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Rapid Responses: Rapid Responses published:
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Sentinel-node biopsy:"standard of care" for the staging of melanoma
- Malcolm R. Kell (26 April 2008)
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Sentinel lymph node biopsy in malignant melanoma
- Nighat Butt, Hamid Chatha and Chidi Ekwobi (26 April 2008)
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SLNB: Crucial prognostic tool for patients and clinicians
- David G Samuel (27 April 2008)
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Lets get back to the basics
- Anthony Dixon (29 April 2008)
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Sentinel Lymph Node Biopsy for Melanoma
- Carlos Garcia (29 April 2008)
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Surveillance rather than Sentinel Node Biopsy for Malignant Melanoma
- Andrew J Hayes (29 April 2008)
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Sentinel Node Biopsy in Patients with Primary Cutaneous Melanoma
- Michael Sladden (1 May 2008)
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Sentinel Node biopsy for melanoma
- Barry Powell (2 May 2008)
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Why Should a Surgeon Leave Cancer Cells Behind?
- Ilkka Koskivuo (4 May 2008)
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Sentinel lymph node biopsy in melanoma
- J Meirion Thomas (7 May 2008)
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Sentinel lymph node biopsy in malignant melanoma
- Nicholas Cawrse, David Oliver and Christopher Stone (14 May 2008)
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Sentinel lymph node biopsy has an important role in the management of melanoma
- Rachel A Abbott, Katharine Acland, Robin Russell-Jones, Frank Nestle, Mark Harries, Ciaran Healy, Eduardo Calonje, Michael O'Doherty (21 May 2008)
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Corrections to 'Sentinel lymph node biopsy has an important role in the management of melanoma'
- Rachel A Abbott, Katharine Acland, Robin Russell-Jones, Frank Nestle, Mark Harries, Ciaran Healy, Eduardo Calonje, Michael O'Doherty (22 May 2008)
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A personal experience of sentinel lymph node biopsy
- Perry N Board (23 May 2008)
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What is a pathologically negative nodal basin?
- Gary L Ross (27 May 2008)
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Malcolm R. Kell, Consultant Surgical Oncologist and Senior Lecturer Mater Misericordiae University Hospital, Dublin 7, Ireland.
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Dear Sir, this article offers a timely reminder of the role of sentinel lymph node biopsy (SLNB) in the management of malignant melanoma. Unfortunately, I feel that the content belies the inherently negative view the author holds towards this valuable staging technique. Previous work from Thomas et al has suggested that SLNB for melanoma will lead to high rates of recurrent and in transit disease, subsequent studies have clearly shown this not to be the case1,2. The multicenter selective lymphadenectomy trial (MSLT-1) study clearly shows that SLNB patients have prolonged disease-free survival when compared to observation: this end point is accepted by the Food and Drug Administration (FDA) when testing a new drug, so clearly valid 3. This editorial also suggests that ultrasound may be as good as SLNB in the detection of occult metastatic disease. PET-CT is currently regarded as the optimum imaging modality for cancer staging; however we have previously shown that PET-CT is inferior to SLNB for melanoma, so it seems implausible that ultrasound will be superior to SLNB. I believe the key role for SLNB in melanoma is not for those patients with positive results but the majority with a negative SLNB. A negative SLNB following a diagnosis of melanoma dramatically improves long term prognosis and has a remarkably positive effect on individual patient’s survivorship. The current body of evidence strongly supports the role of SLNB in melanoma, the current lack of effective adjuvant therapy means SLNB may not only offer crucial prognostic information but also the potential for efficacious surgical therapy. 1. Thomas JM, Clark MA.Selective lymphadenectomy in sentinel node- positive patients may increase the risk of local/in-transit recurrence in malignant melanoma.Eur J Surg Oncol. 2004 ;30(6):686-91. 2. Kang JC, Wanek LA, Essner R, Faries MB, Foshag LJ, Morton DL. Sentinel lymphadenectomy does not increase the incidence of in-transit metastases in primary melanoma. J Clin Oncol. 2005 ;23(21):4764-70. 3. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307-17. 4. Kell MR, Ridge JA, Joseph N, Sigurdson ER.PET CT imaging in patients undergoing sentinel node biopsy for melanoma. Eur J Surg Oncol. 2007; 33(7):911-3. Competing interests: None declared |
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Nighat Butt, Plastic Surgery SHO Department of Plastic Surgery, Royal Preston Teaching Hospital, Preston, PR2 9HT, Hamid Chatha and Chidi Ekwobi
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The main premise of the article by Thomas1 was that sentinel lymph node biopsy is unnecessary as micro metastases can be detected by ultrasonography. But the case for ultrasound in the management of melanoma is negated by some of the evidence presented in his editorial. Firstly ultrasound can only detect metastatic disease greater that 3-4 mm.2 Secondly, the paper by Van Akkooi et al3 which was referred to in the editorial demonstrated in their study that those with micro metastases <0.1mm had a 100% 5-year overall survival. Though 6.3% of these patients (1/16) went on to develop distant metastases. If one looks further at their data 5 year survival fall to 35% with those with micro metastases >1mm. With this in mind, what would Thomas suggest for the cohort of patients with micro metastases between 0.1 – 3mm? Would they be better served by ultrasonography or sentinel lymph node biopsy, which is now an established technique in management of cancer beyond melanoma.4,5 Then touching on ‘prognostic false positivity’6 the reason that those with micro metastases <0.1mm have a better prognosis is the dissemination of the disease is in an early stage. Prognostically they represent a group with a better outcome for a