Too much surgery and too little benefit? Sentinel node biopsy for melanoma as it currently stands
Authors: J. M. McGregor
Journal: British Journal of Dermatology (2013)

In a recent BMJ article the validity and motive for sentinel lymph node biopsy (SLNB) in the management of melanoma was questioned, citing vested interest in part, and even hinting at conspiracy.1 Many will have been uncomfortable with the style of this commentary, calling for a more balanced, informed debate, but there is good reason to revisit the controversies and to question whether the procedure is currently fit for routine purpose. The National Institute for Health and Care Excellence (NICE),2 after all, does not think that it is. SLNB is costly (estimates place the U.S. spend in the order of 500 million dollars a year)1 and it is not without its risks:3 pain and scarring (100%), seroma (5–20%), persistent lymphoedema and nerve damage (1–5%) and (albeit very rarely) anaphylaxis and even death. Furthermore, it is generally accepted that, overall, only one in five patients undergoing SLNB for intermediate-thickness melanoma will have a positive node – thus four out of five patients will have had unnecessary surgery.4 For those with thinner melanomas (0·76–2·00 mm) the chance of having a positive node is even lower, with figures ranging from 2% to 10%,4 so that nine out of 10 will not have required surgery to be done. These might still be acceptable odds, were there a clear long-term survival advantage for those in whom a positive node was removed – but there is not, at least not yet. The rationale for SLNB is predicated on the idea that tumour cells migrate sequentially from the primary tumour site to the nearest draining lymph node (the sentinel node), thence to deeper chains, only later spreading by haematogenous routes. Thus, examining the sentinel node for the presence of micrometastases should, if this is correct, provide early prognostic information, improve survival chances by removing residual microscopic tumour at the earliest possible stage in the disease and, finally, provide results to direct further management to improve survival. Keep these three outcomes in mind, as any one might serve to justify the routine place of SLNB in melanoma. Firstly, we should question the much cited view that SLNB provides accurate prognostic information for individual patients; it does not, especially for those patients with thinner melanomas whose prognosis is good.5, 6 What it does provide is accurate staging information and survival rates for populations, which justify its use in clinical trials. Kaplan–Meier plots do not translate smoothly into clinically relevant information for any individual patient where a myriad of other factors determine outcome. Moreover, we already have good enough predictors of survival from melanoma pathology7 for this purpose, especially for thin and intermediate-thickness melanomas – SLNB does not sufficiently enhance this to justify its use, and certainly not at any cost. Secondly, in melanoma, the basic premise that surgical removal of residual tumour after resection of the primary can improve survival in the long term has not, to date, been clearly shown in any study, suggesting perhaps that haematogenous and/or lymphatic seeding occurs much earlier in the disease than was thought. Finally, and most importantly, whatever the result, SLNB does not yet inform further management in melanoma to improve survival outcome. Sentinel node biopsy was first described in the management of melanoma in the early 1990s and the technique was subsequently pioneered as a means of reducing the fairly considerable morbidity from the standard of care at the time for intermediate-thickness melanoma – namely elective lymph node dissection (ELND). Approximately 80% of all patients with melanoma have no clinical evidence of nodal or metastatic spread at presentation, but a proportion of these will nonetheless have occult disease. This is fairly predictable, so that tumour thickness, ulceration and mitoses are each independently associated with likelihood of spread and decreasing survival.7 SLNB positivity ranges from < 5% in nonulcerated thin melanomas to 30–40% in thick or ulcerated intermediate-thickness melanomas.4 Historically, a patient with an intermediate or poor prognosis melanoma, but without clinical evidence of spread, would be managed by an ELND with its attendant significant morbidity, in the hope that removing clinically occult nodal metastases (usually the first site of relapse) as early as possible in the disease process would improve the patient's survival chances. But no survival advantage could be found in prospective randomized trials comparing the outcome of those patients offered ELND or nodal observation followed by therapeutic lymph node dissection. Critics observed that the studies were underpowered as only 15–20% of those in the ELND arm would be expected to have occult disease anyway and thus potentially benefit from early surgery. But the routine use of ELND was challenged by these findings and the case for SLNB emerged. In this respect it was a reasonable path to take, as SLNB was clearly much less invasive, and only those with a positive node would then progress to what became known as selective (s)ELND. The technique of SLNB has been refined over the years and it is now in routine use in the management of breast cancer, where the results direct ongoing