University of Groningen
Evolving treatment of locoregional metastatic melanoma
Faut, Marloes
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10.33612/diss.93011206
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Faut, M. (2019). Evolving treatment of locoregional metastatic melanoma. University of Groningen.
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Evolving Treatment of Locoregional
Metastatic Melanoma
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het college voor Promoties
De openbare verdediging zal plaatsvinden op woensdag 4 september 2019 om 16:15 uur
door
Marloes Faut geboren op 10 maart 1988
Promotor
Prof. dr. B.L. van Leeuwen
Copromotor
Dr. L.B. Been
Beoordelingscommissie
Prof. dr. G.M. van Dam Prof. dr. C. Verhoef Prof. dr. J.A. Gietema
Paranimfen
Samantha Damude Esther van der Linde
Table of contents
General introduction and outline of thesis 9
Part I Surgical treatment of metastatic melanoma in the past & present
Chapter 1 Nodular histologic subtype and ulceration are tumor factors 21
associated with high risk of recurrence in sentinel node negative melanoma patients
Chapter 2 Pelvic lymph node dissection in metastatic melanoma to 43
the groin should not be abandoned yet
Chapter 3 Morbidity after inguinal lymph node dissections. It is time 67
for a change.
Part II Surgical treatment of metastatic melanoma in the present & future
Chapter 4 Minimaal invasieve videoscopische liesklierdissectie 93
Chapter 5 Preoperative BRAF inhibition in patients with 109
irresectable locally advanced stage III melanoma
Summary 131 Nederlandse samenvatting 139 Future perspectives 147 Appendices List of publications 154 Curriculum Vitae 157 Dankwoord 158
10
Cutaneous melanoma is the most lethal form of skin cancer with an incidence of 132,000 new melanoma patients globally each year. The incidence of melanoma has increased world-wide over the last decades.1-3 In 2016, 6800 melanoma’s
were diagnosed in The Netherlands.4 In current times, the treatment of metastatic
melanoma in the Netherlands is centralized and executed in 8 melanoma centers and 6 partner centers.5 The institution of these melanoma centers has been the direct
consequence of the development of new therapeutic strategies in melanoma care. Cutaneous melanoma mainly spreads through the lymphogenic route.6 In the early
days of melanoma care, an elective lymph node dissection was performed to find and treat any potential occult metastatic disease in the adherent lymph node basin. This became controversial when elective lymph node dissection (ELND) trials showed no survival benefit7-10 and only one trial reported some benefit for a certain subset of
patients (intermediate thickness, nonulcerated melanoma in patients <60 yrs).11
In the early nineties, the sentinel lymph node biopsy (SLNB) concept was explored by Donald Morton and colleagues.6,12 The SLNB procedure allowed intraoperative
identification of the nearest draining lymph node, most likely to contain occult metastatic melanoma. The MSLT I trial showed that in case of a negative SLNB, a completion lymph node dissection (CLND) could be abandoned.12 If a SLNB was
positive, a completion lymph node dissection used to be the standard surgical therapy.13 Since its introduction, the SLNB has become a widely accepted staging
procedure and has become one of the most important prognostic variables in predicting outcome in cutaneous melanoma. At the time of primary staging, approximately 20% of melanoma patients are SLNB positive.6,14,15 SLNB positivity
is associated with several tumor characteristics, such as Breslow thickness, mitosis and the presence of ulceration.16,17
In current times, a SLNB is performed when patients are diagnosed with melanoma stage IB and higher. In case of a clinically palpable lymph node in a regional basin, the SLNB is abandoned and a therapeutic lymph node dissection (TLND), after PET-CT staging, is the standard surgical therapy.18 Unfortunately, over the past decades,
11
lymph node dissection has been associated with high rates of wound complications. With the lowest complication rate in the head & neck region, followed by the axillary region and the highest complication rate in the groin.19 In the groin, the incidence of
wound infection, seroma and wound necrosis can be as high as 50%.19-23 In addition,
long-term lymph oedema is seen in 32% of patients following inguinal lymph node dissection.14 The latter has been a cause for an on-going debate regarding the
necessity of the CLND after a positive SLNB. The first MSLT trial showed that SLNB based management prolongs distant disease free survival and melanoma specific survival in patients with intermediate thickness melanomas with nodal metastasis.24-26 Following these results, the MSLT-II trial was designed to determine
if a sentinel node procedure followed by an immediate completion lymph node dissection is mandatory in patients with malignant melanoma. The MSLT-II trial showed no survival benefit for direct CLND following a positive SLNB. And with only 5% improved disease free survival in the direct CLND group, these results limit the added value of lymph node dissections after a positive SLNB.27 The results of
the MSLT-II justify a wait and see policy with ultrasonography of the draining lymph node basin. As a direct result, the number of executed lymph dissections are likely to decrease in the future.
For many decades surgery was the only curative treatment strategy for cutaneous melanoma and its metastasis. In the past, patients with extensive metastatic disease were offered systemic treatment with dacarbazin as monotherapy or combined with other systemic treatment options. With a median survival duration of 6–9 months and 5-year survival rates of approximately 6%, patients with extensive metastatic melanoma had a poor prognosis.28
In the current era, with the availability of drug targeting therapies and immune-checkpoint inhibitors as a systemic treatment option, the treatment options and long-term outcome have changed dramatically.29,30
12
Approximately 50% of cutaneous melanomas harbor a BRAF-mutation.31 These
patients can be treated with a BRAF inhibitor. This can result in an exceptionally rapid and extensive response in 50% of patients.29,32 Unfortunately, responses are
finite in the majority of patients with a median time to progression of approximately six months. The addition of a MEK inhibitor prolongs progression free survival to a median of 9·3 months.33,34 In a small subset of patients (~20%) durable responses on
the BRAF and MEK inhibitors combination have been described.35 Treatment with
the anti-CTLA4 monoclonal antibody ipilimumab results in long-term survival in approximately 20% of patients.30,36 Objective responses are seen more frequently
with the anti-PD1 monoclonal antibodies nivolumab and pembrolizumab compared to ipilimumab, and long-term survival data are predicted to be even better.37,38
By combining local surgical therapy for symptomatic metastases with systemic treatment, long-term survival can be pursued, even in patients with extensive metastatic melanoma. The latter has changed the diagnostic work-up, indications for- and timing of surgical treatment of metastatic melanoma. The increase in treatment options and different treatment sequences demands a close collaboration between the different disciplines, e.g. surgical-oncologist, medical-oncologist, radiation-oncologist and others involved in the diagnosis and treatment of melanoma patients.
Outline of thesis:
This thesis aims to describe the evolvement of the treatment of metastatic melanoma. The majority of clinical studies in melanoma focus on either the surgical treatment or the systemic treatment of metastatic melanoma. The present thesis attempts to obtain better insight in the surgical treatment of metastatic melanoma as well as the combined treatment of metastatic melanoma by combined systemic and surgical therapy.
The first part focusses on the surgical treatment of metastatic melanoma in the past and present, e.g. risk factors for recurrent disease in sentinel node negative patients, the extent of lymph node dissection in the groin, the short- and longterm morbidity of groin dissections. The second part of this thesis focusses on the surgical treatment
13
of metastatic melanoma in the present and future, e.g. neo-adjuvant treatment with BRAF-inhibitors in primarily irresectable stage III melanoma and videoscopic inguinofemoral lymph node dissection.
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3. Erdmann F, Lortet-Tieulent J, Schuz J, et al. International trends in the incidence of malignant melanoma 1953-2008--are recent generations at higher or lower risk? Int J Cancer. 2013;132(2):385-400.
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14
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15
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16
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