Minitub: Prospective registry of Sentinel Node (SN) positive melanoma patients with minimal SN tumor burden who undergo Completion Lymph Node Dissection (CLND) or Nodal Observation

Over the past two decades, the Sentinel Node (SN) biopsy (SNB) procedure has
become a standard staging procedure for stage I/II melanoma patients worldwide.
It is widely accepted that the SN status is the most important prognostic
factor for disease outcome in AJCC stage I/II melanoma patients (Ref. 1, Ref.
2, Ref. 3, Ref. 4). The therapeutic value of the SN procedure followed by early
Completion Lymph Node Dissection (CLND) is still widely debated (Ref. 5, Ref.
6, Ref. 7, Ref. 8, Ref. 9, Ref. 10, Ref. 11, Ref. 12, Ref. 13, Ref. 14, Ref.
15, Ref. 16). If a patient has a positive SN, this patient will usually be
offered a completion lymph node dissection to remove all lymph nodes from that
same nodal basin. However, only approximately 15 - 20% of all SN positive
patients have further lymph node metastases detected in that basin at this time
(Ref. 1, Ref. 4, Ref. 17, Ref. 18, Ref. 19). Therefore approximately 80 - 85%
of SN positive patients may undergo unnecessary surgery. Any possible reduction
of unnecessary CLND procedures would have an obvious benefit for those
patients. Moreover, it remains unclear if the minority (15 - 20%) of patients
with additional nodal involvement at CLND is the subgroup which has a survival
benefit by undergoing an early CLND (Ref. 3, Ref. 15, Ref. 16). Over recent
years many research groups have looked at different types of micro-staging of
the tumor burden within the SN, as indicator or prognostic factor for
additional nodal positivity in the CLND specimen, but also for disease-free
(DFS), disease/melanoma specific (DSS/MSS) and overall survival (OS). Starz et
al. (Ref. 20, Ref. 21) developed a classification for tumor burden by measuring
the distance from the capsule to the most interior margin of the metastasis.
This was prognostic for the probability of non-SN metastases. Cochran et al.
(Ref. 22) calculated the surface area involved by the metastasis and
demonstrated its prognostic significance. Dewar et al. (Ref. 23) developed a
classification system based on the location of the metastasis within the SN.
Subcapsular metastases were accompanied with no additional spread to other
lymph nodes in the same lymph node basin. At the same time many studies have
identified only very rough cut-off values for SN tumor burden, such as >2 or <2
mm in maximum diameter of the metastasis (Ref. 19, Ref. 24, Ref. 25, Ref. 26,
Ref. 27). This was only useful for prognostic purposes, but not for the
clinical decision making process. The principle of SUB-micrometastases has been
described earlier in breast cancer (Ref. 28, Ref. 29) as metastases <0.2 mm in
maximum diameter. It has been demonstrated in breast cancer patients that
minimal tumor burden in the SN can be safely managed without performing a CLND
(Ref. 28, Ref. 29). However, the question remains if the same situation exists
in melanoma. This is an important reason to conduct the present trial. The
principle of SUB-micrometastases was defined by van Akkooi et al. (Ref. 4) in
melanoma as <0.1 mm in maximum diameter of the largest lesion, regardless of
the site within the SN. Patients with SUB-micrometastases in their SN did not
have further involvement of their lymph node basin and had excellent prognosis
for long-term survival. These results were validated by an EORTC multicenter
retrospective study, conducted in 388 patients from Berlin, Rotterdam and
Warsaw (Ref. 30). Similarly, a study from Canada by Govindarajan et al. showed
that none of the patients with metastases <0.2 mm had additional non-SN
metastases in the CLND specimen (Ref. 31). These results were confirmed by the
most recent studies, which have also investigated minimal SN tumor burden (Ref.
32, Ref. 33, Ref. 34). More recently, a large EORTC retrospective analysis by
van der Ploeg et al. in 1080 SN positive patients from 9 centers, demonstrated
that patients with metastases <0.1 mm in maximum diameter according to the
Rotterdam classification for SN tumor burden had a 5-year 91% MSS, which is
virtually identical to SN negative patients (Ref. 35). The CLND positivity rate
was 9% in these cases. Rotterdam-Dewar Combined (RDC) classification further
isolated excellent prognosis patients; in those with <0.1 mm subcapsular
metastases had a 2% CLND positivity rate and a 95% 5-year MSS (Ref. 35). In a
more recent evaluation (van der Ploeg & van Akkooi, personal communication),
the Breslow thickness was confirmed to be an independent prognostic factor.
Indeed, the 5-year MSS rate of those SN-positive patients with T1 (Breslow
thickness <1 mm) and minimal SN tumor burden (defined as Rotterdam criteria
<=0.1 mm, or those with a subcapsular infiltration up to 0.4 mm) who received
CLND (N=9) was 100%, whereas the 5- and 10-year MSS rate was 67% and 45% for
patients with thick melanoma (T4, Breslow thickness > 4 mm) and minimal SN
burden (N=21). Meanwhile, patients with melanoma of intermediate Breslow
thickness, namely T2-T3 (Breslow thickness 1.01 - 4 mm) (N=110), and minimal SN
burden had a 5- and 10-year MSS rate of 87% and 80%. Based on preliminary data
(van der Ploeg & van Akkooi, personal communication), the incidence of patients
with T1 and T4 tumors presenting with minimal SN tumor burden is nearly
non-existent. T1 tumors have very few metastases at all (<5% SN positive),
while T4 tumors usually have advanced SN metastases, infrequent cases of
minimal SN tumor burden which develop distant metastases within a very short
time-frame exist. In addition, as the Breslow thickness remains of high
prognostic importance, MSS rates are very high for T1 patients and low for T4
patients, as compared to MSS rates in T2-T3 patients. Hence, T1 and T4 patients
represent two population groups with distinct prognostic and clinical
characteristics compared to T2-T3 patients. For this reason, T2-T3 patients
will be the focus of this study, as it is currently unknown if this patient
population really benefits from immediate CLND or not. Patients with T1 and T4
melanomas will be excluded from the primary aim study population, but allowed
to enter the registry for descriptive analyses. All these studies suggest that
certain patterns or sizes of metastatic spread are not associated with further
metastases in other lymph nodes of the same lymph node basin. At the moment the
standard practice in most countries (Europe, U.S.A & Australia), as defined in
the national guidelines, is that patients with a positive SN, regardless of
amount, pattern or size, undergo completion lymph node dissection. This is a
second operation for all these patients, which is accompanied with all the
risks of a surgical procedure, but is also associated with significant
post-operative morbidity, such as wound infections and chronic limb lymphedema
(Ref. 36, Ref. 37, Ref. 38, Ref. 39). Although most countries suggest CLND as
standard treatment for a positive SN in melanoma, there are large differences
in local application of this guideline. A study by Bilimoria et al.
demonstrated that only 50% of SN positive patients undergo a CLND in the
U.S.A., regardless of SN tumor burden (Ref. 40). Likewise, the treatment of SN
positive patients is quite heterogeneous across Europe (Ref. 41). Both CLND and
nodal observation (with or without regional nodal ultrasound) are being
performed. Based on the previous studies regarding SN tumor burden, some major
melanoma centers have adjusted their protocol/standard of care in these cases
with minimal SN tumor burden. Moreover, the MSLT-1 study has not yet been able
to identify a survival benefit for SN followed by early CLND compared to nodal
observation (Ref. 3, Ref. 15, Ref. 16). Therefore, the choice for nodal
observation can be justified. Currently, there is one prospective randomized
trial worldwide, the MSLT-2, which randomizes SN positive melanoma patients
between CLND and nodal observation, regardless of SN tumor burden (Ref.