positive sentinel node status. In the context of melanoma we do not feel the term ‘prognostic false positivity’, to be a helpful one. It will be interesting to observe these patients beyond the 5 -year mark especially as late relapse beyond 10 years is not unknown in melanoma. Identification of these patients with better prognosis would not be feasible with ultrasound even in combination with an FNA, which one can easily see may give false negative results if the area of interest is missed. The third case against ultrasound is that alone it only identifies a third of those with positive sentinel nodes which is a low pick up rate and though this rises to 50% in combination with lymphascintography this is poor in comparison with sentinel lymph node biopsy.1 The paper by Morton et al5 which compared sentinel lymph node biopsy and nodal observation in melanoma has been mis-represented in this article. In the study of 1269 patients, those with nodal metastases proven by sentinel lymph node biopsy had a higher 5-year survival rate among those who underwent immediate lymphadenectomy than those in which it was delayed (72.3±4.6% vs. 52.4±5.9%; hazard ratio for death, 0.51; 95% CI, 0.32 to 0.81; P = 0.004). In this study 16% of those undergoing sentinel lymph node biopsy had positive nodes and demonstration of a positive sentinel node combined with early lymphadenectomy conferred a therapeutic advantage to a small but important group of patients. Considering that sentinel lymph node biopsy is such an important prognostic factor which was included in the revised AJCC staging criteria and that technically it is a simple technique, sentinel lymph node biopsy is easily performed at the same time as wide local excision of histologically confirmed melanomas.7 We conclude that sentinel lymph node biopsy is an important tool in the management of malignant melanoma in which the management is primarily through surgery. It allows us to identify those with prognostically worse disease who can potentially derive some benefit from surgery. As with all new techniques at their inception, sentinel lymph node biopsy is offered by only a few centres giving rise to the illusion of a postcode lottery,1 but as more surgeons become familiar with the technique and new services established, its use will become widespread. Most doctors faced with a patient with an intermediate thickness melanoma we feel would offer sentinel lymph node biopsy if available especially as no real alternatives exist beyond surgery at the present time. References 1. Thomas JM. Sentinel lymph node biopsy in malignant melanoma. BMJ 2008; 336: 902-903. 2. Bafounta ML, Beauchet A, Chagnon S, Saiag P. Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis. Lancet Oncol 2004;5:673-80. 3. Van Akkooi AC, de Wilt JH, Verhoef C, Schmitz PI, van Geel AN, Eggermont AM, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol 2006;17:1578-85. 4. Kretschmer L, Hilgers R, Mohrle M, Balda BR, Breuninger H, Konz B, et al. Patients with lymphatic metastasis of cutaneous malignant melanoma benefit from sentinel lymphonodectomy and early excision of their nodal disease. Eur J Cancer 2004;40:212-8. 5. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307-17. 6. Thomas JM. Prognostic false-positivity in the sentinel node in melanoma. Nat Clinic Pract Oncol 2008;5:18-23. 7. Rousseau DL Jr, Ross MI, Johnson MM, Prieto VG, Lee JE, Mansfield PF, Gershenwald JE. Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol. 2003 Jun;10(5):569-74. Competing interests: None declared |
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David G Samuel, final year medical student - Cardiff University CF48 2AS
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While I acknowledge the concerns that Dr Thomas has regarding the therapeutic benefits of Sentinel Lymph node biopsy I have to disagree that the procedure is not warranted in the management of Malignant Melanoma. Having undertaken an 8 week elective study at the Sydney melanoma centre, one of the leading centres in Melanoma research and treatment, and a major player in the development of SLNB and the subsequent MSLT trials, I have seen first hand the prognostic benefits that SLNB brings for clinicians and patients. Patients are informed that the procedure offers no proven therapeutic benefits to them, but does offer a significant prognostic indicator as well as identifying their suitability to enter treatment trials, something that must be encouraged in a condition that has very limited successful therapeutic options. A patient are more than willing to undergo this minimally invasive procedure to gain that prognostic information and also helps them to come to terms with their diagnosis and plan for the remaining time they have. In addition, while the accuracy of Ultrasound analysis continues to improve, smaller lesions, as well as those located within the node capsule are still difficult to detect, and requires a level of expertise in the Ultrasonographer that most individuals who do not do this procedure on a daily basis would fail to obtain. In addition, the MSLT-2 trial is offering a hope that PCR analysis of Sentinel lymph nodes will be able to detect a single melanoma cell if present, something far superior to event the most advanced Ultrasound analysis. SLNB is now being used more and more in the UK for Breast cancer patients for similar reasons – to avoid unnecessary nodal dissection in EVERY patient undergoing mastectomy. I also feel long term results will show that Sentinel lymph node biopsy does offer a survival benefit to patients, as detecting that micro metastases and removing the nodal basin will hopefully prevent recurrence and distant spread. I hope to enter into oncology in the future and only hope that I can offer my patients the opportunity to gain the most accurate prognostic analysis as well as receiving effective medical therapy. Competing interests: Undertook an 8 week undergraduate elective at the Sydney Melanoma Centre, on of the major centres involved in the MSLT trials |
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Anthony Dixon, Censor, Australasian College of Skin Cancer Medicine Geelong, 3216
