MeMaLoc: Magnetic Marker Localization for Melanoma Surgery. A feasibility study.

Since the 1990s, the incidence of melanoma has nearly quadrupled], and although
it occurs fewer than other skin cancer types, it is the most deadly type with
approximately 10.000 annual deaths in the USA alone.

Melanoma diagnosis is based upon diagnostic excision of the area of interest,
in the Netherlands usually performed by a general practitioner. If the
pathology analysis turns out to be melanoma, surgery is the cornerstone of
further treatment. A surgeon will perform a wide local excision (WLE) of the
area, combined with sentinel lymph node biopsy (SLNB) for tumours with a
Breslow thickness larger than one millimetre, to assess lymphatic involvement.
In the case of involved lymph nodes, an additional Complete Lymph Node
Dissection (CLND) of the involved area is indicated.

Unfortunately, melanoma is prone to recur in 19% of patients. Recurrence may be
1) local (* 3cm of primary lesion); 2) in-transit (anywhere in the lymphatic
trajectory between the site of the primary lesion and the nearest connected
lymph node); 3) Regional (in the nearest lymph nodes) and 4) distant. It is
important to recognize that *recurrent* lesions may occur concurrently with
diagnosis of the primary lesion.

IN TRANSIT AND DISTANT METASTASES
Of these recurrences, in-transit metastases (ITMs) occur in approximately 4-8%
of all melanoma cases. These rates are considerably higher for SLNB-positive
cases, at approximately 22%. ITMs have large implications for survival.
Patients with ITMs have a 5-year survival rate ranging from 46% to 59%, as
opposed to for example local recurrences (74%). In a surgical curative
approach, removing all ITMs with a relevant margin is essential to maximize
chances at survival.

Distant metastases occur in 14% of cases, and have even bigger implications for
survival. Only 30% of patients with distant metastases are alive five years
after diagnosis. Increasingly, our surgeons are faced with the request to
remove leftover distant subcutaneous or muscular metastases of stage IV cancer
after successful systemic therapy (e.g. immunotherapy or targeted therapy) to
improve prognosis.

Unfortunately, localizing these recurrences during surgery can be very
challenging, especially in limbs that are severely affected by lymphedema after
CLND, making the lesions essentially non-visible and non-palpable (or
clinically occult). In current clinical practice, a radiologist is required to
assist in this matter: pre-operative localization of occult lesions is
performed using ultrasound (US), and the approximate locations are marked on
the skin with a pen. In correspondence with our melanoma surgeons, it was
hypothesized that more accurate localization of these recurrences is expected
to lead to more successful surgeries, narrower margins or * at the least * more
confidence of optimal surgical treatment.

The rudimentary type of localization applied for these melanoma recurrences
contrasts sharply with localization procedures in breast cancer care. There,
both primary and recurrent occult lesions as well as sentinel lymph nodes are
marked using radioactive iodine seeds for accurate intra-operative localization
using a gammaprobe. There are several case reports in which this Radioactive
Seed Localization (RSL) approach was applied for surgical treatment of for
example ITMs, however due to legislative and certification challenges there is
currently no expectation of this technology becoming clinical practice in the
(near) future.

MARI PROCEDURE
As stated above, marking the axillary lymph node with radioactive iodine seeds
(MARI procedure) has recently been tested as a feasible technology in breast
cancer patients that are treated with neoadjuvant systematic therapy. The
technology allows axilla-conserving surgery in patients responding well to
neoadjuvant therapy.

Unfortunately, the use of radioactive seeds for this purpose is stated to
*require authorization by the government and safety issues need to be
addressed*. This fact is inherent to using radioactive iodine seeds for
localization and most notably it is the reason for the relatively poor uptake
of radioactive seed localization for breast conserving surgery. This fact,
combined with the limited availability of radioactive substances in the western
world * reported as low as 60% * and the European Commission that urges the
development of non-radioactive alternatives to current radioactive technologies
warrants the scientific exploration of feasible alternatives.

THE MAMALOC TECHNOLOGY
Recently, our research group has developed and tested a novel method for
localization of primary breast lesions. In this method, a magnetic marker (or
magnetic seed) is used in combination with a magnetic detection platform during
surgery to reach essentially the same goal as Radioactive Seed Localisation
(RSL): accurate intra-operative localization of a tissue of interest. The
technology was named MaMaLoc (Magnetic Marker Localization).

By using the physical principle of magnetism for localization rather than
radioactivity, the clinical applicability of the MaMaLoc technology is
hypothesized to be much larger. There is little to no legislation or regulation
involved as magnetism is inherently safe. In a first safety and feasibility
trial in this institute (MaMaLoc-1, N15MML, data yet unpublished) the
technology was applied successfully, without marker migration and without
adverse events in 15 patients for non-palpable breast tumour localization.

After this successful application, we are now interested in obtaining
proof-of-principle of the technology for additional clinical indications. As
stated, the challenge of surgical localization is at times just as apparent in
surgery for melanoma metastases as it is in breast surgery, however the
application of iodine seeds for this type of surgery is not possible due to
certification issues with the iodine seeds. Second, the possibility to mark,
detect and remove a suspect lymph node using our technology would open the door
for a future in which high-morbidity and unnecessary CLNDs may become history,
without compromising patient survival. In addition, the possibility of
accurately localizing and removing a marked lymph node has implications for all
lymphogenetically metastasizing tumour types.

Concluding, the aim of current study is to show feasibility of the MaMaLoc
technology for surgical localization of clinically occult melanoma lesions, as
well as to show feasibility of the MaMaLoc technology for lymph node detection,
both in the axilla and inguinal region.

Non-controlled, non-blinded, non-randomized interventional study to assess
feasibility of a novel intraoperative localisation technology (MaMaLoc) for
patients with a history of melanoma.

Subjects will receive an ultrasound-guided placement of a magnetic marker (the
MaMaLoc marker) in a lesion that will be later removed during surgery. This is
either a locoregional or distal non-palpable ((sub)cutaneous or muscular)
metastasis (Group 1) or a (suspect) lymph node in an area that is to be removed
during a complete lymf node dissection of the axillar or inguinal region.

Burden is limited to one extra visit to the radiology department for echoguided
placement of the marker, this also means one extra injection. This takes
approximately 15 minutes. Ideally, this appointment is planned at the same day
as another appointment at the hospital to avoid extra travelling. For patient
enrolled in group 2, surgery may last an additional 5-10 minutes.

Risk is low. The technology has been successfully applied in 15 patients with
breast cancer (no adverse events, no marker migration). The areas that are
marked need to be removed anyhow and there is no adjustment of the clinical
practice.