SLNB effective for disease-free survival in select cases

Los Angeles - Sentinel lymph node biopsy (SLNB) for management of localized primary melanoma continues to have its critics, but Alistair Cochran, M.D., says that current data supports the procedure as a standard approach for staging patients with clinically localized, intermediate-thickness melanoma.

“Lymphatic mapping sentinel node biopsy is a minimally invasive staging procedure that is useful as a prognostic tool, and when combined with immediate complete lymph node dissection, can improve the survival of node-positive patients,” says Dr. Cochran, professor, departments of pathology, laboratory medicine and surgery, David Geffen School of Medicine, University of California, Los Angeles, Jonsson Comprehensive Cancer Center and John Wayne Cancer Institute, Los Angeles.

Technique history
According to Dr. Cochran, the lymphatic mapping and sentinel node biopsy techniques were originally conceived to address patients with intermediate thickness primary melanoma (Breslow thickness 1.2 mm to 3.5 mm). According to historical data, these patients had a chance of developing metastatic melanoma but did not at the time of presentation have clinical evidence of melanoma in the regional lymph nodes or elsewhere.

Following a wide excision of the primary melanoma, many patients were simply followed in the clinic, but about 20 percent of these patients developed a metastasis in the regional nodes within three to five years, Dr. Cochran says.

Patients were watched carefully, and as soon as they developed clinical evidence of disease in the lymph nodes, a lymph node dissection was performed. Alternatively, some patients were treated with a prophylactic lymph node dissection, but the difficulty here was that if all patients were treated with a lymph node dissection, approximately 80 percent would have received an unnecessary procedure from which they could not derive any benefit.

Which is which?
Elective lymph node dissection and sentinel node biopsy are two procedures that are often confused, Dr. Cochran says. In an elective lymph node dissection, the surgeon will “blindly” excise clinically normal regional lymph nodes as a prophylactic measure, he explains, whereas a sentinel node biopsy results in the selective removal of only the most likely nodal target(s) of metastasis.

According to Dr. Cochran, an elective lymph node dissection carries considerable potential morbidity, while a sentinel node biopsy does not.

“The sentinel node biopsy allows us to accurately identify the 20 percent of patients who have subclinical metastatic disease in the regional lymph nodes. Compared to patients who are observed after a wide excision of the primary tumor, those patients with clinically occult nodal metastases who undergo a sentinel node biopsy procedure have a significant disease-free survival benefit if treated with an immediate complete lymphadenectomy,” Dr. Cochran says.

Additional tools
When assessing the regional lymph nodes, Dr. Cochran says the number of nodes affected is a relatively crude predictor of outcome. This can be made more accurate if combined with measurements of the amount of tumor in the nodes using micrometry or morphometry techniques. Tumor colonies can be identified using H&E stains, he says, but some dispersed melanoma cells could be missed, indicating the need for more precise staining techniques.

According to Dr. Cochran, lymphoscintigraphy reliably identifies the lymphatic drainage pathways from a particular anatomic site to a specific sentinel lymph node. This node can then be closely evaluated by using sensitive immunohistochemical markers such as S100 protein, Mart-1 and HMB-45.

Using radioactive isotope injected at the site of the primary tumor, lymphoscintigraphy techniques have been fine-tuned. If read within an hour of the isotopic injection, they can identify not only the target lymph node group, but specifically the sentinel node, Dr. Cochran says.

“In the procedure, if a sentinel node is positive, the patient has about a one-in-six chance of having tumor in other lymph nodes in the nodal basin, so-called nonsentinel nodes,” Dr. Cochran says.

MSLT-1 update
The Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) was designed to clarify whether it would be better for patients who have a positive sentinel lymph node removed to have immediate nodal dissection or to have nodal surgery deferred until clinically palpable node(s) became apparent. According to Dr. Cochran, data from the trial indicate that early surgical management of tumor-positive regional nodes confers substantial clinical benefits over surgery delayed until metastases become clinically detectable.

Patients who were randomized to watch and wait in the MSLT-1 trial were seen regularly for physical assessment and in some cases nodal ultrasound. However, ultrasound can only detect tumors 4 mm to 5 mm in diameter, while many of the metastases detected in sentinel nodes are considerably smaller. The MSLT-1 data show no evidence of a lower cut-off size at which the patient may be spared complete nodal dissection, Dr. Cochran says.

According to Dr. Cochran, the 20 percent of patients in the watch-and-wait group who developed lymph node metastases did so on average a year and a half after their wide excision. At that point, those patients had more positive lymph nodes, and the amount of tumor in the lymph nodes was significantly greater than the tumor burden of sentinel node specimens removed after wide excision of the primary.

“Observation allows the disease time to progress, not only as growth within a single lymph node, but to develop the capacity to spread from one lymph node to the next. This underscores the benefit to patients with a positive sentinel lymph node of undergoing early complete lymph node dissection,” Dr. Cochran says.

The statistical analysis of the MSLT-1 data had drawn criticism, Dr. Cochran says, because it had compared a group of patients in whom the lymph node status was immediately known with a second group where nodal status did not become apparent until after a period of follow-up.

However, he says, a recent study (Altstein LL, Li G, Elashoff RM. Stat Med. 2011;30(7):709-717) demonstrates a technique that permits the comparison of outcome in trial groups where one group is latent as far as the outcome is concerned and the other group is not.

“That study certainly shows that patients who have a positive sentinel node and who undergo an immediate complete lymph node dissection have a survival experience significantly better than patients who are observed until the emergence of clinically detectable disease,” Dr. Cochran says.

Disease-free survival
Immediate complete lymph node dissection for a positive sentinel node also confers a statistically significant improvement in disease-free survival, Dr. Cochran says, which is true of local, regional and distant metastasis.

The Altstein data show that patients with an intermediate-thickness melanoma who have a positive sentinel node and undergo immediate complete lymph node dissection have a survival advantage at 10 years follow-up, compared to patients managed by observation and delayed nodal dissection, he says.

Moreover, patients who have an immediate complete lymph node dissection after a positive sentinel node biopsy have on average 1.4 tumor-positive nodes, he says. This is in stark contrast to those patients who after observation develop clinically detectable nodal metastases who have on average 3.2 tumor-positive positive nodes.

“We currently recommend that all patients with melanomas greater than 1 mm in thickness undergo lymphatic mapping and a sentinel node biopsy to determine nodal tumor status,” Dr. Cochran says. “At present, it appears that all patients with melanoma in the sentinel node need a complete lymph node dissection, a situation that may change when the results of the MSLT-2 trial become available. Decisions on therapy should however be made only after a detailed discussion between physicians and their patients.”

Disclosures: Dr. Cochran reports no relevant financial interests.