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I find the intense debate about sentinel node biopsy somewhat puzzling, - particularly in the Australian context now bought to our attention.. Clinicians are getting bogged down with this issue while the fundamentals of managing cutaneous melanoma are being neglected. John Kelly in his recent study1 on management of melanoma in Victoria showed that medical practitioners perform poorly in the key aspects of managing this aggressive tumour. Kelly shows that only 1 in 3 doctors excise cutaneous melanoma with the margins recommended by the Australian guidelines. A third of doctors excise with excessively large margins. More concerning, one third of patients have their melanoma excised with a margin more narrow than recommended. Further, most Victorian doctors fail to check the skin in follow up appointments. They also very frequently diagnose suspicious lesions by biopsy rather than by local excision. Surgeons in Australia are slow to acquire the dermoscopic skills that have been shown to improve early diagnosis of melanoma. A patient with a thin melanoma is more likely to develop a second cutaneous primary than metastatic disease. Yet dermoscopy and skin checks, (aspects fundamental to early detection of a second primary) are neglected by far too many managing melanoma. It is disturbing to hear so much about the sentinel node biopsy procedure which has not been shown to improve five year survival on an intention to treat basis2 when there is so much neglect of the things known to improve outcome in diagnosis, early diagnosis and excision with appropriate margins. If surgeons redirected the time they spent doing the sentinel lymph node procedure into time examining the skin as a routine part of their follow up of their melanoma patients, there would be a tangible gain for our patients. In contrast, a procedure with a 10% complication incidence3 and no 5 year survival improvement2 is hardly a tangible gain. Let us get back to the basics. Let’s offer our patients skin checks for life, ensure dermoscopy is a routine part of such an examination and excise suspicious lesions rather than biopsy them to gain histology. Most importantly, let’s give our patients with invasive melanoma a minimum 10 mm margin of normal skin rather than skimp. 1. Kelly JW, Henderson MA, Thursfield VJ, Slavin J, Ainslie J, Giles GG. The management of primary cutaneous melanoma in Victoria in 1996 and 2000. Med J Aust 2007;187:511-4. 2. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Glass EC, Wang HJ. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307-17. 3. Morton DL, Cochran AJ, Thompson JF, Elashoff R, Essner R, Glass EC, Mozzillo N, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Wang HJ. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg 2005;242:302-11; discussion 311-3. Competing interests: None declared |
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Carlos Garcia, Associate Professor and Director of Dermatologic Surgery Department of Dermatology at the University of Oklahoma, Oklahoma City, Oklahoma, USA 73104
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In my opinion, and based on a critical analysis of randomized trials, the facts are clear with respect to sentinel lymph node biopsy in melanoma: It offers no survival advantage and there is no effective adjuvant therapy for disseminated disease. Nevertheless, most of the published work supports the procedure in spite of growing contradictory evidence. The editorial by Meirion Thomas offers interesting alternatives and questions current dogma and the BMJ should be congratulated for publishing it. I share with the author serious concerns about our ability to control melanoma by merely identifying cancer cells in lymph nodes and then excising them, as the process of metastasis is much more complex and involves not only physical deposition of cancer cells but expression of adhesion molecules,(1) secretion of cytokines, interaction between multiple cells and tissues, and unknown immunologic mechanisms. An interesting theory has been proposed recently suggesting that cancer cells interact with organ tissues and other cells to create "tunnels" of dissemination and a favorable microenvironment that allows even "non- metastatic" tumor clones to develop macrometastases after a variable period of "dormancy".(2) The concept is fascinating, and if true, could explain several shortcomings of the sentinel node biopsy, including false positives and distant metastases after a negative biopsy. Supporters of the procedure should welcome these findings and thoughts and incorporate them into future trials instead of just trying to find survival advantages in retrospective or sub-group analyses. As usual in Medicine, we are unlikely to find the truth unless we consider alternative and opposing ideas. References: 1.- Carlos Garcia, Eduardo Poletti. Sentinel lymph node biopsy for melanoma is still controversial. Journal of the American Academy of Dermatology 2007;56(2):347-348 2.- François-Clément Bidard, Jean-Yves Pierga, Anne Vincent-Salomon, Marie -France Poupon. A “class action” against the microenvironment: do cancer cells cooperate in metastasis? Cancer Metastasis Rev 2008;27:5–10 Competing interests: None declared |
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Andrew J Hayes, Consultant Surgeon, Sarcoma and Melanoma Unit Royal Marsden Hospital
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Sir The early responses to the editorial by Thomas1 on the role of Sentinel Node Biopsy (SNB) in malignant melanoma show a spectrum of opinion regarding possible role of this procedure in the management of malignant melanoma, which is probably representative of the spectrum of opinion and confusion in the medical community in general. At one extreme, one author considers , based on a non randomised subgroup analysis in MSLT-1, that SNB and subsequent completion lymphadenctomy imparts a full 20% survival advantage for patients undergoing SNB even though the primary end point of overall survival was identical in both arms of the trial2 . At the other extreme, another author argues that, if it is now proven that SNB confers no overall survival benefit to patient, focussing attention on a procedure that essentially has only a prognostic role in melanoma detracts from the one medical intervention that can improve outcome, i.e. the early diagnosis and appropriate excision of the primary melanoma. In the middle ground another author argues that if the procedure improves disease free survival even though it does not influence overall survival, then this is a valid trial endpoint and justifies the use of this procedure. In the face of such divergent