image Daniel G. Coit, MD, is professor of surgery at Weill Cornell Medical College, attending surgeon at Memorial Sloan-Kettering Cancer Center, New York City, and chair of the National Comprehensive Cancer Network (NCCN) Melanoma Guidelines Panel.
image Matthew H. Kanzler, MD, is clinical professor in the Department of Dermatology at Stanford University’s School of Medicine, in California.
image Martin S. Karpeh Jr., MD, is chairman of the Department of Surgery at Beth Israel Medical Center, and director of surgical oncology and associate director, Continuum Cancer Centers of New York.
image Stanley Leong, MD, is president of the Sentinel Node Oncology Foundation, chief of cutaneous oncology and associate director of the Center for Melanoma Research and Treatment, California Pacific Medical Center, and professor emeritus of surgery at the University of California, San Francisco School of Medicine.
image Anna Pavlick, MD, is associate professor, co-director of the Melanoma Program and assistant director for Clinical Research Education in the Departments of Medicine and Dermatology at the NYU Cancer Institute, New York City.
image Jennifer A. Wargo, MD, is assistant surgeon in the Division of Surgical Oncology at Massachusetts General Hospital and an instructor of surgery at Harvard Medical School, Boston.
Written and complied by Rosemary Frei, MSc

Sentinel lymph node biopsy remains a controversial topic in the diagnosis and treatment of melanoma. The most significant landmark trial—the MSLT (Multicenter Selective Lymphadenectomy Trial)-I—made a stir in the oncology community when it demonstrated that wide excision of intermediate-thickness primary melanoma and sentinel lymph node biopsy (SLNB) followed immediately by completion lymphadenectomy (CL) produces similar rates of melanoma-specific survival as wide excision and observation of regional lymph nodes with CL performed only if nodal relapse occurred (N Engl J Med 2006;355:1307-1317).

Additionally, the mean estimated five-year disease-free survival (DFS) rate was higher in the SLNB group. The investigators also reported that the five-year survival rate in patients with micrometastases found by SLNB was significantly higher than in observation patients who later developed clinically palpable nodal metastases.

A follow-up randomized trial, MSLT-II, is under way and may help to solve some of the remaining questions (http://clinicaltrials.gov/​ct2/​show/​NCT00297895). The investigators will focus on whether completion lymph node dissection (CLND) should be performed immediately in patients with intermediate-thickness melanoma who have positive nodes on SLNB, or whether patients should first be observed and undergo CLND only if and when nodal ultrasound detects more positive nodes. The primary outcome is 10-year melanoma-specific survival, with secondary

outcomes including 10-year DFS and 10-year recurrence rate. However, the first set of interim results are not expected until at least 2017 and the full 10-year results won’t be reported until at least 2024.

In the meantime, General Surgery News asked experts from across the country how they use this controversial procedure in their patients based on the currently available evidence. Once you’ve read their opinions, we’d like to hear yours. You can email editor Kevin Horty at khorty@mcmahonmed.com.

QDo you feel MSLT-1 results clearly support routine SLNB in intermediate-thickness melanoma?

Matthew H. Kanzler, MD: MSLT-1 was designed and appropriately powered to answer only one question: Does performing SLNB increase overall survival of melanoma patients compared with removing clinically detected LN if and when they appear during follow-up? The results do not support routine SLNB as a therapeutic procedure in intermediate-thickness melanoma. The fact that the authors completely failed to mention the primary outcome results in the abstract of the paper, but instead chose to emphasize the results of inappropriate subset analyses of MSLT-1 data, clearly shows the authors’ bias regarding this procedure.

Subsequent publications have shown that the small improvements in DFS found on subset analyses were in fact entirely attributable to lead-time bias and lack of appropriate handling of both false-positive and false-negative patients in the study.

Daniel G. Coit, MD: MSLT-1 is probably the highest-quality data defining the role of SLNB in melanoma. I don’t care how the investigators analyzed the results, I care that the trial has provided top-quality data: The interpretation is up to the readers, clinicians and patients.

