Is sentinel node biopsy in melanoma an essential component of care? Despite a large multinational trial and recently published or updated guidelines, the question is still a thorny one according to experts who debated the issue at the recent meeting of the Society of Surgical Oncology in Washington, DC.1,2
“It’s safe and it’s prognostic,” said Giorgos C. Karakousis, MD, Assistant Professor of Surgery at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. Moreover, he contended, it facilitates regional control and may play a therapeutic role.
On the contrary, said Mary S. Brady, MD, Associate Attending Physician at Memorial Sloan-Kettering Cancer Center, there is no high-level evidence that sentinel node staging provides better regional control or contributes to survival. There is level 1 medical evidence that the procedure is diagnostic, and not therapeutic. And while sentinel node biopsy is prognostic, the value of staging is questionable when standard adjuvant therapies have limited effectiveness and are poorly tolerated.
Both speakers marshaled their arguments around the different levels of thickness of the primary lesion. For thin melanomas (Breslow thickness ≤ 1 mm), positive sentinel nodes are uncommon, especially in those with tumors < 0.76 mm. The procedure is not recommended in thin melanomas by either the guidelines published by ASCO and the SSO last year,3 or the latest NCCN guidelines, revised in early 2013.4
However, Dr. Karakousis noted that it might be warranted for patients whose primary lesion is between 0.76 and 1 mm, and particularly for those who have certain other higher-risk features. “In thin (T1) lesions, the incidence of positive sentinel nodes tends to be very low overall,” he said. “In very thin lesions (< 0.75 mm in depth), the sentinel lymph node positivity rate is even lower and the procedure generally is not recommended in this group, although it may be very selectively considered if other factors such as high mitotic rate, ulceration, lymphovascular invasion, or positive deep margins (of a transected specimen) are present.”
“Can we select for patients with thin melanomas that have a higher risk of sentinel node positivity? I think the answer is ultimately yes,” he said. “There is still debate in part about which factors are predictive.”
Dr. Brady agreed, cautiously, that sentinel node biopsy could be a “rational option” for higher-risk, thin melanomas. However, she said in an interview, patients offered this option should understand that while it may give them information about prognosis, that is all it will do. “It has nothing to do with therapy,” she said.
That theme—the possible value or lack of value of sentinel node biopsy for therapy and regional control—continued as the speakers moved to intermediate lesions (1–4 mm Breslow thickness).
A major source of data for intermediate melanomas is the first Multicenter Selective Lymphadenopathy Trial (MSLT-1),5 which compared wide excision with sentinel node biopsy and immediate lymphadenectomy if necessary to wide excision with surveillance and delayed lymphadenectomy if necessary. There was no difference between the two arms in melanoma-specific survival, the primary endpoint of the trial.
Dr. Karakousis emphasized that MSLT-1 “validated the tremendous prognostic utility of the [sentinel lymph node] biopsy technique.” He noted that in the sentinel node biopsy group, there was a statistically significant improvement in the estimated 5-year disease-free survival, due in large part to the higher nodal relapse rate in the observation group.
Also, he pointed out, in the subgroup of patients with nodal metastases, those who had immediate lymph node dissection had a significantly higher melanoma-specific survival rate than those in the observation group who had delayed lymphadenectomy (72% vs 52%). This suggests that “there may be some therapeutic effect of the sentinel node biopsy procedure in patients with micrometastases,” he said.
Dr. Brady argued that subgroup analyses are not high-level evidence. “That’s post hoc analysis,” she said in an interview. And comparing people who got delayed lymphadenectomy (and thus had clinically palpable nodes) to those who got immediate lymphadenectomy (with microscopic nodal metastases) “is completely invalid,” she commented.
“The primary endpoint of the trial,” she continued, “demonstrated that there was no difference in melanoma-specific survival, indicating that sentinel node biopsy offered no therapeutic advantage to patients with intermediate-risk melanoma. We already knew that the sentinel node biopsy provides prognostic information, and that patients with clinically apparent nodal metastasis (those in the observation arm for whom treatment failed) have a worse outcome than patients with microscopic nodal disease. These were secondary endpoints of the trial, and rightly so,” Dr. Brady said.
“The main reason, in my mind, for doing a sentinel node biopsy is to give patients good news,” she said, adding that good news in itself is clinically valuable. But for those who get bad news—a positive sentinel node—and go on to have a completion lymph node dissection, there is bad news plus the risk of lymphedema and other complications.
The need for completion lymph node dissection after a positive sentinel node biopsy, another contentious issue, was the subject of a separate debate at the SSO meeting (see page 1).The ongoing MSLT-2 trial is investigating whether completion lymph node dissection improves survival in this group.
Patients with thick melanomas (> 4 mm Breslow thickness) may have > 30% chance of lymph node involvement but are also are at high risk for distant metastases. “So the question is not whether the yield of finding a metastatic event justifies the procedure,” said Dr. Karakousis, “but does it add prognostic information?” There are fewer studies specifically looking at thick melanomas, but most have demonstrated that sentinel node biopsy is prognostic. It also offers important regional control in this group, he said.
The ASCO/SSO guidelines recommend the procedure in thick melanomas “for staging purposes and to facilitate regional control.” And the NCCN guidelines say that the “main advantage” in this group of patients is regional control.
Again, Dr. Brady argued that there is no high-level evidence supporting these guidelines. And although she agreed that sentinel node biopsy and completion lymph node dissection “can very precisely stratify risk in intermediate melanomas,” she questioned that as a rationale for the procedure. Staging, she argued, should help identify patients for adjuvant therapy, but in melanoma, the standard is high-dose interferon, which is a “very toxic therapy of marginal benefit.”
The value of staging, all agreed, may improve as more systemic therapies prove effective in early melanoma. Ipilimumab (Yervoy), a targeted antibody, and vemurafenib (Zelboraf), a selective BRAF inhibitor, have already been approved for advanced melanoma. Others including MEK inhibitors show promise. In the adjuvant setting, a trial of ipilimumab has been completed but not yet published.
Michael S. Sabel, MD, Associate Professor of Surgery at the University of Michigan, Ann Arbor, who moderated the debate, said, “This is a very exciting era in melanoma. But it is a shifting ground on which we stand that we have to continuously reevaluate.” ■
Disclosure:Drs. Brady, Karakousis, and Sabel reported no potential conflicts of interest.
1. Brady MS: SLN biopsy: An optional diagnostic procedure. SSO Annual Cancer Symposium. Presented March 7, 2013.
2. Karakousis GC: SLN biopsy: An essential component of care. SSO Annual Cancer Symposium. Presented March 7, 2013.
3. Wong SL, Balch CM, Hurley P, et al: Sentinel lymph node biopsy for melanoma: ASCO/SSO joint clinical practice guideline. J Clin Oncol 30:2912-2918, 2012.
4. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 2.2013. Available at www.nccn.org. Accessed April 5, 2013.
5. Morton DL, Thompson JF, Cochran AJ, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307-1317, 2006.