opinions it might be worth reiterating what information is known with certainty over what is less secure. Given the negative results as regards the primary endpoint of MLST-1, we know with certainty that in patients with intermediate thickness melanoma who undergo SNB and completion lymphadenectomy have no overall survival advantage over patients who undergo delayed lympadenctomy at the time of palpable nodal disease. Given this lack of overall survival benefit, quoting survival differences in the order of 20% between non randomised subgroups either from within MLST-1 or other nonrandomised series erroneously implies a huge therapeutic benefit for the procedure that is not supported by randomised data. Because the results of MLST-1 included regional nodal recurrence in the assessment of disease free survival, the effect of the procedure on disease free survival is less certain2. This is because patients undergoing the SNB procedure underwent prophylactic clearance of the regional node basin. It has not been shown that SNB has any influence on disease free survival at distant sites when the nodal basins are excluded from the anlaysis. Finally at this point in time the standard advice for patients with metastatic melanoma in a sentinel node, microscopic or macroscopic, is that they should undergo a full nodal clearance and this second operation carries substantial morbidity, even if the removal of the sentinel node itself does not. Thomas’s hypothesis of prognostic false positivity of microscopic deposits in the sentinel node presents an explanation as to why patients with sentinel node positive patients appear to fare so much better than those with palpable nodal disease , even though overall the survival of patients in both arms were the same. Ultrasound surveillance is a simple logical extrapolation of that hypothesis If his hypothesis is correct then up to 25% of the patients with positive sentinel nodes have been saved a morbid nodal clearance they did not need. If patients with microscopic disease do progress- as inevitably some must - then no harm befalls these patients as we know that SNB does not impact on overall survival and they will still undergo appropriate surgery for small volume disease detected by ultrasound surveillance. Andrew Hayes MA PhD FRCS
References 1. Thomas JM. Sentinel lymph node biopsy in malignant melanoma. BMJ 2008; 336: 902-903. 2. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307-17. Competing interests: None declared |
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Michael Sladden, Consultant Dermatologist and Hon Senior Lecturer Department of Medicine, University of Tasmania, Launceston, Tasmania
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Sir, The recent editorial concerning the role of sentinel lymph node biopsy (SLNB) in melanoma [1], and corresponding rapid responses, provide excellent debate about this controversial issue. The MSLT-1 trial [2], to date the only published randomized controlled trial comparing SLNB with nodal observation, demonstrated no melanoma specific survival advantage between the two study groups (the only non-controversial conclusion from the study), although the other trial conclusions have been challenged and debated in the international literature [3,4]. Many questions remain unanswered about the utility of SLNB. Is SLNB a good prognostic tool? Clearly the answer is yes, but just how good, and is ultrasound (or other imaging techniques) more cost- effective, safer, better? SLNB is useful for staging of melanoma before offering patients entry into controlled clinical trials. However, there are false positives and false negatives, as with all such tests, and well- reported side effects and complications (even in expert hands). Patients with negative sentinel nodes presumably require follow-up assessment for recurrent melanoma, as well as for early detection of a second primary. Does SLNB provide survival benefit? To date, MSLT-1 shows no overall survival advantage from the procedure but debate remains whether certain patient (non-randomised) subgroups may benefit. What is the best management for patients with micrometastases detected by SLNB? It is not known whether completion lymphadenectomy provides a survival advantage for node positive patients, although this might be clarified by MSLT-2, and currently no effective chemotherapy is available to treat melanoma patients [3]. Patients should be advised of this uncertainty prior to selecting treatment, and given the option to enrol into ongoing clinical trials. In Australia, as part of the process of revising national melanoma guidelines, there has been intense, cordial and constructive debate about the value of SLNB. Whilst MSLT-1 and MSLT-2 are ongoing, clinicians should be aware of both sides of the SLNB debate, and not pre-empt study results. We must aim to reach sensible consensus, develop balanced guidelines, provide patients (and their families) with the best possible care, and assist patients to make wise and informed choices, at a time of great stress and vulnerability. References [1] Thomas JM. Sentinel lymph node biopsy in malignant melanoma. BMJ 2008; 336: 902-903. [2] Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Glass EC, Wang HJ. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355:1307-17. [3] Thompson JF. The value of sentinel node biopsy in patients with primary cutaneous melanoma. Dermatol Surg. 2008; 34: 550-4; discussion 554-5. [4] Zitelli JA. Sentinel lymph node biopsy: an alternate view. Dermatol Surg. 2008; 34: 544-9; discussion 549. Competing interests: None declared |
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Barry Powell, Consultant Plastic Surgeon Melanoma Unit, St George's Hospital,London. SW17 0QT