management, including the use of adjuvant radiotherapy and chemotherapy, with proven survival advantage.8, 9 It is also in routine use for melanoma in many countries, but without proven survival advantage to date. More importantly, it does not direct further management in melanoma because we have no effective adjuvant intervention as yet. Nonetheless, In the U.S.A. it is claimed as the standard of care, following publication of the interim results of the Multicenter Selective Lymphadenectomy Trial (MSLT)-1 in 2006,10 and a subsequent editorial stating that SLNB ‘identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy’. Although this was certainly the outcome we would all have hoped for, and many have accepted it, there remain doubts among a vocal minority and in the minds of many silent others; it seems reasonable among enquiring professionals, even morally correct, to continue to question the interpretation of the data11 in anticipation of the final 10-year analysis, which may consolidate the position one way or another. In the MSLT-1 trial, patients with intermediate-thickness melanoma (1·2–3·5 mm) were randomized, either to undergo SLNB and then sELND if a positive node were found (n = 764) or to the observation-only arm, followed by therapeutic lymphadenectomy in the event of nodal relapse (n = 500). At 5 years, the interim data were published but no overall survival advantage was found for the SLNB arm compared with the observational arm of the study. No controversy here and the outcome was clearly disappointing; supporters argue that once again, it is likely the study was underpowered, given that the majority of patients in both arms survived. But surely that is the point – either there is no survival advantage or, if there is, and it is yet to be proved, then it remains a very small survival advantage if it did not show up in this trial – notwithstanding the very large number of surgical interventions undertaken. What were claimed as secondary endpoints, and subsequently used to endorse the role of SLNB in melanoma management, were that (i) SLNB and subsequent immediate lymphadenectomy significantly increased disease-free survival at any site in the interventional arm, and diminished the trauma of nodal recurrence; (ii) observation allowed nodal micrometastases to enlarge and spread to other nodes, thereby potentially increasing the risk of distant metastases and decreasing overall survival; and (iii) there was a survival advantage for node-positive patients who underwent lymphadenectomy compared with those with nodal relapse in the observational group. On the face of it, these sound like good enough reasons to support SLNB in melanoma, and for many, they are – so why the controversy? Taken point by point, the disease-free survival advantage, while present for any site, disappears when nodal relapse is excluded – as it surely should have been given that nodal relapse was the starting point for intervention in the observational arm. This argument has now been broadly accepted. It is true, though, that the trauma of nodal recurrence is diminished by early intervention; morbidity from lymphadenectomy at nodal relapse is significant, and better control of locoregional disease, which can otherwise be challenging, could justify the SLNB in its own right, were it not a pretty uncommon outcome across all melanomas. It is especially pertinent, though, for patients with thicker melanomas in whom locoregional disease is more likely to occur. Ironically, SLNB is not generally indicated for melanomas > 4 mm, but it is in these patients that there is potential for real benefit in this respect. Moreover, in this group particularly, there is evidence to suggest that sentinel node status provides more relevant individual prognostic information than pathological staging, as the survival rates differ so greatly between node-positive and node-negative patients.12 This is not the case for those with thinner melanomas.5 What the study clearly did demonstrate was that observation, at least in the majority of cases, allowed nodal micrometastases to enlarge and spread – an uncomfortable notion for both physician and patient. There was striking parity in the incidence of sentinel node micrometastases (15·8%) and nodal relapse during observation (16%), but in the SLNB group, the median number of involved nodes was 1·4, compared with 3·3 at nodal relapse in the observational arm (P = 0·004). However, what is still not clear is whether this translates into an increased risk of distant metastases and death for the patient. The MSLT-1 article claims that it does, and on first inspection the data appear to support it – there was a 5-year survival advantage seen for node-positive patients (72%) from the interventional arm compared with those with nodal relapse (52%) in the observational arm (P = 0·004). However, critics argue that this comparison is invalid – that these were not matched groups and that it was a not an intention-to-treat analysis, the gold standard required to demonstrate benefit in therapeutic trials. There is also potential bias that has not been acknowledged; for example, when 32 node-negative patients in the biopsy arm with nodal relapse are included (the false-negative cases), the 5-year survival for the biopsy arm falls to 66% (P = 0·02). Still statistically significant in this small subgroup of patients, but is it sufficient to justify a hugely