With this prospective registry we aim to evaluate the outcome of patients with
a T2-T3 primary melanoma and minimal SN tumor burden, treated by CLND or nodal
observation:
* The main objective is to determine if T2-T3 melanoma patients with minimal SN
tumor burden and managed by nodal observation have a 5-year DMFI comparable to
similar patients (T2-T3 melanoma patients with minimal SN tumor burden) treated
by CLND based on historical data from the literature. We will compare this with
SN-negative patients, based on historical data as well.
* We will also determine the actual proportion of patients and their
characteristics, who opt to undergo a CLND compared to those, who opt to
undergo nodal observation.

This is a prospective registry of all melanoma patients with minimal SN tumor
burden attending the participating sites, aiming to evaluate whether management
of these patients with serial nodal observation only provides an equal outcome
than immediate CLND.
Since the focus of this study is represented by patients with minimal SN burden
and melanoma of intermediate Breslow thickness, the primary aim population will
be composed of T2-T3 (Breslow thickness 1.01-4 mm) patients with minimal SN
tumor burden. However, T1 and T4 patients with minimal SN tumor burden will be
allowed to enter the registry for descriptive analyses.
This is not a randomized trial. At each site melanoma patients with minimal SN
tumor burden will be managed with CLND or serial nodal observation only
according to patient decision, and will be offered the possibility to be
included in the registry. Participating patients will be registered after
signing the informed consent form and after eligibility criteria have been
assessed. Data and blood samples for TR will be collected.
Accrual will last approximately 5 years. Patients will be followed up for 10
years.

Very low / minimum risk study. Possibly slightly higher risk for regional lymph
node recurrence. However, this can be excellently treated.

Benefit for study population; do not need to undergo a surgical procedure and
can be spared the possible morbidity.