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EDITORIALS: J Meirion Thomas and Erica J Patocskai The argument against sentinel node biopsy for malignant melanoma BMJ 2000; 321: 3-4 [Full text]

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What is a prognosis worth?

Sarah Wookey   (2 July 2000)

Sentinel Lymph Node Biopsy: Cost Implications & the Oxford Experience

David Lam   (2 July 2000)

Sentinel Node Biopsy for Staging and Prognosis

M Dalvi Humzah   (12 July 2000)

No UK trials are currently recruiting, but future ones deserve support

Barry Powell   (19 July 2000)

Psychological benefits of sentinel lymph node biopsy

Sukh Rayatt   (24 July 2000)

The argument for sentinel node biopsy

Robin Russell-Jones   (14 August 2000)

Sentinel Node Biopsy

Paul E Baguley   (29 August 2000)

What is a prognosis worth? 2 July 2000
Sarah Wookey, General Practitioner West Bar Surgery, Banbury Send response to journal: Re: What is a prognosis worth?	Thomas and Patocskai seem to consider and dismiss the value of sentinel node sampling as a prognostic tool, since they feel that there is so little to be done to modify the natural hisory of the disease once there is evidence of micrometastases. They seem not to appreciate that patients may want to have the opportunity of being given as accurate a prognosis as possible, despite knowing that effective treatment may not be available if more widespread disease is diagnosed. Last month my intermediate thickness melanoma was excised. I was aware that a negative sentinel lymph node biopsy would increase my 5 year survival chances to above 90%, and that a positive result would reduce this to around 50%. I was also aware that I had between a 7% and 20% chance of the biopsy being positive. These were statistics my 11 year old daughter could understand. If my mother had just had Huntington's disease diagnosed I feel it unlikely that my request for a prognostic test would be turned down on the basis that the disease is untreatable. Perhaps there should be a fuller debate about the amount of money the NHS is prepared to spend on establishing prognoses.
Sentinel Lymph Node Biopsy: Cost Implications & the Oxford Experience 2 July 2000
David Lam, SpR Plastic Surgery The Radcliffe Infirmary, Oxford Send response to journal: Re: Sentinel Lymph Node Biopsy: Cost Implications & the Oxford Experience	Dear Sir, We would agree with the comments of Thomas and Patocskai (1) regarding caution with the indications for the use of sentinel lymph node biopsy (SLNB). Currently, cost implications at our Unit have been calculated as being £714 per SLNB compared to £2,575 per completion lymph node dissection (2). (This is based on an average stay without complications being taken into account). From January 1999 to present we have performed 42 SLNB's at a cost of £29,988. This is in addition to the cost of the gamma probe at approximately £15,000. Seven SLNB positive patients went on to completion lymph node dissection at a cost of £18,025, a total expenditure of £48,013 without equipment or complications being accounted for. Although this would have been regarded as cost saving with regard to the US practice of elective lymph node dissection (42 patients would have cost approximately £108,150), the more selective UK approach of therapeutic lymph node dissection would have cost only the £18,025 as detailed above. Hence, it is vital to emphasise that there will be at least a doubling of service costs to perform SLNB's. The teamwork approach also cannot be overemphasised since accurate histological analysis is paramount. The number of sections examined, together with the use of immunohistochemical stains such as S-100 or HMB- 45 in conjunction with H&E, appear to be more specific than reliance on reverse transcriptase polymerase chain reaction analysis, which has a high false positive rate (3). However, the SLNB does confer distinct advantages in that it may be identifying the same group of patients who would benefit from completion lymph node dissection at an earlier stage with micrometastases before the onset of palpable nodal disease (4). Until the results are published from trials to validate the therapeutic efficacy of sentinel node biopsy using survival as an endpoint (5), the technique must be restricted to specialist Units. The staging information gleaned from the SLNB will effectively double service costs if there is to be widespread implementation. D.G.K. Lam Specialist Registrar M.D. Humzah Consultant Dept. of Plastic & Reconstructive Surgery, The Radcliffe Infirmary, Oxford, UK.. References 1. Meirion Thomas J, Patocskai EJ The argument against sentinel node biopsy for malignant melanoma . BMJ 2000;321:3-4 ( 1 July ) 2. Lam DGK, Millard P, Shepstone B & Humzah MD 'Sentinel lymph node biopsy:cost implications & the Oxford experience. Research Viewpoint: 2nd Melanoma Research Meeting, Milan, Abstract Book 2000:48-49. 