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Sir, I would like to raise issue regarding the editorial by Mr. Thomas1 The first relates to the concept of “false positivity”. In the 3rd interim analysis of MSLT-I 2 15.6% of patients developed nodal recurrence in the observation arm as compared to 19.4% in the SLNB positive arm and those who were false negative. This leads to the assumption that there are a group of false positive. However, in the 4th interim analysis, recently presented in February 2008, those figures have now changed.3 At 10 years the group of nodal recurrence is 20.5% and the biopsy group is 20.8%. This implies that microscopic disease will eventually become macroscopic disease. Clinicians have long argued that we must wait for the full term data of MSLT-I rather than speculate. Melanoma is a fickle disease which can take many years to manifest. Assumptions are made about ultrasound and Fine Needle Aspirate. These findings are based on the work of a single unit 4. This work has yet to be reproduced by others. The work is exceptional but clearly indicates that it is very operator dependant and, as yet, not been subjected to any prospective, randomised trial. Furthermore, in order for SNBs to be identified by this technique the node must contain metastases of at least 4mm or larger. In MSLT-I, in the group of patients with tumours with Breslow thickness between 1.2-3.6mm, the majority of nodal metastases were less than 4 mm (usually <1mm) thereby preventing detection. Also, a negative SNB on US and FNA does not confirm a negative SNB. In the article the author refers to “clinically relevant micro metastases” What is “clinically relevant” and where is the evidence? Where is the proof that treating these groups of patients offers a survival advantage? Until this is undertaken we must purely speculate. At present no specific adjuvant treatment exists. This does not mean that we will not find one. The argument that staging melanoma is pointless as we cannot treat it means that we will never move forward with trying to establish a cure. The results of EORTC 18991 peg –Interferon (INF) trial shows a statistically significant relapse free survival, distant metastases free survival and a tendency to overall survival in those patients who where SNB positive, underwent a CLND and had INF as compared to those with watch and wait, therapeutic dissection and INF. 5 Without the technique of SNB we would never know the answers to such studies as these. The morbidity of SNB has been published in MSLT-I and is low (<10%.) 1 Thomas JM. Sentinel lymph node biopsy in malignant melanoma. BMJ 2008; 336: 902-903 2 Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel node biopsy or nodal observation in melanoma. N Engl J Med 2006; 355:1307-17. 3 Morton DL. IVth Interim analysis of MSLT-I. 6th Biennial International Sentinel Node Society Meeting, 18 – 20 th February Sydney 2008. 4 Voit CA, van Akkooi AC, Schafer-Hesterberg G, Schoengen A, Sterry W, Eggermont AM. Role of ultrasound (US) and US-guided fine needle aspiration cytology (US-FNAC) prior to sentinel lymph node biopsy (SLNB) in 500 melanoma patients: reduction of need for SLNB by high US-FNAC SN positive identification rate. J Clin Oncol 2007; 25(18S):8512. 5 Eggermont AM et al. EORTC 18991: Long term adjuvant pegylated interferon-a2b (PEG-IFN) vs. observation in resected stage III melanoma: final results of a randomized phase 3 trial. (2007) J Clin Oncol 25 (Supplement): 8507 Competing interests: None declared |
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Ilkka Koskivuo, Consultant Plastic Surgeon Department of Surgery, Turku University Hospital, 20521 Turku, Finland
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Sir, Regarding the hypothesis of false-positive sentinel nodes, there are two main points that Thomas fails to consider (1). Firstly, the excellent prognosis of nodal submicrometastasis may be associated with lead time bias, i.e. to the long, slow and natural progression of the disease. Occasionally, nodal relapse will not occur until beyond many years. An important question arises: Could those late appearing nodal metastases have been detected initially as submicrometastases or as isolated tumor cells in the sentinel node, if SLNB had been performed at the time of disease presentation? The answer is yes. Scolyer at al identified a small number of melanoma patients, whose sentinel nodes were originally reported as pathologically negative, but who had subsequently developed regional nodal recurrence; subsequent more detailed pathologic reanalysis found very small submicrometastatic deposits in the subcapsular sinus region of the sentinel node (2). This possibility of lead time bias was also discussed by van Akkooi et al recently (3,4). Secondly, the detection of submicrometastases is based on SLNB, i.e. on the excision of metastatic nodes - which is their treatment. On the positive side, the perfect outcome within this small patient population may be considered as an indicator that in this subgroup of patients with a low metastatic tumor volume and no nonsentinel metastases, SNLB provides a true survival benefit. Thomas stated correctly that "the prognosis worsens as the tumour burden increases". Logically, if we do not exactly know whether a micrometastasis will develop into clinically relevant nodal disease or not, why should we leave those malignant cells behind and wait until as the tumour burden increases? To date, there is no empirical evidence of benign metastases in patients with cancer. Thomas argues that the use of SLNB is not justified for its prognostic value, because no effective adjuvant therapy exists. However, adjuvant therapy is not the only aim of accurate staging. The patient with melanoma will be followed up for several years and the follow-up schedule should be tailored for each patient according to the individual prognosis which is based on the result of SLNB. Because sentinel-positive patients have a high risk of recurrence, they should be referred for intensive specialist follow-up. In contrast, low-risk patients constitute the majority of the melanoma population and if they are sentinel-negative, this predicts favourable outcome. Without SLNB, which is minimally invasive one-step procedure, these patients would need regular ultrasound (US) controls lasting for several years. Finally, we cannot understand that US-guided fine needle biopsy could replace the current SLNB staging. Such an argument is not based on sufficient and controlled evidence. In our recent study, a majority of sentinel-positive patients had their micrometastasis of ≤ 1.0 mm in centripetal penetrative thickness (5). This is far below the detection level of US, which is 4-5 mm (6-8). Ilkka Koskivuo
