Diffuse reflectance spectroscopy measurements during a ultrasound guided vacuum assisted excision procedure of breast tumors

The current treatment of breast cancer by breast-conserving surgery (BCS) plus
radiotherapy shows excellent local tumor control rates, but comes at the cost
of an invasive procedure under general anesthesia (also for small tumors) and
still comprises patient*s satisfaction by suboptimal cosmetic outcome, scar
tissue, and local painful breasts.

This raises the question of whether for patients with small breast tumor
surgery can be replaced by image-guided minimal invasive radiological
procedures that, like BCS, in combination with radiotherapy, may result in
equal local control rates, but a better cosmetic outcome, less scar tissue and
fewer complaints of painful breast areas. Since such procedures can be
performed under image guidance, optimal cosmetic results can be obtained by
more precise tumor excision while sparing more healthy breast tissue. Moreover,
such procedures can be performed under local anesthesia in an outpatient
setting and would also obviate the need for additional tumor localization
techniques by guide wires or radioactive I-125 and magnetic seeds.

However, the widespread use of this technology for breast cancer is hampered by
the lack of quality control during the procedure, as definite histopathological
information on whether all tumor is removed is lacking. Without such real-time
histopathological control, the medical community is reluctant to further apply
VAE technology for malignant breast lesions. In this project, we will solve the
quality control issue by using optical technology for real-time tissue sensing
during the ultrasound-guided VAE procedure. In this way, we will be able to
predict the margins of the excised tumor and assess whether minimal invasive
treatment of breast cancers by VAE is successful, and all tumor tissue is
removed adequately.

To this end, we developed a tissue sensing introducer with integrated optical
fibers that enable diffuse reflectance spectroscopy (DRS) measurements. The
developed tissue sensing introducer can be used in conjunction with a standard
vacuum-assisted biopsy (VAB) needle to form a smart tissue sensing VAE device
suitable for tumor excision. DRS is a light-based technology that enables
discrimination of tissue types based on their optical characteristics. The DRS
measurements reflect functional, biochemical and morphologic information of
measured tissue and in that way are able to discriminate tumorous tissue from
healthy tissue. DRS technology has already been successfully evaluated in
multiple oncological domains for discriminating tumor tissue from healthy
tissue with classification accuracies of 0.86-1.00. The advantages of DRS are
that it is non-destructive, does not require exogenous contrast with dyes, and
has the potential to be performed in real-time.

In our previous studies, we show that fiber-optic DRS is able to detect
invasive carcinoma (IC) and Ductal Carcinoma In Situ (DCIS) ex-vivo and in-vivo
with high accuracies (93-100%) without the substantial influence of patient
factors such as menopausal status and neoadjuvant chemotherapy. Our result
mainly relies on the NIR wavelength range, which eliminates the influence of
blood on the measurements, which is of great benefit for in-vivo measurements
during surgery or VAE. Moreover, we showed the feasibility of DRS integration
in a standard biopsy needle, able to perform continuous DRS measurements during
ultrasound-guided biopsies and capable of detecting cancerous tissue at the
biopsy site.

With DRS measurements (derived from ex-vivo breast specimen), a real-time
tissue classification algorithm was developed for the discrimination of tumor
from healthy breast tissue using the optical introducer. In this study, we will
investigate the feasibility and efficacy of the tissue sensing VAB device
during an ultrasound-guided VAE procedure (in-vivo). Real-time tissue sensing
during the VAE procedure should be easy to handle and intuitive and allowing
assessment of the excision margins and hence guarantee radical tumor excision.

This study consists of two phases. The first phase includes a pilot study for
the feasibility of using this new developed smart VAE device. If this pilot
study is successful we will continue to the second phase. This phase includes a
proof of concept study performed on a larger patient group.

Phase 1
Primary Objective:
The primary objective of this study is to assess usability of performing DRS
measurements in combination with a vacuum-assisted excision procedure.

Phase 2
Primary Objective:
To determine whether ultrasound-guided vacuum-assisted tumor excision (VAE) by
the sensing VAB device (smart VAE) results in complete removal of malignant
breast tumors.

Secondary Objective(s):
The secondary objective includes the evaluation of complications, pain during
and after the procedure, patient satisfaction, and short-term cosmetic outcome.