And it very clearly confirmed that sentinel node status is the most important prognostic factor in intermediate-thickness melanoma. This is what has kept SLNB in the forefront of management of patients with intermediate-thickness melanoma.

The other thing it showed us is that it is probable that positive sentinel nodes will evolve into clinical disease. Additionally, it said that SLNB detects about 25% of the nodes that will develop into regional disease—that is, the false-negative rate is about 25%. And also, if you take all comers, SLNB is a staging procedure and not clearly a treatment, because the study could not demonstrate an improvement in melanoma-specific survival. The distant DFS curve is an extremely important curve that has never been shown.

The point that people really struggle with is that the study didn’t show an improvement in melanoma-specific survival even though DFS and nodal recurrence did improve. I believe it’s because the study was under-powered to show a statistically significant difference in melanoma-specific survival.

Stanley Leong, MD: I agree that the study showed SLN status is irrefutable as a prognostic indicator. And for that reason SLNB is the standard of staging in melanoma. People who criticize MSLT-1 do not even do SLNB. Nothing is perfect, for every study there are always unanswered questions, but the study provided level I evidence that sentinel node status is a very strong prognostic indicator.

Jennifer A. Wargo, MD: I do believe MSLT-1 supports the use of SLNB in intermediate-thickness melanoma for prognostic reasons and for durable regional control, but I do not believe it provides evidence of any survival benefit.

In MSLT-1 there were patients in the SLNB group with microscopic deposits of melanoma that would be unlikely to progress to a palpable nodal recurrence, and these patients were compared with patients who presented with bulky nodal metastases. Additionally, the groups were selected for comparison after randomization, making statistical considerations invalid. Furthermore, the authors did not include patients in the analysis who had a false-negative SLNB result and later presented with nodal recurrence.

QIs all disease detected by SLNB, including micrometastases, clinically relevant?

Dr. Coit: It clearly is. The patients with even micrometastases in their lymph nodes do worse than patients with negative lymph nodes. That’s well documented. And that’s the basis of the American Joint Committee on Cancer (AJCC) staging—that even isolated tumor cells in a lymph node are clinically significant. It’s not as clinically significant as macro disease, but when it is actionable is a different question.

Dr. Leong: We know that cancer is an aggressive disease. We published a paper a year ago showing that different levels of tumor burden in melanoma SLNs are associated with different levels of survival. So that confirms it’s a spectrum, and hence early diagnosis and early eradication of growing cells in the SLN are intuitively beneficial. The only problem is we can’t demonstrate yet that they’re therapeutically beneficial.

Anna Pavlick, MD: I do not believe all disease detected is clinically significant, especially micromets. The amount of disease and location of the disease is more clinically meaningful. Many retrospective trials in the past five years have tried to answer that question and most of the data suggest that the amount and location are the most clinically relevant.

Dr. Wargo: I disagree that all disease detected by SLNB including micrometastases is clinically significant. There is clearly heterogeneity within stage III patients that contributes to the widely variable survival rates seen in this group. At one extreme are patients with a single melanoma cell identified within one sentinel node and at the other are patients who present with bulky nodal metastases. Based on survival rates, it is fairly clear that there are patients with minimal microscopic disease who will never have a recurrence.

Dr. Kanzler: MSLT-1 authors imply that all microscopically involved nodes will progress to macroscopic disease. If such an assumption were correct, 19.4% of the patients randomized to the SLNB intervention arm of the study would have been expected to develop clinically palpable nodes by the end of the study—that is, the sum of the 16% of patients with positive SLNB results plus the 3.4% of patients who initially had a negative SLNB result but who later developed nodal disease during follow-up. This incidence is 24% higher than the actual incidence of 15.6% found during follow-up for patients assigned to the observation arm. The discrepancy can only be explained if one-fourth of patients with positive sentinel nodes in the SLNB arm would never have developed palpable nodes if followed by observation.