3. Van Diest PJ Histopathological workup of sentinel lymph nodes: how much is enough? J Clin Pathol. 1999;52(12):871-3. 4. Balch CM, Soong SJ, Bartolucci AA, Unst MM, Karakousis CP, Smith TJ, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 1996; 224: 255-266 5. Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg O, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Ann Surg 1999; 230: 453-465
Sentinel Node Biopsy for Staging and Prognosis 12 July 2000
M Dalvi Humzah, Consultant Plastic Surgeon Radcliffe Infirmary, Oxford Send response to journal: Re: Sentinel Node Biopsy for Staging and Prognosis	EDITOR - Thomas and Patocskai make several statements in their editorial that should be carefully considered (1). Currently there is no effective adjuvant therapy for stage III disease patients with melanoma and unfortunately less than 20% of patients in the UK who are eligible for clinical trials are actually entered into them. In order to get useful results from the new trials being proposed it is important that the patients are accurately staged. Sentinel node biopsy will enable further delineation of patients with regard to their nodal status; this technique will therefore become a useful discriminator between Stage II and Stage III disease and would need to be considered prior to entry into a clinical trial. Thomas and Patocskai contend that patients who have a negative sentinel node would need to be kept under review. One would hope that all patients with melanoma (whether sentinel node negative or positive) are kept under review according to current guidelines. The sentinel node technique is not a reason to stop following-up node negative patients. They rightly state that node positive patients have a worse prognosis (67%) compared to node negative patients (93%); however they question the prognostic information obtained by this technique. The incidence of melanoma in the UK is relatively low (4,000), but tends to affect younger individuals. A prognosis of 93% compared to 67% will be of immense importance to them. Given that we are in an era of ‘informed consent’, one wonders how many of their patients are informed that there is an investigation available that would potentially up-stage 20% (1 in 5) of those patients who have a melanoma >1mm thick. This ability ‘to stratify patients prognostically’ may not be important to their practice but the individual patient who has this information can now make important decisions regarding their future. None of the patients in our trials refused this procedure despite being informed of the lack of effective treatments available and the inaccuracies in the technique. Thomas and Patocskai state that sentinel node biopsy has no therapeutic value, and current evidence supports this. However, they fail to acknowledge that at present this is an effective technique for accurately staging a patient and identifying those regional and “in- transit” basins at risk for disease (2). Although they do not offer sentinel node biopsies to their patients, the newer technique that they mention i.e. reverse transcriptase-polymerase chain reaction is experimental, expensive, has a high false positive rate (3) and does not have any therapeutic value. Sentinel lymph node biopsy is widely available to patients with melanoma in the United States, Australia and Europe. The World Health Organisation has recommended that sentinel node biopsy become a standard procedure for patients with melanoma. Information regarding sentinel node biopsy is freely available and accessible by the general public; who will expect their specialist to give them the opportunity to be involved in the decisions regarding their management and prognosis – failure to do so may lead to a loss of confidence. In the UK only a few centres currently offer sentinel node biopsy. All our patients are entered into ongoing clinical trials within the UK and Europe and this should be supported. Those centres that offer sentinel node biopsy will continue to be at the forefront of all current ideas and look forward to the support from those units that do not offer this procedure. References 1. Meiron Thomas J, Patocskai EJ The argument against sentinel node biopsy for malignant melanoma. BMJ 2000; 321:3-4. (1July) 2. Norman J, Cruse CW, Wells K et al. A redefinition of skin lymphatic drainage by lymphoscintigraphy for malignant melanoma. Am J Surg. 1991;162: 432-7. 