The first phase study is designed as a feasibility study and is part of the
ongoing product development cycle. A product development cycle was used to
design and manufacture an ultimate VAB tool (tissue sensing introducer)
suitable for the clinical setting planned in this project. Adding DRS tissue
sensing functionality to a VAB device is challenging, as vacuum suction
mechanisms and the location of the needle aperture set strict constraints for
integrating the optical fibers within the device. The developed tissue sensing
introducer turns a standard VAB device in a smart VAE device, making DRS
measurements during the excision procedure possible. However, the design and
methodology need to maintain the full functionality of the VAB system as well
as the DRS system.

In this phase we want to assess the usability and functionality of this newly
designed tissue sensing introducer with integrated optical fibers. Therefore, a
variety of patients will be treated with different breast sizes, breast density
and ultrasound features of the tumors to obtain sufficient initial experience
on the feasibility. The procedure will be performed within the OR under general
anesthesia. In the normal situation patient would undergo a standard wide local
excision of the breast lump. In this study, initially an ultrasound-guided
vacuum-assisted excision (VAE) procedure will be performed followed by excision
of the biopsy cavity or removal complete breast. In this way it is guaranteed
that the tumor is completely removed in a way comparable to the standard wide
local excision or mastectomy. The main study endpoint is the usability and
functionality of DRS measurements in combination with a vacuum-assisted
excision procedure. The ease of use of the developed tissue sensing VAE device
will be reported by the involved radiologist(s). This information will be used
to improve the functionality and optimize the design for this device for the
second phase of this study.

For the second phase of this study, we will perform a proof of concept study.
In this proof of concept study, we will use the sensing VAB device with
integrated DRS technology for ultrasound-guided VAE of small breast tumors and
will use the tissue sensing algorithm developed and validated in earlier study
to guide the procedure. The aim of this study is to show that such a *smart*
VAE procedure is safe and effective. Critical to this approach is to achieve a
comparable radical resection rate to BCS. To this end, we will investigate the
success rate of complete tumor excision by the *smart* VAE procedure by
confirmatory surgery of the VAE excision cavity 3 weeks after the VAE
procedure. Success will be defined as the absence of residual cancer tissue in
the resected VAE cavity. A time frame of 3 weeks between VAE and confirmatory
surgery (instead of immediate excision) allows us to register short term
complications such as post-procedural pain, hematoma and infection. After the
VAE procedure and confirmatory surgery (wide local excision plus sentinel node
procedure), patients will further be treated with adjuvant radiotherapy like in
standard BCS.

During the first phase of this study, we want to assess the usability and
functionality of the newly developed tissue sensing introducer with integrated
optical technology. For this, a variety of patients with different breast size,
breast density and ultrasound characteristics of the tumor will be treated. The
procedure is performed in the operating room under general anesthesia. In the
normal situation, the patient would undergo a standard local excision
(lumpectomy). In this study, an ultrasound-guided vacuum-assisted excision
(VAE) procedure will be performed initially, followed by surgical excision of
the biopsy cavity or removal of the complete breast. In this way, it is ensured
that the tumor is completely removed in a manner similar to the already planned
lumpectomy or mastectomy.

In the second phase of this study, we want to use an ultrasound-guided
vacuum-assisted excision procedure for the complete removal of the breast
tumor. This will be performed in an outpatient setting. After a local
anesthetic, the radiologist will make a small incision to insert the biopsy
needle in the breast. The entire tumor will be removed using the tissue sensing
introducer. After the procedure, the patient can go home immediately. 3 weeks
after the procedure, the patient is admitted for planned breast conserving
surgery (lumpectomy). In this way, it is ensured that the tumor area will be
removed completely. The patient completes a questionnaire after the VAE
procedure, which makes it possible to monitor minor complications of the
treatment.

Phase 1 of this research:
The vacuum assisted excision procedure takes place under general anesthesia in
the operating room. The planned breast-conserving or mastectomy procedure
follows immediately after the procedure. Besides the (already known) risks of
this standard procedure, there are no additional risks for the patient. The
patient will be under anesthesia for 20 extra minutes.

Phase 2 of this research:
The vacuum-assisted excision procedure takes place under local anesthetic in
the radiology department. The patient can experience some discomfort after the
procedure which is related to minor pain and / or bruising (hematoma) at the
site of the treatment. In very minor cases, infection of the entrance wound can
occur. In addition, the patient needs one extra hospital visit for this
procedure and a questionnaire must be completed afterwards.