Dr. Karpeh: My preference is to perform SLNB in patients with intermediate-thickness melanomas or those with thin melanomas between 0.75 and 1 mm that show evidence of ulceration or increased mitotic rate. There is as high as a 10% chance of having positive nodes in that subgroup of thin melanomas and I do recommend SLN mapping. The morbidity is fairly low and the information gained is clearly prognostic and may be helpful as new therapies for melanoma are developed. Having said that, I feel each patient has to be counseled individually and that comorbidities, age and the patients’ informed decision also factor heavily into making the final decision.

QShould SLNB be the standard of care in melanoma in the United States?

Dr. Kanzler: From a therapeutic perspective, the answer is fairly clear: There is no role for SLNB in the standard care of patients with melanoma. And although it clearly has been shown that as a single prognostic factor, the status of the SLN is the strongest predictor of outcomes, the procedure is expensive, invasive and leads to complications in 10% of patients undergoing the procedure.

What has not been investigated to date is whether or not a combination of other important noninvasive prognostic factors would result in prognostic information comparable to SLNB data. In fact, predicted survival rates can currently be obtained by inputting specific known prognostic data for a particular patient into a large computer database containing known outcomes for patients with similar demographic information (http://cancer.lifemath.net/​melanoma/​outcome/​). The accuracy of this mathematical database has been confirmed with data on hundreds of thousands of patients in Surveillance, Epidemiology and End Results (SEER) national data sets. Use of such a database can provide excellent prognostic information to melanoma patients and should be offered to patients as an alternative to invasive SLNB procedures.

Dr. Wargo: As of 2012, SLNB should be offered as standard of care in melanoma in the United States. SLNB clearly has prognostic benefit as well as potential benefit with durable regional control.

Dr. Coit: I can’t answer that question because “standard of care” is a legal term. I think it’s more appropriate to say that for patients with invasive melanoma, you should have a discussion about the pros and cons of SLNB. The NCCN guidelines include phrases like “discuss SLNB” and “offer SLNB,” but nowhere is SLNB mandated. Because the information gleaned from it is primarily prognostic, and I don’t think you can mandate a prognostic test, it depends on whether the patient wants the information.

QUnder what conditions should clinicians counsel patients that it’s advisable to go ahead with SLNB?

Dr. Pavlick: Patients need to be educated about the negative risk factors associated with melanoma, the percentage of risks such as infection and lymphedema versus benefit of this procedure and how this procedure would increase the patients’ access to adjuvant clinical trials. There should be an informed decision made by the patient and his or her melanoma team after all of the pros and cons have been discussed.

Dr. Coit: Probably the single most controversial issue in SLNB is where the cutoff of probability of having a positive SLN [is] for going ahead with SLNB. Right now it seems to be somewhere between 5% and 10%, but where it is in that spectrum depends enormously on a number of factors, including patient age. In an editorial we wrote for the Annals of Surgical Oncology—and the NCCN guidelines—SLNB is generally not recommended for patients with melanoma under 0.75 mm in thickness. For many patients with a thickness of 0.75 to 1 mm, SLNB should be discussed and offered, and most patients with melanoma greater than 1 mm thick will end up having SLNB because the probability of positive sentinel nodes is significantly higher in this group.

Dr. Kanzler: Since publication of the MSLT-1 data, several physicians have advocated including patients with increasingly thinner melanomas into the appropriate candidate pool, including patients with melanomas thinner than 1 mm if they are found to have other negative prognostic characteristics such as increased mitotic rates. This has been done despite the lack of evidence that SLNB has clinically significant prognostic benefits in these groups of people.

A recent meta-analysis of 3,651 patients enrolled in 34 studies involving patients with melanomas of no more than 1 mm was performed. The SN positivity rate in these patients was only 5.6%, well below the cutoff suggested by an expert panel headed by Charles Balch, MD, from Johns Hopkins in Baltimore, who suggested that SLNB should be discussed with patients whose risk for harboring clinically occult nodal disease is 10% or greater. More importantly, analysis of survival data from these patients with thin melanomas showed an equal number of melanoma-related deaths in the SNB-positive and SNB-negative groups, making the prognostic utility of this procedure doubtful in this group. These patients all had at least one additional risk factor, including ulceration, regression or invasion to Clark level 4 or 5.

