Should all patients with a positive sentinel lymph node biopsy have a complete node dissection?

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Background

In the past most melanoma patients with lymph node involvement presented with clinically apparent disease for which therapeutic lymph node dissection (TLND) was and remains the standard treatment recommendation. Prior to the development of sentinel lymph node biopsy (SLNB), other patients, especially those treated in specialised melanoma centres, at moderate and high risk for lymph node involvement, would undergo elective lymph node dissection (ELND). Since the introduction of SLNB, ELND should no longer be performed. Depending on referral patterns in an area, around half the patients identified as having metastatic nodal disease are being diagnosed with microscopic disease by SLNB.[1] Overall around 16% of patients with intermediate thickness melanomas and 33% with thick melanomas have a positive SLNB (see SLNB chapter).[2]

Consistent with the intervention arm of the first Multicenter Selective Lymphadenectomy Trial (MSLT-I), completion lymph node dissection (CLND) has, until recently, been recommended for patients with a positive SLNB. However, from as early as 2004 the question of whether CLND is necessary was addressed by the MSLT-II[3] and from 2006 by the DeCOG-SLT study[4]. In both these clinical trials, patients with a positive SLNB were randomised to immediate CLND versus active surveillance. Active surveillance was defined as 3-4 monthly clinical and ultrasound monitoring for at least 2 years then at least 6 monthly clinical and ultrasound assessment until 5 years, followed by annual review. In the event of isolated nodal relapse delayed CLND was done. In MSLT-II when CLND was done for a positive SLNB the incidence of further disease in the non-sentinel lymph nodes (non-SLNs) was 11.5% but, depending on the circumstances (patient factors, tumour factors and sentinel lymph node tumour burden factors), retrospective literature suggests that the rate of non-SLN positivity can range from 3% to 66.7%.[5][6][7] The presence of non-SLN involvement is associated with a worse prognosis.[5]

Practice-changing randomised controlled trials

The overwhelming evidence from the publication of the interim results of these two RCTs is that for patients with a positive SLNB there is no melanoma-specific survival benefit associated with the early removal of non-SLNs by CLND compared to active surveillance and CLND only if isolated regional relapse occurs.[3][4] The MSLT-II[3] and DeCOG-SLT[4] studies also reported equivalent median 3-year melanoma distant metastasis-free and overall survival. The two trials showed that those patients with residual disease in the regional lymph node field benefited in terms of improved immediate regional cancer control. However, all patients having CLND are exposed to the risk of morbidity that can compromise quality of life (QOL). Possible complications of CLND include wound healing problems, cosmetic issues, sensory and motor neural disruption, fibrosis and tightness, limitations in range of movement and lymphoedema, which is more common after CLND in the groin than axilla.[8]

Possible limitations of the MSLT-II and DeCOG-SLT data

Although these studies are highly supportive of the safety of avoiding CLND, the interpretation and application of these results should take into account a number of factors including the fact that they are both reporting interim results, with quite short median follow-up periods (43 months for MSLT-II, 35 months for DeCOG-SLT) and the final results may possibly be somewhat different.[3][4]

Regarding DeCOG-SLT other limitations include the study not meeting the recruitment target, a lower than predicted event rate, recruiting only 39% of the eligible patient population, the fact that that around two-thirds of the patients had SLN deposits ≤1 mm, the exclusion of head and neck primary melanomas, and the fact that around 60% of patients received adjuvant interferon, which may delay recurrence.[4]

Regarding MLST-II it is unclear how many patients who were eligible for the study were offered randomization but 38% of screened patients declined randomization, only 18-19% of patients had more than 1 sentinel node involved, and similar to DeCOG-SLT only 1/3 of patients had a sentinel node tumour burden >1 mm.[3]

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Summary of systematic review results

Cancer control

Two RCTs have shown that patients with a positive SLNB who have immediate CLND have equivalent 3 year survival to those who have active surveillance. CLND after a positive SLNB has reduced rates of subsequent lymph node field relapse. Both MSLT-II and DeCOG-SLT are supportive of active surveillance as a strategy.[3][4]

The patients not undergoing CLND in DeCOG-SLT and MSLT-II had a standardised active surveillance protocol, described above.