3. Van Diest PJ Histological workup of sentinel lymph nodes: how much is enough? J Clin Pathol. 1999 52(12):871-3. Mr. M. Dalvi Humzah Consultant Plastic Surgeon Department of Plastic & Reconstructive Surgery, The Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK dalvi.humzah@nds.ox.ac.uk
No UK trials are currently recruiting, but future ones deserve support 19 July 2000
Barry Powell Send response to journal: Re: No UK trials are currently recruiting, but future ones deserve support	Dear Sir - Thomas and Patocskai highlight that all patients undergoing sentinel node biopsy for malignant melanoma should be confined to trials (1). All those involved in the technique would support this. However, at the present time, no trial exists for these patients. The Multicentre Sentinel Lymphadenectomy trial has stopped accruing patients (2) and an EORTC trial is only coming on line in September 2000. A sub- group of the Melanoma Study Group is going through the stage of ethical approval for a multicentre prospective trial in the UK. However, with such a limited number of centres undertaking the technique, numbers will be small. It is to support both these forthcoming trials that I believe sentinel node biopsy should be supported in the UK. The authors quote the American Intergroup Melanoma Trial showing a survival benefit in patients <60years old, with tumours between 1.1- 2.0mm and no ulceration in those who underwent wide local excision (WLE) and elective lymph node dissection (ELND) versus WLE alone (3). The WHO Melanoma program (Trial 14) confirmed a survival benefit in men with melanoma less than 4.0mm who underwent WLE and ELND compared with WLE alone (p=0.03) (4). A further update to this trial has been published. After an 8 year follow up, the 5 year survival rate in patients with occult nodal metastases was 48.2% in patients with ELND as compared to 26.6% in whom WLE and therapeutic (delayed) lymph node dissection was carried out (5). The belief is that sentinel node biopsy will help us define that population who will benefit. It is of note that the recent AJCC classification being reviewed has taken into account the development of sentinel node status and it is now included in staging the disease (6). It is also of note that the World Health Organization has recommend that sentinel node biopsy become standard procedure for patients with tumours of Breslow thickness >1.0mm (7). These comments alone must surely justify the inclusion of this valuable investigation in all future Health Service funding proposals. Following 300 sentinel node biopsies undertaken in the Melanoma Unit at St. George's Hospital, we have not seen any increased evidence of entrapment. A number of patients have developed local recurrent disease following sentinel node biopsy but the numbers have not changed from the days of WLE alone. Barry Powell Consultant Plastic Surgeon Melanoma Unit St. George's Hospital London SW17 0QT 1. Thomas M and Patocskai EJ. The argument against sentinel node biopsy for malignant melanoma. BMJ. 2000 321: 3-4 (1 July) 2. Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Niewig O. et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early stage melanoma: a multicentre trial. Ann. Surg. 1999; 230:453-65 3. Balch CM, Soong SJ, Bartolucci AA, Unst MM, Karakousis CP, Smith TJ et al. Efficacy of an elective regional lymph node node dissection of 1-4mm thick melanomas for patients 60 years and younger. Ann. Surg. 1996; 224: 255-66. 4)Cascinelli N. The role of clinical trials in assessing optimal treatment of cutaneous melanoma not extending beyond the regional nodes.Eur. J. Surg. Oncol. 1996:22:123-133 5) Cascinelli N, Morabito A, Santinami M, et al. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomized trial. Lancet 1998; 351:793-796 6) Balch C, Buzaid A, Aitkins M, Cascinelli N, Coit D, Fleming I et al. A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 2000: 88: 1484-1491 7) Reintgen D. Mediview Express Report. 4th Perspectives in melanoma. 2000 June. Pittsburgh
