An Argument for Aggressive Resection in Melanoma

Since William Norris’s initial recommendation in 1857 to “not only remove the disease, but to cut away some of the healthy parts,”[1] melanoma surgery has had a history of progressively minimizing intervention and morbidity while preserving patient outcomes. Prior advances include reduced margins for wide local excision and the advent of sentinel lymph node biopsy (SLNB). In their review, Martin and colleagues describe current initiatives to further reduce morbidity.

Much of the morbidity from melanoma surgery results from lymphadenectomy, and management of the regional nodal basin remains controversial. Despite published guidelines recommending completion lymphadenectomy (CLND) after a positive SLNB, a 2009 population study suggests that only 50% of patients will actually undergo this procedure.[2] Concerns over the morbidity of the operation and questions regarding the necessity of CLND were cited as the principle reasons for noncompliance.[2]

What do we lose when we choose not to operate? For one, lymphadenectomy has been shown to provide good regional disease control. In a review of patients with a positive SLNB who did not undergo CLND, Wong et al found nodal disease as a site of first recurrence in 15% of patients.[3] In comparison, data from the Sunbelt Melanoma Trial demonstrated a 4.9% rate of regional nodal recurrence after CLND.[4] A similar rate of 4.2% was found for nodal recurrence after CLND in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I). Subgroup analysis of MSLT-I limited to patients with nodal disease demonstrated improved 5-year survival in those who underwent CLND after SLNB compared with those who required lymphadenectomy after failing observation (72.3% vs 52.4%, P = .004).[5] While not definitive proof that CLND improves survival, it is likely that CLND does result in improved survival, and possibly cure, for at least a subset of patients.[4]

Furthermore, an aggressive approach to lymphadenectomy may actually lead to decreased morbidity. In looking at patients who underwent CLND vs those with delayed lymphadenectomy, Sabel et al found fewer wound complications in the CLND group (14.4% vs 27.5%, P = .02),[6] while Faries et al demonstrated a significant difference in lymphedema (12.4% in the CLND group vs 20.4% in the delayed lymphadenectomy group, P = .04).[7] By withholding early CLND, we are potentially subjecting our patients to increased morbidity if they go on to develop palpable nodal disease. Interestingly, patients may not regard the surgery as carrying the level of morbidity that their surgeons ascribe to the procedure. In a 2009 quality-of-life survey, patients who underwent SLNB with or without CLND reported a higher overall quality of life than a control group without melanoma. The authors were also unable to prove their underlying hypothesis that patients who underwent inguinal CLND would report a lower quality of life than patients who underwent SLNB alone.[8]

These patient perspectives raise questions as to what constitutes clinically significant morbidity: is it as prevalent as we fear? For instance, Chang et al reported a 77% rate of wound complications following inguinal lymphadenectomy. However, the study had a broad definition of complications, which included such entities as erythema in the absence of any other signs of infection, or dehiscence as small as one centimeter.[9] The rates for major complications, defined as those requiring readmission, IV antibiotics, or secondary procedures, were more modest: 34% for wound infection, 13% for dehiscence, and 11.3% for seroma.[9] In the Sunbelt Melanoma Trial, the overall complication rate for patients who underwent CLND was 23.2%, although for inguinal dissection the complication rate was 51.2%, including a 31.5% lymphedema rate.[10] While one could argue that CLND complications are less than we think, substantial morbidity remains, particularly for inguinal dissection.

Given the need to balance risk and benefit, how do we then evaluate the attempts to reduce morbidity discussed in the review? Two broad strategies are proposed, including increased use of minimally invasive techniques and improved patient selection. Videoscopic inguinal lymphadenectomy (VIL) proposes to reduce morbidity by decreasing incisional complications of superficial lymphadenectomy. An analysis of immediate and long-term complications in 29 patients who underwent VIL demonstrated rates of 27% and 14.6% for minor and major complications, respectively, with a median follow-up of 604 days.[11] Currently the only comparison we have between videoscopic and open inguinal lymphadenectomy matches 13 patients treated by VIL with a cohort of 28 patients treated by open lymphadenectomy. There was a trend towards decreased wound complications with VIL; however, this did not reach statistical significance.[12] VIL also required a significantly longer operative time than open resection (245 vs 138 min, P = .0003),[12] which could represent a barrier to adoption. Data on long-term oncologic outcomes are also lacking, although a randomized controlled trial is in progress. Nonetheless, the promising early results with VIL suggest that this approach is worthy of further study.