1. Thomas JM. Sentinel lymph node biopsy in malignant melanoma. Bmj 2008;336(7650):902-3. 2. Scolyer RA, Murali R, Gershenwald JE, Cochran AJ, Thompson JF. Clinical relevance of melanoma micrometastases in sentinel nodes: too early to tell. Ann Oncol 2007;18(4):806-8. 3. van Akkooi AC, de Wilt JH, Verhoef C, Schmitz PI, van Geel AN, Eggermont AM, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol 2006;17(10):1578-85. 4. van Akkooi AC, Bouwhuis M, de Wilt JH, Kliffen M, Schitz PI, Eggermont AM. Authors' reply: Multivariable analysis comparing outcome after sentinel node biopsy or therapeutic lymph node dissection in patients with melanoma (Br J Surg 2007; 94: 1293-1299). Br J Surg 2008;95(5):664-5. 5. Koskivuo I, Talve L, Vihinen P, Maki M, Vahlberg T, Suominen E. Sentinel lymph node biopsy in cutaneous melanoma: a case-control study. Ann Surg Oncol 2007;14(12):3566-74. 6. Hafner J, Schmid MH, Kempf W, Burg G, Kunzi W, Meuli-Simmen C, et al. Baseline staging in cutaneous malignant melanoma. Br J Dermatol 2004;150(4):677-86. 7. Sibon C, Chagnon S, Tchakerian A, Bafounta ML, Longvert C, Clerici T, et al. The contribution of high-resolution ultrasonography in preoperatively detecting sentinel-node metastases in melanoma patients. Melanoma Res 2007;17(4):233-7. 8. Starritt EC, Uren RF, Scolyer RA, Quinn MJ, Thompson JF. Ultrasound examination of sentinel nodes in the initial assessment of patients with primary cutaneous melanoma. Ann Surg Oncol 2005;12(1):18-23. Competing interests: None declared |
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J Meirion Thomas, Professor of Surgical Oncology Royal Marsden Hospital, London SW3 6JJ
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I am grateful to colleagues on both sides of the opinion spectrum for contributing to the debate about sentinel lymph node biopsy (SLNB) in melanoma. With regard to the letter from Mr Malcolm Kell, my calculation of the increased incidence of local and in-transit recurrence after completion lymphadenectomy in sentinel node-positive patients was based on an overview of studies published by units advocating SLNB1. Two units who were signatories to MSLT-1 have independently reported this finding. Since that paper, another unit advocating SLNB has concluded that “sub- groups of patients can be identified who seem to have an increased risk of developing in-transit metastases as site of first recurrence and individual therapeutic strategies should be developed for these patients”2. As presently calculated, a disease-free survival in MSLT-1 is inevitable because of a bias caused by study design. The most likely site of first recurrence in patients with intermediate thickness melanoma is the sentinel node basin and in MSLT-1, sentinel node-positive patients in the biopsy arm were treated by “prophylactic” lymphadenectomy at the time of diagnosis. Therefore, there will inevitably be more nodal recurrences as site of first recurrence in the observation arm and this is confirmed in the table relating to site of first recurrence (11% versus 3%)3. Following an appeal on this matter to the National Cancer Institute, who funded MSLT-1, the reply from it’s Clinical Investigations Branch states that “We have indicated to Dr Morton our belief that he should include a DFS analysis in the next update of this study that excludes nodal recurrences“ (personal communication). In other words, in future, DFS will also have to be calculated on the competing incidences of local/in- transit and distant recurrences only. Mr Nighat Butt’s comment about a 20% survival benefit in sentinel- node positive patients who have early lymphadenectomy derives from what is now agreed to be a statistically invalid sub-group analysis that was prominently reported as one of the two conclusions in the Abstract of MSLT -13. In this calculation from the third interim analysis, the survival of 122 sentinel node-positive patients who had early lymphadenectomy was compared to the survival of 78 patients in the observation arm who had delayed lymphadenectomy. However, the 26 false-negative patients in the biopsy arm were omitted from this survival calculation and this error is the basis of my argument for prognostic false-positivity. These 26 patients were also sentinel node-positive but their true status was not identified by the SLNB procedure4. Therefore, the 20% survival advantage is explained by a prognostic difference between the two groups of patients compared and is not due to any therapeutic benefit from early lymphadenectomy. With regard to Mr Barry Powell’s argument, the fourth interim analysis is at a median follow-up time of eight years and since the third interim analysis at five years, there have only been six more patients in the observation arm and two false-negative patients in the biopsy arm who have developed palpable nodal recurrence. As Dr Morton explained in Sydney in February 2008, only 80% of results for the fourth interim analysis had been collected and therefore, both of these figures may increase slightly. Nevertheless, this means that 16.8% (84/500) of patients in the observation arm have recurred compared to 19.6% [(122+28)/764] of patients in the biopsy arm. This difference includes patients who are false-positive and the tiny number of patients who will recur after the fourth interim analysis. It is not clear to me how the comparable figures quoted by Mr Powell (20.5% v 20.8%) were derived. I am grateful to Dr Ilkka Koskivuo for coining the term “benign metastasis” which encapsulates the argument for prognostic false- positivity. Because tiny deposits of melanoma cells have reached the sub- capsular sinus of the sentinel node, it does not mean that they will inevitably progress to “malignant metastases”. For this to happen a complex series of biological events must take place. The melanoma cells must first develop a proliferative potential and the ability to both induce angiogenesis and overcome host resistance to progression in the micro-environment. This situation may be similar to that described in other cancers where patients are found to have tumour cells in the circulating blood and in the bone marrow but who never develop metastatic disease. Anyone who doubts the possibility of prognostic false- positivity should read a fascinating paper recently published about delayed-SLNB meaning SLNB performed at a median time of 3.8 years after wide excision of the primary tumour5. Are these “sleeper cells” not “benign metastases”? J Meirion Thomas MS FRCP FRCS