Psychological benefits of sentinel lymph node biopsy 24 July 2000
Sukh Rayatt, SpR in Plastic Surgery Sandwell Healthcare NHS Trust Send response to journal: Re: Psychological benefits of sentinel lymph node biopsy	EDITOR, The editorial by Thomas and Patocskai1 summarises the current state of Sentinel lymph node biopsy (SLNB) for malignant melanoma.(1) What they omitted to address was the patient's perception of the procedure. Anecdotal evidence suggests that melanoma patients derive psychological benefit from having the procedure, regardless of the result. To investigate any such benefit our unit carried out a study looking at the acceptability and benefits of the procedure. A specially designed questionnaire regarding the procedure was sent to 110 patients, who had undergone the procedure between August 1997 and February 1999. Ninety-eight patients (89%) replied, including all those who had had a positive SLNB (19/110). To study any time dependant trends the respondents were subdivided into 3 sub-groups depending on length of follow up. (Table 1) The majority of patients (95/98) were glad they had the procedure. Specifically, 86% (84/98) felt that SLNB provided them with general peace of mind. Forty-seven percent (46/98) felt that SLNB helped them plan for the future and 87% (85/98) felt that they were being well looked after. Seventy-two percent (71/98) felt that it reassured them that the malignancy had not spread and 34% (33/98) felt cured. These effects decreased with time. (Table 1) Overall 91% (89/98) believed they gained some benefit from SLNB and 98% (96/98) indicated that they would recommend it to other patients. There is no doubt that that most melanoma patients derive at least short- term psychological benefits from having a SLNB. This effect appears to be independent of the result of the SLNB itself. The decreased reassurance with time may simply represent a time dependent factor. However we feel it maybe due to the frequent clinic visits and additional biopsies of suspicious lesions which are known to cause increased anxiety in melanoma patients (2). The procedure has high patient acceptability and offers them a proactive option in addition to regular clinic reviews, following initial diagnosis. However, it does not appear to significantly influence patients' worries about being "cured" or fully enable patients to "plan for the future". Moreover, the small psychological benefit demonstrated in our study, cannot be used to justify routine SLNB in melanoma patients. The cost and morbidity of this procedure must be balanced by proven survival benefit. We agree with others that until such benefit is demonstrated, SLNB should only be offered in a multidisciplinary setting as part of a clinical trial .(1, 3) Table 1. Follow-up period (Number (%)) Benefit 6 months 7-12 months 13-18 months Overall P value Peace of mind 50/54(92) 27/33(81) 7/11(63) 84/98(86) 0.03 Planning for the future 29/54(53) 13/33(39) 4/11(36) 46/98(47) 0.23 Well looked after 51/54(94) 26/33(79) 7/11(63) 84/98(87) 0.01 Reassured of no spread 42/54(78) 25/33(76) 4/11(36) 71/98(72) 0.02 Cured 22/54(41) 9/33(27) 2/11(20) 33/98(34) 0.2 Analysed by chi squared for trend REFERENCES 1. Meirion Thomas J, Patocskai EJ The argument against sentinel node biopsy for malignant melanoma . BMJ 2000;321:3-4 2. Baughan CA, Hall VL, Leppard BJ, Perkins PJ. Follow-up in stage I cutaneous malignant melanoma: an audit. Clin Oncol (R Coll Radiol) 1993; 5(3):174-80 3. Morton D, Chan A. Current status of intraoperative lymphatic mapping and sentinel lymphadenectomy for melanoma: is it standard of care? J Am Coll Surg. 1999; 189: 214-223 AUTHORS (current Positions) S.S.Rayatt FDS FRCS SpR in Plastic Surgery Dept. of Plastic surgery Sandwell Healthcare NHS Trust Lyndon, West Bromwich, West Midlands B71 4HJ Tel: 0121 553 1831 S.P.Hettiaratchy FRCS SpR in Plastic Surgery (LAT) Dept. of Plastic surgery Selly Oak Hospital, Raddlebarn Road, Birmingham B29 6JD
The argument for sentinel node biopsy 14 August 2000
