils, etc.),
tumour cells, fibroblasts and adipocytes (fat cells). EVs are promising novel biomarkers
because: 1) their molecular content is a fingerprint of the releasing cells and their status
and consists of proteins, lipids, and nucleic acids, 2) they are released in easily
accessible body fluids including blood and 3) they are enriched for highly selected
biomarkers which otherwise would constitute only a very small proportion (less than 0.01%) of
the total molecular content of blood. Analysis of Glypican-1 positive EVs in circulation
distinguishes with absolute specificity and sensitivity healthy subjects and patients with a
benign pancreatic disease from patients with early- and late-stage pancreatic cancer. EV
transfer from stromal to breast cancer cells regulates therapy resistance pathways. miRNA
levels in circulating EVs identify remnant vital tumour tissue and are suitable to measure
therapy response and relapse monitoring. These pioneering studies suggest that quantification
and characterization of EVs can be implemented to predict therapy response.
20 non-metastasized female breast cancer patients receiving neoadjuvant chemotherapy (CT)
will be randomized between preop or postop RT. For each patient, a biopsy with tumor
histology, histological grade, ER/PR status, Her2/Neu status (amplification or not) and Ki67
status will be available. Menopausal status will be assessed before the start of treatment.
Patients with regular menses will be considered premenopausal. Patients > 50 years old with >
1 year of amenorrhea will be considered postmenopausal. In all other patients or patients
with an intrauterine device or hysterectomy, plasma levels of LH, FSH and estradiol will be
measured and documented.
Patients with clinically suspicious axillary lymph nodes will receive a fine needle biopsy.
If lymph node involvement is confirmed by fine needle biopsy, they will receive an axillary
clearance after neoadjuvant treatment and axillary RT will be performed (either preop or
postop). In clinically node negative patients with a tumour of ≤ 5 cm, a sentinel node biopsy
will be performed before the start of RT or CT. Patients with a tumour of > 5 cm, clinically
node negative, will receive axillary clearance and axillary RT since a sentinel node biopsy
is unreliable in these large tumours. Patients receiving postop RT will receive neoadjuvant
CT followed by surgery (21-28 days after CT) and adjuvant RT starting 28-35 days after
surgery. Patients receiving preop RT will receive RT first, followed by CT (5-8 days after
the end of RT) and surgery (21-28 days after CT). All patients will receive a clip to locate
the tumor before the start of any treatment.
The feasibility of preop RT will be evaluated based on overall treatment time. From a
clinical point of view, it is not warranted that preop RT leads to an increase in the overall
treatment time, since this may compromise locoregional control and survival. However, it is
expected that preop RT will shorten the overall treatment time with about 14 days (SD 9 days)
since the interval between RT and CT is shortened considerably. A difference of less than 14
days is not considered clinically relevant. With 20 patients (10 patients in every treatment
arm), a 14 days' difference in overall treatment time can be detected with a power of > 90%
(2-sided t-test, α = 0.05).
