A radiopaque hydrogel to improve target definition of boost or partial breast irradiation in patients with low cavity visualization scores

Oncoplastic techniques are increasingly used worldwide in breast conserving
surgery to reduce seroma formation and improve cosmesis [1-3]. This development
creates challenges for tumorbed delineation at the time of adjuvant
radiotherapy planning, because of reduced post-operative seroma size and lower
cavity visualization scores. Accurate tumorbed delineation to target breast
radiotherapy is essential in patients treated with partial breast irradiation
or a tumorbed boost. While partial breast irradiation is a treatment option for
selected low-risk breast cancer patients [4, 5], young or high-risk patients
will benefit from boost irradiation[6].
Radiotherapy target definition using clips has poor inter-observer agreement in
patients following oncoplastic surgery[7]. Our team tested the use of a
radiopaque hydrogel during lumpectomy cavity closure in the Target-1 Study. The
intervention was feasible and safe and resulted in both higher CVS and
inter-observer agreement of the tumorbed delineation compared to using clips
only. However, these advantages were most prominent in patients with little
seroma. In contrast, patients with large size seromas are known to have high
CVS and good interobserver agreement [8]. These patients might not benefit from
the use of a radiopaque hydrogel.
Therefore, in the present study we will inject the hydrogel at time of
radiotherapy planning instead of during surgery. This facilitates the selection
of patients based on the cavity visualization score. Previous research showed
that visualization of the surgical cavity for radiotherapy planning using
ultrasound is feasible [9].
We hypothesize that the injection of a radiopaque hydrogel in patients with a
low CVS on the original plannings-CT is feasible and safe and will increase CVS
and interobserver agreement during tumorbed delineation, compared to standard
clips only.

Primary objective: Estimate the added value of using hydrogel in addition to
clips only in terms of the Conformity Index (Cx) of tumorbed delineation
Secondary objectives: Estimate the Cavity Visualisation Score (CVS), distance
between the center of mass (dCOM) of the observers* target volumes, feasibility
of the hydrogel marker injection, stability of the hydrogel marker volume over
time, comparison of target volumes defined by clips and hydrogel, adverse
events, ease of use, motion of hydrogel marker/clips over time, feasibility of
using the hydrogel for patient positioning and comparison of dose to organs at
risk for treatment plans with and without hydrogel.

An intervention study on 20 patients across 5 observers. All 5 observers will
delineate all 20 patients. All 20 patients will receive hydrogel injection
after the original CT-scan (CT1) for radiotherapy planning. A second CT scan
(CT2) will be made 1-3 days after injection. Tumorbed delineation will be
performed on both CT-scans, with the original CT-scan (clips only) as an ideal
comparator for the interventional CT-scan (clips+hydrogel) from the same
patient. A third CT-scan (CT3) will be made during the course of the
radiotherapy delivery for treatment (and hydrogel) monitoring. Study will be
performed combined in a large secondary hospital (Franciscus Gasthuis,
Rotterdam) and a tertiary hospital (Erasmus MC, Rotterdam).

The intervention will be performed under sterile conditions and, if needed,
with local anesthesia of the skin using lidocaine 1% (max 5cc). 2-4 ml of
Iodined PolyEthyleneGlycol, brandname *TraceIT* will be injected in the
post-surgical seroma after identification by ultrasound. If no fluid seroma is
visible the product will be injected at the center of the visible surgical
scar. A repeat planning CT will be performed 1-3 days later to facilitate
diffusion of the hydrogel to cover the cavity as much as possible.
During the radiotherapy treatment course, one CT-scan for monitoring patient
positioning and treated volumes will be used for study purposes.

Tolerance of the investigational product is expected to be good based on
existing safety data. Data from other studies inserting applicators at this
moment in time (2-4 weeks after surgery) show low infection rates[10]. Burden
of the injection is deemed to be low, as sensitivity and pain resulting from
the injection will be low in the surgical scar. If needed an additional local
anesthesia can be administered. Radiation dose of the extra study images (max
2x CT-scan) is negligible with regards to total radiation dose of the
radiotherapy treatment. Furthermore, target definition may be improved by this
new technique, with possibly lower radiation dose to healthy tissue, fewer
geographical misses and increased eligibility for patient friendly partial
breast radiotherapy techniques. We conclude that the benefits of the treatment
when used as intended considerably outweigh the risks.