Robin Russell-Jones, Director skin tumour unit, St Johns institute dermatology, St Thomas's hospital London as above Send response to journal: Re: The argument for sentinel node biopsy	Sir, Your editorial, "The argument against sentinel node biopsy for malignant melanoma" (BMJ 321: 3-4, 2000), accepts the value of sentinel node biopsy (SNB) as a staging procedure for melanoma, but then argues against its use on the grounds that its effect on survival is uncertain. This of course is true, but staging procedures are not supposed to affect survival: they predict outcome, identify those patients that require further therapy, and reassure those who do not. In recognition of this, the most recent staging system published by the American Joint Committee on Cancer (AJCC) includes a separate category for patients with micrometastatic disease in the sentinel node,pathological stage 111a.(Ref 1). In addition the president of the WHO Melanoma program has stated "Sentinel node biopsy currently represents the standard of care in the management of primary melanoma."(Ref 2).The authors of your editorial may see no advantage in staging patients with melanoma, but it needs to be recognised that world-wide, theirs is a minority view. The main issue is not in fact SNB, but the lack of consensus as to the best management of patients with Stage 111 melanoma. Even so, high-dose adjuvant therapy with Interferon alfa 2b is licensed in the UK for the treatment of high-risk melanoma, including patients with Stage 111 disease, so this can be offered to patients who are SNB positive (Ref 3 ). In addition, knowing the lymph-node status of the subject is a prerequisite for obtaining useful information from clinical trials, and one could argue that new trials of clinical Stage 1b/11 melanoma should not be permitted unless patients are stratified according to their lymph node status.In particular it would seem pointless undertaking wide and often mutilating surgical excisions of primary lesion in patients who are already SNB positive. By contrast your editorial verdict is that no patient should undergo SNB unless they are entered into a clinical trial.This seems rather extreme. What about patients who are SNB negative? Do they have to enter a clinical trial? What about those many well-informed informed patients who independently wish to know their sentinel node status? Are they to be told that they can only learn their prognosis by agreeing in advance to enter a clinical study? Surely the sensible approach is to offer SNB as a staging procedure in those centres that are skilled and experienced in the technique, and to then discuss with the patient the options available in the event that they are SNB positive. Clinical trials are crucial provided they stratify patients according to their sentinel node status, and provided the patient is willing to embark on a study with an observational arm. What is not acceptable is for centres that do not rely on SNB to dictate to other centres how their patients should be managed. Yours Sincerely Robin Russell-Jones MA FRCP, Director Skin tumour Unit, St John’s Institute of Dermatology Ciaran Healy MD FRCS Dept Plastic Surgery St Thomas Hospital Eduardo Calonje DipRCPath, Director Diagnostic Dermatopathology,St John’s Institute of Dermatology Michael Doherty MD FRCP, Dept Nuclear Medicine, St Thomas Hospital Peter Butler FRCS(I),FRCS, Dept Plastic Surgery, Royal Free Hospital Alison Jones MD FRCP, Dept Clinical Oncology Royal Free Hospital Sean Whittaker MD,FRCP Dept of Dermatology, Royal Free Hospital Katharine Acland MRCP, Dept of Dermatology, Hammersmith Hospital, London Ref 1 .Balch C., Buzaid A., Atkins M., Cascinelli N, Coit D, Fleming I, et al A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 2000; 88: 1484-91. Ref 2. WHO declares lymphatic mapping to be the standard of care for melanoma Oncology 1999, 13: 288. Ref 3 Kirkwood J, Strawderman M, Ernstoff M, Smith T, Borden E, Blum R. Interferon alfa 2b adjuvant therapy of high risk resected cutaneous malignant melanoma: the Eastern Oncolog
Sentinel Node Biopsy 29 August 2000