Efforts at refining patient selection based on characteristics of the sentinel node yield results parallel to those seen with VIL: they potentially reduce morbidity but with unproven outcomes. Only 20% of patients with a positive sentinel node will have disease in the remaining nodes, leading some to question the role of CLND.[13] Despite the heterogeneity of tumor burden and biology within sentinel nodes, multiple factors associated with less aggressive disease have been identified.[13] Scoring systems such as the Rotterdam or Dewar criteria show promise in identifying patients at low risk for developing disease in non-sentinel lymph nodes. Nevertheless, no scoring system is perfect, and evidence persists that even patients with minimal nodal tumor burden are still at increased risk for regional disease progression.[14,15] Moving forward, randomized controlled trials such as MSLT-II should further clarify which patients ought to undergo lymphadenectomy.

William Norris’s insight into melanoma surgery is just as relevant today as it was over 150 years ago. Although since that time we have reduced the morbidity associated with surgery, these advances resulted from prospective randomized controlled trials showing that minimizing interventions did not compromise outcomes. Martin and colleagues present a comprehensive review of future directions to reduce morbidity in the treatment of melanoma,[16] and although many of these methods are unproven, they deserve continued investigation through controlled trials. Perhaps, as the authors conclude, one day these developments will decrease or obviate the need for surgery. Until then, any minimization of therapy in the name of reducing morbidity requires careful consideration. Reducing morbidity in melanoma is certainly a laudable goal, but locoregional disease control and cure must remain our primary objectives.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Norris W. Eight cases of melanosis with pathological and therapeutic remarks on that disease. London: Longman, Brown, Green, Longman, and Roberts; 1857.

2. Bilimoria KY, Balch CM, Bentrem DJ, et al. Complete lymph node dissection for sentinel node-positive melanoma: assessment of practice patterns in the United States. Ann Surg Oncol. 2008;15:1566-76.

3. Wong SL, Morton DL, Thompson JF, et al. Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol. 2006;13:809-16.

4. McMasters KM. Why does no one want to perform lymph node dissection anymore? Ann Surg Oncol. 2010;17:358-61.

5. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307-17.

6. Sabel MS, Griffith KA, Arora A, et al. Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy. Surgery. 2007;141:728-35.

7. Faries MB, Thompson JF, Cochran A, 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;17:3324-9.

8. de Vries M, Hoekstra HJ Hoekstra-Weebers JE. Quality of life after axillary or groin sentinel lymph node biopsy, with or without completion lymph node dissection, in patients with cutaneous melanoma. Ann Surg Oncol. 2009;16:2840-7.

9. Chang SB, Askew RL, Xing Y, et al. Prospective assessment of postoperative complications and associated costs following inguinal lymph node dissection (ILND) in melanoma patients. Ann Surg Oncol. 2010;17:2764-72.

10. Wrightson WR, Wong SL, Edwards MJ, et al. Complications associated with sentinel lymph node biopsy for melanoma. Ann Surg Oncol. 2003;10:676-80.

11. Master VA, Jafri SM, Moses KA, et al. Minimally invasive inguinal lymphadenectomy via endoscopic groin dissection: comprehensive assessment of immediate and long-term complications. J Urol. 2012;188:1176-80.

12. Abbott AM, Grotz TE, Rueth NM, et al. Minimally invasive inguinal lymph node dissection (MILND) for melanoma: experience from two academic centers. Ann Surg Oncol. 2013;20:340-5.

13. van der Ploeg AP, van Akkooi AC, Verhoef C Eggermont AM. Completion lymph node dissection after a positive sentinel node: no longer a must? Curr Opin Oncol. 2013;25:152-9.

14. Murali R, DeSilva C, McCarthy SW, et al. Sentinel lymph nodes containing very small (<0.1 mm) deposits of metastatic melanoma cannot be safely regarded as tumor-negative. Ann Surg Oncol. 2012;19:1089-99.

15. Scheri RP, Essner R, Turner RR, et al. Isolated tumor cells in the sentinel node affect long-term prognosis of patients with melanoma. Ann Surg Oncol. 2007;14:2861-6.

16. Martin BM, Master VA, Delman KA. Minimizing morbidity in melanoma surgery. ONCOLOGY (Williston Park). 2013;27:1016-27.