Is Sentinel Lymph Node Biopsy Truly the Standard of Care in Melanoma?

December 2011, Vol 2, No 7

Grapevine, TX—Two expert oncologists presented the clinical data in support for and against the use of sentinel lymph node biopsy (SLNB) in melanoma as the standard of care during the 2011 College of American Pathologists annual meeting.

Vernon Sondak, MD, Chair, De - partment of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, supported the use of SLNB as the standard of care in melanoma.

J. Meirion Thomas, MD, attending oncologist, Royal Marsden Hospital and Imperial College, London, said that routine SLNB in melanoma is unwarranted.

Boris Bastian, MD, PhD, Professor of Dermatology and Pathology, Uni - versity of California San Francisco, moderated the debate. He told Value Based Cancer Care (VBCC) that “standard of care” should be reserved for procedures supported by conclusive evidence that the benefits outweigh the risks. “While SLNB is unquestionably commonly practiced, this is not sufficient to qualify it as the standard of care. There is compelling evidence that patients with a positive sentinel lymph node have a worse prognosis, but the knowledge of this information currently does not translate into a significant survival benefit, and instead may lead to inappropriately aggressive treatment in patients.”

The Pivotal Trial: MSLT-1
The debate largely centered on the results of the ongoing, randomized Multicenter Selective Lymphadenect - omy Trial 1 (MSLT-1). An interim analysis was published in 2006, and more than 15 years of follow-up data were presented at the 2010 Society of Surgical Oncology annual meeting.

A total of 1269 patients with intermediate- thickness primary melanoma were randomized to wide excision plus SLNB, or to wide excision alone (observation). Lymphadenectomy was performed immediately in patients in the SLNB arm who had a positive biopsy. In the observation arm, lymphadenectomy was delayed after a regional lymph node metastasis became clinically apparent.

The interim analysis results did not show a survival difference between the 2 approaches, but the 5-year diseasefree survival (DFS) rate was higher in those undergoing SLNB (78.3% vs 73.1%, respectively). In addition, the 5- year overall survival (OS) rate was 20% higher in the SLNB arm.

Skewed Results?
Dr Thomas noted that the 5-year DFS was based on a post-hoc analysis of subgroups who had different characteristics. In the MSLT-1 trial, more patients in the observation arm had first recurrence in the nodes than in the biopsy arm, which was used to suggest that SLNB followed by lymphadenectomy extends DFS. However, he contends that using nodal disease to assess DFS is problematic, because the nodal basin was preemptively removed in one group but not in the other. To determine whether SLNB and complete lymphadenectomy im - prove DFS, nodal recurrence should have been excluded and only distant metastases included.

Jeffrey Abrams, MD, Chief of the Clinical Investigations Branch of the Cancer Therapy Evaluation Program, National Cancer Institute, supports this view. In a 2007 letter to Dr Thomas, Dr Abrams wrote, “we agree that in a trial where one arm has nodal disease removed at the outset and the other arm does not, calculation of either distant disease-free survival or excluding nodal recurrence from the calculation is appropriate.”

The 5-year OS analysis is also being challenged because the study also compared potentially heterogeneous subgroups: SLNB-positive patients with microscopic disease and patients in the observation arm who developed clinically detectable or macroscopic nodal disease.

Dr Thomas pointed out that the proportion of patients in the immediatelymphadenectomy arm with positive sentinel lymph nodes was more than 20% higher than the proportion of patients in the observation arm who developed regional metastases.

“A proportion of the nodes deemed positive in patients who were then given immediate lymphadenectomy must therefore have been false-positives,” Dr Thomas said, noting that “a large part of these false-positives are micrometastases that are not destined to progress to palpable nodal disease.”

He therefore said that the results of the trial were inappropriately skewed in favor of biopsy and immediate lymphadenectomy in patients with positive SLNB. Hence, clinicians and patients who take this approach are not making a fully informed choice, at least for intermediate-thickness melanoma.

“Patients come to me after having been advised by a surgeon to have SNB, and of course they are inclined to do what the surgeon tells them. But I tell them there is another option, to have ultrasound screening and surveillance instead,” Dr Thomas said.

“Ultrasound is less invasive, and also ultimately is cheaper….The problem is that this term ‘standard of care’ with respect to SNB is being pushed very hard by a group of people in the US who are the heads of important surgical/ academic institutions and of the surgical journals.” Dr Thomas discusses his position regarding MSLT-1 in a letter to the editor of the Annals of Surgical Oncology (Epub July 20, 2011).

Defending the Use of SLNB
Dr Sondak noted that Dr Thomas has not published or presented any new data to support his position. “None of the recommendations for use of SLNB are based on its impact on disease- free survival. It’s obvious that SLNB reduces lymph-node reoccurrence, and that’s important to patients. They’d rather have us do a biopsy while we’ve got them in the [operating room] to excise their primary tumor than having them back in a couple of years, when they feel a lump in their groin and want it investigated. But frankly none of us who do SLNB do it because of the [DFS] advantage. We do it because of all the other advantages of SLNB, and they outweigh any disadvantages. Plus, patients really want to know whether their lymph nodes are positive or not.”

Dr Sondak stood by the MSLT-1 results, stating that the available data indicate all disease detected by SLNB, including micrometastases, is clinically significant. Most, if not all, micro - metastases will eventually progress to tumors that will require resection, whether they are in the lymph nodes or in distant sites, he believes.

In response to the claim that SLNB alone can cause lymphedema in 6% of patients, based on a study of 250 patients with melanoma by Estourgie and colleagues, Dr Sondak stood by the conclusions from MSLT-1, stating that “the long-term risk of lymphedema from SLNB is less than 1%, and, in fact, most of this may actually be due to lymphedema from the wide excision itself.”

He pointed to a response to Dr Thomas’s letter written by Donald Morton, MD, lead investigator of MSLT-1, and colleagues (Faries MB, et al. Ann Surg Oncol. Epub Aug 12, 2011). Citing their previous study, these authors state that “[Dr Thomas] ignores our published data that show no significant difference in lymphedema rates between patients treated by wide excision alone or wide excision with SLN biopsy.”

Routine Use of SLNB for Melanoma?
Dr Sondak supports these views. He said that clinicians can deviate from the standard of care whenever they feel it is in the patient’s best interest, but “deviating from standard medical treatment ethically and legally re - quires informed consent and a discussion of the reasons why and the potential consequences.”

Dr Bastian told VBCC, “by no means does it appear justified for proponents of SLNB to warn of legal consequences if the procedure is not performed. This is a development that is really surprising, unsettling to some degree, because the evidence is very thin that there is a true outcome benefit delivered to the patient by this procedure….There’s a variety of incentives behind this, but clearly the argument for SLNB is being overplayed on several levels.”

Dr Sondak says that surgeons are not simply performing SLNB for the sake of doing surgery. Rather, SLNB “is uniformly incorporated into na - tional and international management guidelines as the standard of care. This procedure is useful to our patients, and informed patients continue to choose sentinel node biopsy.”

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