Recent developments in lymph node surgery for melanoma

Abstract

There has been a historical emphasis on radical surgery both for the primary melanoma and for possible metastases within regional lymph nodes. This is because, in the absence of effective systemic therapy options, surgery was viewed as the only potential curative treatment. There are alternate hypotheses for the role of surgery in lymph node metastases in melanoma. Firstly, there is the ‘orderly progression’ of the metastatic process, initially through locoregional lymphatics to the regional lymph nodes, and subsequently to the second-echelon lymph nodes and bloodstream. Therefore, early interruption of this process would in some way prevent further progression to distant visceral metastases and thereby improve overall survival (OS). The alternate hypothesis is that the development of metastatic disease within the locoregional lymph node(s) is an ‘indicator’ of metastatic potential and correlates with the development of distant metastases. However, removal of disease within lymph nodes at an early stage will not prevent the development of distant metastatic disease, which is governed by a complex interplay of the biology of the primary tumour and the host’s innate defences. These two hypotheses are not mutually exclusive within a population of patients or indeed within an individual patient. The first trials that analysed elective lymph node dissection (ELND) vs. nodal observation failed to demonstrate any survival advantages, and, after the introduction of the sentinel node (SN) procedure, ELND was abandoned because of prohibitive morbidity. It has been suggested that in these trials of ELND, the potential therapeutic effect of ELND on patients with lymph node metastases was not evident, because the majority of patients within the trials in fact did not have any lymph node metastases, which diluted the patients in whom a treatment effect might have been seen. The potential advantage of SN biopsy (SNB) is that it would be able to identify the correct subgroup of patients with nodal metastases who would potentially benefit from an early surgical intervention. One area in which there is little debate is that the SNB procedure provides additional prognostic information over that available from analysis of the primary tumour. Furthermore, analysis of tumour burden within the SN is an even more accurate way of determining prognosis within the heterogeneous group of SN-positive patients. Patients with SN metastases > 1 mm have a poor prognosis, which is similar to that in patients with macroscopically (palpable or image detected) metastases. Although many different ways have been proposed to assess SN tumour burden, the most reproducible technique uses the Rotterdam criteria, adopted by the European Organisation for Research and Treatment of Cancer (EORTC). Many of the pivotal adjuvant therapy trials have used this 1mm SN tumour burden cut-off for risk stratification based the Rotterdam–EORTC criteria. The Multicenter Selective Lymphadenectomy Trial (MSLT)-I randomized patients (60 : 40) to wide local excision + SN [followed by completion lymph node dissection (CLND) in case of SN-positive disease] vs. wide local excision only (and nodal observation), with therapeutic lymph node dissection (TLND) upon the development of clinically apparent nodal disease on follow-up. The study failed to demonstrate a survival benefit of SN vs. nodal observation, with 10-year survival rates of 81 4% vs. 78 3% (P = 0 18). A similar argument was made for the lack of a survival advantage in this study to that made for the trials of ELND – that the majority of patients in the study did not have lymph node metastases and so could not have gained any benefit from an intervention in the lymph node basin. Indeed, attempts at directly comparing the outcome of patients with nodal metastases identified either by SNB or clinically in follow-up appeared to show an improved outcome for patients undergoing SNB and CLND compared with TLND. Such direct subgroup comparisons may not be valid as they compared nonrandomized subgroups and might have included clinically irrelevant micrometastatic disease. Furthermore, the comparison excluded a small but important group of patients with false negative SNs who developed nodal disease on follow-up and had a very poor prognosis. Hence the predominant view after this study was that SNB provided valuable prognostic information, but that any effect on OS was not proven. The question as to whether there is a therapeutic benefit of undergoing CLND for those patients identified by SNB as having nodal disease has also been analysed in randomized trials. Recently, two prospective randomized trials that examined the value of CLND in terms of survival vs. sequential nodal observation by ultrasound have reported their results. The German DeCOG-SLT study by Leiter et al. reported 3-year OS rates of 81 2% vs. 81 7% (P = 0 87) in 240 vs. 233 patients. This remained true after a median 72 months of follow-up, as presented at ASCO 2018. The MSLT-II trial confirmed this in 824 patients with CLND vs. 931 under observation only, with 3-year OS rates of 86% in both groups (P = 0 42). Both studies did show improved relapse-free survival of the lymph node basin after CLND, which is to be expected after a prophylactic lymph node clearance in one of the two randomized groups. Predictably, the toxicity associated with the lymph node clearance was much greater in the CLND arm, in which all patients underwent a clearance, compared with the observation arm, where only those patients who relapsed