Prior to the publication of these two RCTs[3][4] the best available evidence in support of the prior recommendation for CLND was the MSLT1[2], which found that patients who had a positive SLNB and CLND had a 20% improvement in 10 year melanoma-specific survival (MSS) compared to patients who did not have SLNB but later relapsed in the regional lymph node field and then had a therapeutic LND (TLND).[2] However, these comparator groups were not randomised and the data did not indicate whether SLNB alone was sufficient to gain that potential benefit (which was the question addressed in MSLT-II).

A number of previous retrospective studies, some analysing a prospective data base, also supported the safety of a strategy of close observation after a positive SLNB.[9][10][11][12][13][14] Other retrospective data have been published which was interpreted by authors to be consistent with a role for immediate CLND over the delayed CLND strategy, but the comparisons were acknowledged as biased as the delayed CLND patients all had residual disease whereas most (70-80%) of the immediate CLND patients had no residual regional disease identified.[15][1]

Morbidity and QOL

Morbidity varies depending on the CLND lymph node region. The most significant morbidity following CLND is lymphoedema and MSLT-II reported lymphedema occurred in 24.1% of the patients in the dissection group and 6.3% in the active surveillance group.[8] DeCOG-SLT reported grade 3 or 4 adverse events in 14% of CLND patients.[4] Generally speaking, the morbidity of neck and axillary dissection is less than that of groin CLND. Immediate CLND is less morbid than TLND.[8][16]

Conclusion

Active surveillance is an acceptable treatment recommendation for patients with positive SLNB. Patients can be reassured that careful observation with serial clinical examination and ultrasound surveillance undertaken by an ultrasonographer appropriately trained and experienced in the examination of lymph nodes for metastatic malignancy will offer equivalent survival rates to immediate CLND. Immediate CLND reduces the risk of lymph node field relapse, but there is a risk of significant morbidity.

However, depending on patient preferences, the likelihood of having further regional disease, the probability of the patient having long-term morbidity from CLND and future further evidence from the final results of the MSLT-II and DeCOG-SLT studies, CLND may still have a role in selected patients after a positive SLNB.

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Evidence summary and recommendations

Evidence summary Level References
Patients with a positive SLNB who have immediate CLND have no improvement in 3 year melanoma-specific survival compared to those who have active surveillance. II [3], [4]
CLND reduces the risk of early lymph node field relapse compared with an active surveillance strategy after a positive SLNB. II [8], [3], [4]
Patients having CLND have significantly greater surgical morbidity than those having active observation. II
Evidence-based recommendationQuestion mark transparent.png Grade
CLND is no longer the preferred treatment for patients with a positive SLNB. CLND or active surveillance are equivalent in terms of 3 year melanoma specific survival but CLND is more morbid.
B
Evidence-based recommendationQuestion mark transparent.png Grade
CLND offers high levels of immediate regional control for patients with positive SLNB however good regional control can be achieved with delayed CLND.
C



Practice pointQuestion mark transparent.png

To date there is no subgroup of patients for whom immediate CLND is likely to provide a clear benefit, however patients with a high risk of further non-SLN involvement and particularly those who are less likely to suffer significant morbidity from CLND may choose to have the procedure to reduce the risk of lymph node field relapse. A risk calculator for defining the likelihood of non-SLN involvement such as the N-SNORE (Murali et al. 2010) can be of assistance to more accurately estimate the probability of residual non-SN positive nodes.


Practice pointQuestion mark transparent.png

Close clinical and ultrasound surveillance using a protocol equivalent to that followed in MSLT-II and DeCOG-SLT of 3-4 monthly clinical examination and ultrasound of the regional lymph node field for 2 years and then the same at least 6 monthly for a total of 5 years, then annual clinical review is required if a patient with a positive SLNB chooses active surveillance.