Also, the utility of SLNB in patients under age 20 and over age 60 years has been questioned as it appears that the accuracy of predicting outcomes in these patients by SLNB status is poor—for example, young patients have higher rates of SLNB positivity yet excellent prognosis, whereas elderly patients, whose prognosis is poorer, have a low rate of SLNB positivity.

QShould SLNB plus completion lymphadenectomy of biopsy-positive patients be the standard of care in melanoma in the United States?

Dr. Kanzler: No. A recent 16-center comparative study involving 298 melanoma patients with positive SLNB found that patients had similar survival rates whether a CL was performed immediately after SLNB or was delayed until clinically palpable nodes developed. Thus, while the SLNB does provide prognostic information, to date there is no evidence that performing a CL of biopsy-proven SLNs improves survival. Additionally, although the SLNB procedure is associated with only [a] 10% complication [rate], adding a CL procedure increases the complication rate to 37%, and these complications are typically much more significant, including permanent lymphedema.

Until MSLT-II is completed, the best data available to date shows that lymphadenectomies in the absence of palpable disease—either with or without SNB procedures—do not improve the survival of melanoma patients, and should be avoided outside of the MSLT-II setting.

Dr. Coit: Increasingly, as patients with positive sentinel nodes hear this discussion, they are choosing not to have a CLND. It becomes a patient choice, and right now we’re in a bit of a conundrum. We have enormous experience with CLND, so that’s our standard recommendation for any patients with positive sentinel nodes including micromets. The problem is it’s a morbid procedure and we don’t know whether it makes any difference. So we are very much encouraging patients with positive sentinel nodes to enter into MSLT-II, because it will be the holy grail of this question.

Dr. Pavlick: SLNB and CL of biopsy-positive patients should not be the standard of care anywhere. Clinical judgment is vital in helping patients make that decision. I believe the extent of tumor within the SLNB and its location must play a role in this decision making.

Dr. Wargo: As of 2012, CL following a positive SLNB should be discussed with and offered as standard of care in melanoma in the United States. However, this clearly has less strength than the arguments made for SLNB alone. The majority of patients will not have an additional positive node, and will be subjected to potential morbidity of a CL. The key in the future will be to determine who is most likely to benefit from CL and to do it selectively for high-risk patients. In addition, as we get better adjuvant therapy and biomarker data, the role of CL is likely to diminish significantly. The results of MSLT-II should be helpful in guiding us.

Dr. Leong: I do support CL. Because prognostically you can identify the patients who would do much worse if their CLND is positive. As a surgeon, it is critical that we intervene in the early stages, before the disease spreads from the sentinel nodes to nonsentinel nodes and then beyond.

Dr. Karpeh: I think it should be presented to patients as a common practice that will probably benefit 16% to 20% of patients. The fact that MLST-1 patients undergoing delayed CL had a greater volume of disease than those having early CL for positive SLNB is further evidence that the residual disease does progress over time. The argument against doing the early CL is that there is no survival benefit, but the study was not powered to answer the question of survival benefit in the subset of SLNB-positive patients. This question is being addressed in MSLT-II and I think all patients should be encouraged to enter the trial. My practice is to discuss all the pros and cons of CL with my patients but I do recommend CL in the subset of patients with H&E [hematoxylin and eosin] stain–positive sentinel nodes since we continue to struggle with successfully treating recurrent disease. However, in patients who have immunohistochemistry-positive sentinel nodes only, the data suggests that CL may be over-treatment because the vast majority of the residual nodes are negative.

Daniel G. Coit, MD, Matthew H. Kanzler, MD, Martin S. Karpeh Jr., MD, Stanley Leong, MD, Anna Pavlick, MD, and Jennifer A. Wargo, MD, each report that they have no relevant disclosures.