References 1. Selective lymphadenectomy in sentinel node-positive patients may increase the risk of local/in-transit recurrence in malignant melanoma. Thomas JM, Clark MA. Eur J Surg Oncol 2004;30:686-691 2. Factors predicing the risk of in-transit recurrence after sentinel lymphonodectomy in patients with cutaneous malignant melanoma. Kretschmer L, Beckmann I, Thomas K-M, Mitteldorf C, Bertsch HP, Neumann C. Ann Surg Oncol 2006;13(8):1105-1112 3. Sentinel node biopsy or nodal observation in melanoma. Morton DL. N Engl J Med 2006;355:1307-17 4. Prognostic false-positivity in the sentinel node in melanoma. Thomas JM. Nat Clin Pract Oncol 2008;5:18-23. 5. The sleeper cells: delayed sentinel lymph node biopsy. Murugkar P, Assawi K, Humzah D. J Plast Reconstr Aes Surg 2007;60(12):1357-1360 Competing interests: None declared |
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Nicholas Cawrse, Specialist Registrar Plastic Surgery Department of Plastic Surgery, Royal Devon & Exeter Hospital, EX4 5DW, David Oliver and Christopher Stone
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Editor, The recent editorial on sentinel lymph node biopsy (SLNB) for melanoma provided an interesting update on the role of ultrasound in the detection of occult lymph nose disease as an alternative to sentinel node biopsy. Certainly if a sensitive non-invasive test for melanoma lymph node metastases becomes available it will be keenly embraced by the proponents of SLNB. However, SLNB is a simple technique with very low morbidity and can be undertaken with no extension to operative time alongside the wide local excision of the biopsy scar, even under local anaesthesia. SLNB is undoubtedly the most sensitive staging tool available for melanoma and if effective adjuvant treatments are to be developed then its use will continue. Moreover, SLNB is often demanded by patients who are reassured by a negative result or by early clearance of metastatic disease. The MSLT -1 data on positve SLNB and early completion lmyphadenectmy, compared with delayed therapeutic lymph node dissection for palpable disease, has been interpreted by Morton et al to confer an overall disease-specific survival advantage(1) and most would agree that there is an improvement in the disease free interval to be gained. SLNB is not undertaken simply to fill lists or for the surgical gratification of its proponents but in order to confer these benefits on patients. With improvements in ultrasound technology it is clear that melanoma deposits of ever-smaller dimensions may be detected, although confirming disease on the basis of FNA cytology will remain difficult. At present ultrasound guided cytology can only detect half of all metastases greater than 3mm - so what happens to the other half? Would these patients be happy to simply await the development of macroscopic disease? It is difficult to know what the significance of very low volume disease in the SLN is, but the number of patients undergoing a positive SLNB in MSLT-1 was similar to that requiring a therapeutic lymphadenectomy for palpable disease, suggesting that most, if not all, microscopic disease will progress to clinically detectable nodal metastases(2). Current research is focusing upon avoidance of the completion lymphadenectomy following a positive SLNB where low volume disease is present in the subcapsular sinus of the node, further reducing the overall morbidity associated with the technique in this patient group. Non-invasive staging modalities for the SLN will undoubtedly replace SLNB in the fullness of time, but for now ultrasound in not sufficiently sensitive and needs further evaluation. References 1. Morton DL, Thompson JF, Cochran AJ, Mozzillo, Elashoff R, Essner R, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Glass EC, Wang HJ; MSLT Group. Sentinel-node biopsy or nodal observation in melanoma. N Eng J Med 2006; 355:1307-17 2. McArthur GJ, Powell BW. Sentinel lymph node biopsy in melanoma. In: Stone C, ed. The evidence in plastic surgery. Shrewsbury: tfm Publishing, 2008:117-125 Competing interests: None declared |
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Rachel A Abbott, Dermatology registrar Melanoma Group, Guy's and St. Thomas' NHS Foundation Trust, London SE1 7EH, Katharine Acland, Robin Russell-Jones, Frank Nestle, Mark Harries, Ciaran Healy, Eduardo Calonje, Michael O'Doherty
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The recent editorial concerning the role of sentinel lymph node biopsy (SLNB) in malignant melanoma (MM) requires clarification.1 Firstly, SLNB is the most widely accepted staging procedure in the management of MM and currently forms the basis of the American Joint Committee on Cancer (AJCC) staging criteria.2 Disease staging provides important prognostic information for patients and clinicians in determining appropriate follow up as well as allowing trial eligibility and potential future adjuvant treatment. Thus, in a specialist multidisciplinary team (MDT) setting, SNLB is an integral part of managing MM with low complication rates in experienced hands. Secondly, lymph node ultrasound (US) with scintigraphy and US-guided fine needle aspiration cytology lacks evidence as a screening tool in the management of MM as data has only been presented from a single centre.3 Also, ultrasonography is an operator dependent procedure and only detects MM metastases over 3-4 mm in lymph nodes.4 Thirdly, excision of all MM tumour cells is the mainstay of treatment for primary MM, in-transit metastases and distant metastases. There is no evidence to suggest that lymph node metastases should be treated any differently. Thomas’ speculation regarding prognostic false positivity has been negated by data published by the multicenter selective lymphadenectomy trial (MSLT)-I group which indicates that at 10 years, ‘the incidence of nodal metastases in the observation group will eventually equal the total incidence of nodal metastases detected by biopsy or by biopsy with false negative results’.5 Monitoring those patients with MM AJCC stage 1B-2C until the development of detectable lymph nodes by clinical examination or ultrasound simply leads to a delay in the detection of lymph node metastases and subsequent lymph node dissection. The therapeutic benefit from lymph node dissection in patients with positive SLNB is under evaluation by MSLT-II, in which our centre is the only UK participant.6 This trial is also assessing the role of serial nodal basin ultrasound in patients with positive SLNB. In conclusion, until evidence is available for a more valid staging tool then SLNB should be offered to all patients with MM AJCC stage 1B-2C in a specialist MDT setting. References: 1. Thomas JM. Sentinel lymph node biopsy in malignant melanoma. BMJ 2008;336:902-903. 2. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635-48. 3. Voit CA, van Akkooi AC, Scafer-Hasterberg G, Schoengen A, Sterry W, Eggermont AM. Role of ultrasound (US) and US-guided fine needle aspiration cytology (US-FNAC) prior to sentinel lymph node biopsy (SNLB) in 500 melanoma patients: reduction of need by high US-FNAC SN positive identification rate. J Clin Oncol 2007;25(18S):8512. 4. Bafounta M-L, Beauchet A, Chagon S, Saiag P. Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis. Lancet Oncol 2004;5:673-80. 5. Morton DL, Cochran AJ, Thompson JF. Authors’ response to a letter to the editor re: sentinel-node biopsy in melanoma. NEJM 2007;356:419-421. 6. Amersi F, Morton DL. The role of sentinel lymph node biopsy in the management of melanoma. Adv Surg 2007;41:241-256. Competing interests: None declared |
