The Treatment of Breast Cancer with PercutaneousThermal Ablation: A phase 2 screening trial

With 15,000 new patients per year, breast cancer is the most common type of
cancer among women in the Netherlands. Almost half of the tumors are smaller
than 2 cm. These patients have an excellent prognosis with current surgical
therapy (five year survival rate of 98-99%). However, these patients could
presumably have less invasive treatment without surgery, which might improve
health-related quality of life. Percutaneous thermal ablation has the potential
to replace surgical treatment. The most promising methods of percutaneous
thermal ablation are radiofrequency ablation (RFA), microwave ablation (MWA)
and cryoablation (CA). Success rates of RFA, MWA and CA are 82-87%, 83-90% and
74-75%, respectively. Currently, RFA and CA are tested in large prospective
studies. Preliminary data suggest comparable outcomes to breast conserving
surgery (BCS) with complete ablation rates of 91% and local recurrence rates of
0-0.6% after treatment with RFA an CA.

The differences in success rates (complete ablation) between *follow-up
studies* and *treat and resect studies* remain unexplained. Possible
explanations are heterogeneity of study designs, learning curve of the
physicians or the timing of the evaluation of the complete ablation.

Additionally, activation of the immune system is found after thermal ablation
in mice studies and other types of cancer but is never investigated in patients
with breast cancer (9-12). The immune response might explain the differences in
local disease control, but could possibly also prevent micro metastases and
local recurrences (12,13).

Complications occurred in about 10% of patients in previous studies, mainly
thermal damage to the skin or pectoral muscle (±6%) (14). Major adverse events,
i.e. pneumothorax (0,2%) occurred incidentally (14).
Thus, previous studies indicate that RFA, MWA and CA can be safe and effective,
but the actual success rate remains ambiguous. Even as feasibility in an
outpatient setting, immune response, patient satisfaction and follow-up imaging
of these techniques (6,15-23).

Research direction
A phase 2 study with RFA, MWA and CA under comparable conditions will provide
more insight in which of these techniques has the best potential for treating
early stage breast cancer without jeopardizing compromising treatment
effectiveness compared to standard of care (surgery).

The overall study aim is to determine the efficacy rate of complete ablation
for the most promising types of thermal ablation (RFA, MWA or CA) technique for
patients with early stage breast cancer (cT1N0M0) without an extensive
component of DCIS (<= 25% of the tumor), when these techniques are performed in
a standardized study design and comparable patient population, to warrant a
randomized phase III trial comparing thermal ablation with surgery.

Primary Objective
The primary objective is to investigate if thermal ablation (RFA, MWA and CA)
is an effective treatment, in terms of complete ablation rate, for patients
with early stage breast cancer (cT1N0M0) without an extensive component of DCIS
(<= 25% of the tumor) in an outpatient setting.

A randomized prospective phase II screenings trial (pick-the-winner).

Ultrasound guided percutaneous RFA, MWA or CA will be performed 1-2 weeks after
diagnosis. Surgical resection will take place 3 months after thermal ablation
in all patients. Surgical procedure will be according to the Dutch guideline
(Mammacarcinoom 2.0) and will not be influenced by type of thermal ablation.

The risk of this investigation is mainly related to the risks of treatment by
thermoablation. These risks are reversible and include mainly thermal damage to
the skin or chest muscle.

The burden of the patients consist mainly of the additional treatment, and the
additional examinations such as: an MRI scan, blood samples and completing
questionnaires. These investigations are combined with standard follow-up
appointments where possible. For example, the thermal ablation itself is
combined with the localization of the tumor, which is a standard procedure.
Only one extra appointment will be scheduled to perform an MRI and to collect
blood. During this visit there is also the opportunity for the patient to ask
questions to the coordinating investigator or another authorized person by the
principal investigator.