expensive programme of care and subject the majority of patients to unnecessary surgery as it stands? Clearly NICE didn't think so.2 There were also patients in the interventional arm who had a genuinely negative node (i.e. not a false-negative node) but who nonetheless developed distant metastases – these patients were not included in the analysis, yet they are patients in whom the sentinel node was removed, without benefit, and who are likely to die from their disease. They are, in effect, prognostic false-negative cases. There are further sources of potential positive bias in the interventional arm, including the younger median age of the patients, associated with higher node-positive rates but better outcome,5 and the possibility of prognostic false positives (those node-positive patients in whom the micrometastases might never have progressed). Such cases, if they exist, would always bias the interventional arm towards a better outcome.13 Support for this notion may yet come from the MSLT-1 trial data at the 10-year analysis. The rate of node-positive plus node-negative patients with nodal relapse in the biopsy arm currently stands at 19·4%, compared with nodal relapse of only 15·8% in the observational arm; this discrepancy, if maintained, could be evidence of the elusive false prognostic positivity. Kaplan–Meier curves predict these figures will even out in the longer term – with a projected 18·5% incidence for nodal relapse in the observational arm at 8 years – but we will have to wait and see if they do. It is now nearly 7 years since the publication of the interim analysis of the MSLT-1 data, and attempts by critics to question its upbeat message have largely been silenced by the roar of the establishment voice. We should hope that the establishment turns out to be right, as many, many patients have undergone surgery and many millions of pounds have been spent worldwide on this procedure since then. Maybe the final analyses of the MSLT-1 data, due for publication in 2013 sometime, will clarify this position. What has emerged from it all is that SLNB, as a procedure, is a reliable and reproducible technique, in the right hands, for identification of the sentinel node. Moreover, the sentinel node is a marker of disease progression that is relevant to the biological process of melanoma metastasis, and, in centres with experience, micrometastases can be found with a high degree of sensitivity and specificity; there is little doubt that the procedure is fit for purpose as an effective, objective staging investigation. However, this endorsement of the procedure should not be confused with endorsing its place in the routine management of melanoma, yet it frequently is.14 The pharmaceutical companies have made sentinel node biopsy a requirement for entering patients with melanoma into clinical trials – even though melanoma pathology, updated recently to include mitotic rate and ulceration, is a viable staging alternative, particularly for those with thin and intermediate melanomas of good prognosis.7 For those centres with SLNB expertise, already wedded to the procedure, entering patients for trials should be their focus. In this context the potential benefits of the procedure outweigh the risks, and we should be grateful that patients are willing to consent to this, with uncertain consequences. There is good reason to hope that an effective adjuvant intervention will emerge over the next decade from the burgeoning immunomodulatory and targeted drugs that are currently licensed or in development for melanoma. When it does, sentinel node biopsy will be on firmer footing; for those experienced in the technique, this is probably not the time to drop the ball. Clinical trials aside, and while we await an effective adjuvant treatment, the available evidence suggests that NICE2 guidelines for SLNB make broad sense – with some caveats. For patients with melanoma where the chance of a positive node is low (< 20%; predominantly those with nonulcerated thin and intermediate-thickness melanoma), high-resolution ultrasound (although not without its logistic problems) may be a viable alternative to either SLNB or a watch-and-wait approach, particularly for head and neck melanoma where technical difficulties make SLNB unreliable. It allows significantly earlier detection of nodal relapse than palpation alone.15 As the risk of a positive node increases (30–40% in thick and ulcerated melanoma), so the case for sentinel node biopsy strengthens. Better control of locoregional disease would be a real gain in this situation, and for those facing the prospect of death, there is meaningful difference between an 80% 5-year survival with a negative node compared with 47% where the node is positive.12 To conclude then, it seems that sentinel node biopsy in melanoma is here to stay, unless the 10-year analysis of the MSLT-1 data undermines its position. This is despite concerns that stand up pretty well to scrutiny, including the fact that the majority of patients are undeniably subject to unnecessary surgery and that millions of pounds is spent in doing so, without high-level evidence of survival advantage. If we ask how this can be so, it is probably the case that where there is little to offer, it is deemed by many that it is better to offer little than nothing. Physicians and patients alike continue to put hope, or fear, before evidence – even in the 21st century. None declared.