Breast reconstruction and neoadjuvant radiotherapy, a changing algorithm.

Treatment of patients with breast cancer requires a multimodality approach with
often systemic therapy, radiotherapy (RT) and surgery. Postmastectomy
radiotherapy (PMRT) reduces locoregional recurrences and improves survival,
especially in patients with involved axillary nodes. However, PMRT is known to
substantially increase the complication rate when combined with a breast
reconstruction. Breast reconstructions can be performed within the same surgery
as the mastectomy (i.e. immediate) or in a later stage where patients remain
without a breast contour for several months to years before the reconstruction
is completed (i.e. delayed).
In the Netherlands, most patients are being withheld an immediate breast
reconstruction if there is the slightest risk of PMRT, because PMRT in
combination with immediate breast reconstruction is associated with a severe
increase in postoperative complications, especially in case of an implant-based
reconstruction: complication rates up to 40% have been reported, in comparison
to less than 10% without PMRT. Short-term complications include infection and
loss of implant, while long-term complications include pain, capsular
contracture and fibrosis. Such complications have been shown to negatively
affect quality of life, perceived body image and sexual well-being.
Furthermore, PMRT after an immediate reconstruction is associated with impaired
cosmetic results and lower patient satisfaction, even when no complications
have occurred.
If patients aim for an autologous reconstruction (i.e. use of own tissue),
usually PMRT is performed first, followed by a delayed autologous
reconstruction to avoid radiotherapy on the flap, thereby subjecting patients
to a second major surgical procedure and a long period of living without a
breast contour.
The unsatisfying cosmetic results and high complication rate have led to
controversy and a wide practice variation in reconstruction approaches that are
being offered to this specific group of patients. Since immediate breast
reconstructions have proven to yield better cosmetic outcomes, psychosocial
results and reduced overall costs, solutions that would allow for an immediate
breast reconstruction in combination with radiation therapy (RT), without an
increase in complications, are highly needed. Previous studies in breast cancer
patients indicated that neoadjuvant RT (NART) is a safe approach from an
oncological perspective, and does not increase the overall post-operative
complication rate. However, limited data are available on NART in combination
with an immediate breast reconstruction, and no data are available on
patient-reported cosmetic outcomes.

The purpose of the pilot study is to assess acute post-surgical complications
following mastectomy and immediate breast reconstruction after NART. We
hypothesize that NART will avoid the negative effects of PMRT on the capsule of
an implant, or on the skin and underlying tissue of an autologous flap, and
would therefore lead to better cosmetic results, better quality of life and
less complications compared to PMRT. If this hypothesis is confirmed, NART
would allow more patients to undergo an immediate reconstruction resulting in
superior cosmetic results and quality of life. Furthermore, the use of RT in a
neoadjuvant setting could potentially result in a shorter overall loco-regional
treatment time from diagnosis to receiving the last locoregional treatment.
However, this pilot study will mainly assess whether or not the post-surgical
complications of breast reconstruction with NART are acceptable. Further study
to investigate long term quality of life and oncologic follow-up results will
be conducted after this pilot study, if complication rates are acceptable.

The study will be conducted as a prospective multicenter single arm
interventional pilot study. The primary endpoint is post-surgical complications
at three months after the latest patient has received the final reconstructive
surgery.

The intervention consists of NART followed by mastectomy with immediate
reconstruction, where the standard treatment is mastectomy and PMRT, with an
immediate or delayed reconstruction.

Burden:
Currently, in certain hospitals, the indication for RT is based upon the
pathological nodal status of the sentinel or previously involved nodes, removed
during mastectomy. Since patients in this study will receive NART, the
indication for RT is not always clear prior to surgery. In those cases, an
axillary staging procedure has to be performed prior to the breast surgery, to
determine whether there is an indication for RT at all. This requires two
separate surgical procedures, which is nowadays already common practice in
several hospitals, to determine whether an immediate breast reconstruction is
possible. Currently, for cT1-3N0 patients, it is known that about 25% has a
positive axillary node after neoadjuvant chemotherapy and thus still requires
PMRT; for patients with cT1-3N+ breast cancer, about 55-70% still have positive
nodes after neoadjuvant chemotherapy requiring PMRT. Consequently, some
patients that have given their informed consent for NART but will be excluded
from this study if the sentinel node appears to be free of tumor cells.
Another additional burden can be an additional biopsy of the tumor after
neoadjuvant chemotherapy, to determine whether residual disease is present. If
residual disease is present, there is also an indication for adjuvant systemic
treatment in triple negative patients or her2- positive patients. Since a
biopsy is not sufficiently accurate to determine pCR status, patients are
excluded from the study if the biopsy does not contain tumors cells, since NART
can influence the final pathological tumor status.
Finally, from a patient*s perspective, additional time is required for filling
in questionnaires with regard to cosmetic results and quality of life
(approximately 15-30 minutes).

Risk: Data from current pilot studies indicates that NART is at least as
effective as PMRT with regard to oncologic safety. A risk that is associated
with participation is the possibility of decreased vascularization of the skin
(nipple) flap of the breast after a sparing mastectomy leading to early
complications, especially in the implant group. However, we anticipate that
this risk of necrosis and loss of tissue expander/implant is low, since
previous pilot studies showed that overall short and long-term complications
were similar between PMRT and NART.

Benefit and group relatedness:
NART will allow patients to always receive an immediate breast reconstruction
(both implant-based and autologous), even is RT is indicated. It is
hypothesized that this will result in a better QoL and cosmetic outcome.
Finally total treatment time will be shorter with NART.