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Rachel A Abbott, Dermatology registrar Melanoma Group, Guy's and St. Thomas' NHS Foundation Trust, Katharine Acland, Robin Russell-Jones, Frank Nestle, Mark Harries, Ciaran Healy, Eduardo Calonje, Michael O'Doherty
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Further to yesterday's response to Thomas' editorial (1), Abbott et al. would like to correct two points. Firstly, lymph node ultrasound (US) with scintigraphy and US-guided fine needle aspiration cytology as a screening tool in the management of malignant melanoma (MM) lacks convincing evidence from multiple controlled studies as data has only been presented from a single large study (2) and not from a single centre as previously stated. Secondly, complete removal of all MM tumour cells is not the standard of care in all cases of in-transit or distant metastatic melanoma. References: 1. Thomas JM. Sentinel lymph node biopsy in malignant melanoma. BMJ;336:902-903. 2. Voit CA, van Akkooi AC, Scafer-Hesterberg G, Schoengen A, Sterry W, Eggermont AM. Role of ultrasound (US) and US-guided fine needle aspiration cytology (US-FNAC) prior to sentinel lymph node biopsy (SNLB) in 500 melanoma pateints: reduction of need for SNLB by high US-FNAC SN positive identification rate.J Clin Oncol 2007;25:8512. Competing interests: None declared |
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Perry N Board, Consultant Anaesthetist Leighton Hospital, Crewe, CW1 4QJ
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I am 43 and was diagnosed with intermediate thickness melanoma on my calf in December 2007. I underwent wide local excision and sentinel lymph node biopsy (SLNB), with the chances of the latter being positive only 15%. Unfortunatley a 1mm micrometastasis was found. The risks of completion lymphadenectomy were explained to me as was the the view that it might not alter my prognosis. Major surgery with a high complication rate for nothing? A dilemna. It wasn't a hard decision. I felt it was better to do something than to do nothing. I had the surgery, it went better than expected and apart from the inevitable seroma which has now settled, I had no complications. 4 months on my leg is healed, I feel fine and am off surfing next week. If I'd been referred to my closest tertiary centre, I wouldn't have been offered SLNB and the cancer cells would still be in my groin. A tall order for my immune system and a frightening thought for me. I would have been graded as stage 2 rather than stage 3 and hence not offered any clinical trials of adjuvant therapy. I am now enrolled in a trial of bevacizumab, a drug which has potentially life-theratening complications, yet I was delighted to be randomised to receive it. After 4 cycles, all is well. Again, better to be proactive. Despite the controversy about SLNB, I do not regret having completion lymphadenectomy surgery. The complications were minimal and I have the reassurance that the cancer was dealt with as comprehensibly as is currently possible. Psychologically, much better than wait and see. What affect a positive mindset on the immune system? Competing interests: None declared |
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Gary L Ross, Consultant Plastic Surgeon, Honorary Senior Lecturer Christie Hospital, Manchester M20 4BX
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Sentinel node biopsy is the most important discovery in surgical oncology for decades. It has improved our understanding of the lymphatic drainage systems and focused a number of separate disciplines in the early detection of cancer spread. The combination of radiology, nuclear medicine and surgery with additional pathological staging to sentinel nodes has allowed the identification of micrometastatic disease that previously would have remained undetected. Unfortunately, as highlighted by others we do not know what this means and we do not have treatment protocols as yet to alter prognosis. We must remember that sentinel node biopsy is still a staging tool and as such allows us to clearly define patient populations to identify treatment protocols with the aim to improve prognosis. With sentinel node biopsy we are able to define patient populations more appropriately and by offering these patients more appropriate treatment trial protocols we may improve prognosis. Research into sentinel node biopsy has allowed us to identify and classify micrometastases more appropriately. Anatomical imaging techniques cannot provide these answers and even functional imaging lacks sufficient sensitivity/specificity. Pathologically the delineation between isolated tumour cells and a micrometastasis from a staging standpoint remains contentious. There is no doubt as in other cancers that micrometastatic disease confers a prognostic influence, only time will tell whether isolated tumour cells may have the same effect. Further research into sentinel node biopsy can deliver further answers but will undoubtedly ask more questions which we can further hypothesize over in the future. Centers offering sentinel node biopsy should have appropriate training, appropriate facilities and must provide patients entry into appropriate clinical trials. Sentinel node biopsy should only be offered to patients who can comprehend the pros and cons for such a staging tool, as highlighted by Dr Board, with the ultimate decision on whether to undergo sentinel node biopsy to stage the clinically negative nodal basin left with the patient. Competing interests: None declared |
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