Paul E Baguley, Consultant Plastic Surgeon Middlesbrough General Hospital Send response to journal: Re: Sentinel Node Biopsy	Dr Thomas has made his position clear with regard to Sentinel Node Biopsy in his article from July 1. Unfortunately I feel, as do other surgeons involved in Sentinel Node biopsy, that his logic is flawed and that he does not fully appreciate the reasoning and benefits of upstaging patients with Melanoma. I feel an argument based on the fact that Oncologists cannot treat stage 3 Melanoma, therefore why bother to upstage people, is really quite naïve. His naivety is also well demonstrated in his initial comments where he discusses the benefits of early diagnosis of lymph node metastases, but still cannot bring himself to agree that Sentinel Node is a useful technique. He also seems confused as to what the financial implications of Sentinel Node procedures. He initially comments that the cost of Sentinel Node is less, in relation to ELND, but then later states that Sentinel Node costs more. More than what? After this "throw away statement" he then tries to connect the cost with the statement that since only 20% of patients are expected to have lymph node metastases, 80% of patients are risking complications. This seems to be based on a "we are different than the Americans and Australians because we do not routinely perform ELND" idea. Does Meirion somehow feel that Melanoma is different between these two countries and our own? Aside from this, the whole paper makes confusing reading in terms of the thought processes. Let me make my position clear on Sentinel Node. I firmly believe that Sentinel Node is NOT a treatment modality. It was never intended to be. Rather it is a method of upstaging patients so that they can they be admitted onto adjuvant trials of chemotherapy and immunotherapy. It enables a cohort of patients who, although they have clinically non- palpable lymph nodes, can be offered treatment that may produce a long- term remission. It is important to realize that as soon as a patient presents with clinically palpable nodes the 12-month survival approaches 30%. I believe that you will be doing your patients a disservice by down staging stage 3 patients and treating them as stage 2 if Sentinel node biopsy is not offered to select patients. I, unlike some other surgeons, believe that melanoma is a systemic disease once the "magic" Breslow depth of 1.5 mm is breached, and do not believe in therapeutic ELND. Whether one lymph node is positive (the Sentinel Node) or several, the patient is still stage three and should be placed in an appropriate trial. The only benefit, therefore of Sentinel Node is to upstage patients sooner. Whether this translates in to a positive survival benefit is not known yet. Which is why there is a call for a randomized, controlled trial of Sentinel node followed by randomization into ELND or observation. Meirion also states "newer techniques such as reverse transcriptase PCR measures tumour burden directly in the blood". I know of no randomized, controlled trial that proves this is a viable technique. I am afraid by this statement, Meirion is in danger of setting himself up for criticism by setting himself into a group that believes a technique is useful without definite proof, just as he is criticizing those of us that perform Sentinel Node. As far as "trapping of Melanoma cells", I return to my comment that Sentinel node is investigative and not therapeutic. These "trapped" cells would make there way to the regional lymph node basin eventually and give rise to palpable nodes. My argument again is that positive Sentinel Node allows adjuvant therapy to start sooner rather than later. I do agree with Meirion that this procedure needs to be carefully monitored so that only certain centers that have experience perform this procedure. We have performed over 80 Sentinel nodes. They have all been admitted onto trials for adjuvant therapy for stage three Melanoma and we have a success rate in the first 42 of 97% and 100% in the last 40. I am convinced of the efficacy of this technique and will continue to offer it to my patients - duly admitting them onto adjuvant trials after diagnosing positivity. Interestingly, the 4th perspectives in melanoma conference in Pittsburgh, June 1 - 2, has stated that the WHO has recommended that Sentinel Node biopsy become the standard procedure for patients with MM > 1.0 mm. Also, the new AJCC classification of melanoma relies on the number of lymph nodes positive rather than their size. I will continue to offer my patients this technique as a method of investigation with minimal morbidity.