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Issues requiring more clinical research study

The following issues require further clinical research:

  1. Although the 2017 Nivolumab vs Ipilimumab and the Dabrafenib / Trametinib combination vs observation clinical trials of adjuvant systemic therapy mandated CLND for patients with a positive SLNB this was because these trials commenced before MSLT-II reported its results.[17][18] It can be fairly hypothesised, but remains unproven, that there would be even fewer indications for CLND when effective adjuvant therapies are widely available.
  2. Therapies that improve control of the regional lymph node field but are less morbid than surgery would be desirable for those patients at higher risk of regional failure and should be investigated. These may include targeted or immune-modulating adjuvant systemic therapies as mentioned above, but may also include local therapies.
  3. To date there are no good data assessing the quality of life implications of avoiding CLND and the anxiety of knowing that there is a higher rate of regional failure when CLND is not performed. The physical consequences of CLND are clear but the psychosocial implications of CLND and of not having CLND are undefined.

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References

  1. 1.0 1.1 Spillane AJ, Pasquali S, Haydu LE, Thompson JF. Patterns of recurrence and survival after lymphadenectomy in melanoma patients: clarifying the effects of timing of surgery and lymph node tumor burden. Ann Surg Oncol 2014 Jan;21(1):292-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24052314.
  2. 2.0 2.1 2.2 Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014 Feb 13;370(7):599-609 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24521106.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 2017 Jun 8;376(23):2211-2222 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28591523.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 2016 May 5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27161539.
  5. 5.0 5.1 van Akkooi AC, Verhoef C, Eggermont AM. Importance of tumor load in the sentinel node in melanoma: clinical dilemmas. Nat Rev Clin Oncol 2010 Aug;7(8):446-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20567244.
  6. Nagaraja V, Eslick GD. Is complete lymph node dissection after a positive sentinel lymph node biopsy for cutaneous melanoma always necessary? A meta-analysis. Eur J Surg Oncol 2013 Jul;39(7):669-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23571104.
  7. Gershenwald JE, Andtbacka RH, Prieto VG, Johnson MM, Diwan AH, Lee JE, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol 2008 Sep 10;26(26):4296-303 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18606982.
  8. 8.0 8.1 8.2 8.3 Faries MB, Thompson JF, Cochran A, Elashoff R, Glass EC, Mozzillo N, et al. The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy Trial (I). Ann Surg Oncol 2010 Dec;17(12):3324-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20614193.
  9. Wong SL, Morton DL, Thompson JF, Gershenwald JE, Leong SP, Reintgen DS, et al. Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol 2006 Jun;13(6):809-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16604476.
  10. Bamboat ZM, Konstantinidis IT, Kuk D, Ariyan CE, Brady MS, Coit DG. Observation after a positive sentinel lymph node biopsy in patients with melanoma. Ann Surg Oncol 2014 Sep;21(9):3117-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24833100.
  11. Kingham TP, Panageas KS, Ariyan CE, Busam KJ, Brady MS, Coit DG. Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy. Ann Surg Oncol 2010 Feb;17(2):514-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19924486.
  12. Kunte C, Geimer T, Baumert J, Konz B, Volkenandt M, Flaig M, et al. Analysis of predictive factors for the outcome of complete lymph node dissection in melanoma patients with metastatic sentinel lymph nodes. J Am Acad Dermatol 2011 Apr;64(4):655-62; quiz 637 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21315477.
  13. Satzger I, Meier A, Zapf A, Niebuhr M, Kapp A, Gutzmer R. Is there a therapeutic benefit of complete lymph node dissection in melanoma patients with low tumor burden in the sentinel node? Melanoma Res 2014 Oct;24(5):454-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24811213.
  14. van der Ploeg AP, van Akkooi AC, Rutkowski P, Cook M, Nieweg OE, Rossi CR, et al. Prognosis in patients with sentinel node-positive melanoma without immediate completion lymph node dissection. Br J Surg 2012 Oct;99(10):1396-405 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22961519.
  15. Pasquali S, Mocellin S, Campana LG, Bonandini E, Montesco MC, Tregnaghi A, et al. Early (sentinel lymph node biopsy-guided) versus delayed lymphadenectomy in melanoma patients with lymph node metastases : personal experience and literature meta-analysis. Cancer 2010 Mar 1;116(5):1201-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20066719.
  16. Read RL, Pasquali S, Haydu L, Thompson JF, Stretch JR, Saw RP, et al. Quality assurance in melanoma surgery: The evolving experience at a large tertiary referral centre. Eur J Surg Oncol 2015 Jul;41(7):830-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25595509.
  17. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017 Sep 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28891423.
  18. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 2017 Sep 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28891408.

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Appendices