Melanoma Monday: A Review of the MSLT-II Trial and Completion Lymph Node Dissection

Katherine E. Poruk, MD

Katherine E. Poruk, MD, is a board-certified and fellowship-trained surgical oncologist at Cancer Treatment Centers of America® (CTCA) Atlanta.

Melanoma is a type of skin cancer caused when pigmented cells known as melanocytes start to grow out of control.¹ It is estimated to be the fifth leading cause of new cancer cases each year for both men and women in the United States.² While melanoma is less common than other types of skin cancer, it can be more aggressive due to an increased risk of distant spread.However, screening programs with yearly skin examinations and advancements in treatment have improved the overall survival for patients, especially when these tumors can be identified and treated at an early stage.

The primary treatment of melanoma without clear spread to lymph nodes (often evidenced by palpable lymph nodes) or distant organs is surgery.³ Surgery involves wide resection of the primary melanoma with adequate margins of uninvolved skin to prevent local recurrence of the tumor. For most patients, it also includes an assessment of the regional lymph nodes through a procedure known as a sentinel lymph node biopsy (SLNB). At the time of surgery, a radiotracer and/or blue dye will be injected at the location of the primary skin melanoma. Adequate time is given to allow either or both tracers to travel to the first lymph nodes encountered. During the operation, a probe to identify radioactive activity is used to find these lymph nodes or any lymph nodes in the region that stain with the blue dye.

These lymph nodes, known as the sentinel lymph nodes, are removed in their entirety and sent for evaluation by a pathologist. This does not necessarily mean that these lymph nodes will contain cancer; instead, these are the most likely sites of cancer if the melanoma has spread. The average person will have between 1 and 3 sentinel lymph nodes removed. Based on a variety of factors including tumor depth, mitotic rate, and the presence of ulceration, 5% to 40% of patients undergoing SLNB will have lymph nodes containing micro-metastatic disease.

A pathologist will determine if any or all of the sentinel lymph nodes contain metastatic melanoma cells, which in turn will determine the patient’s pathologic stage and next steps in treatment. In the past, if any sentinel lymph nodes contained metastases, the traditional treatment was a complete axillary lymph node dissection (CLND). This involves the removal of all lymphatic and lymph node tissue in the affected region (for example, axilla or groin). The need for a CLND was based on studies that suggested upwards of 20% of patients would be found to have additional positive lymph nodes in the new specimen at time of CLND.⁴

However, this procedure was not without risks. The risk of lymphedema, or permanent swelling in the nearby arm or leg due to the buildup of fluid due to a blocked lymphatic system, is upwards of 20% to 30% after a CLND for melanoma.³ Although mild in many cases, this can drastically impact a patient’s function and quality of life. Thus, in the 80% of patients who may not have additional lymph nodes and therefore limited benefit of a CLND, there was a real risk of permanent lymphedema without benefit in cancer outcome or survival.

The Multicenter Selective Lymphadenectomy Trial II (MSLT-II; NCT00297895) changed this practice. The trial, performed at 63 hospital centers and published in 2017 in the New England Journal of Medicine, randomized patients with melanoma with a positive sentinel lymph node to either CLND or observation with frequent clinical evaluation.⁵ Patients in the observation group underwent a clinical examination with associated ultrasound assessment every 4 months for the first 2 years and then every 6 months for years 3 through 5. The results of MSLT-II demonstrated no significant difference in distant metastasis–free survival, overall survival, or melanoma-specific survival at 3 years of follow-up between both groups.

Thus, the trial seems to show that CLND alone does not impact local or distant recurrences in patients. A suggested benefit of CLND was that it provided prognostic data for patients by assessing if additional positive lymph nodes were present, and as such may provide regional disease control by reducing the overall risk of regional nodal recurrence. However, this reduction in regional nodal recurrence was minimal and at the risk of increased wound complications and rates of lymphedema (24% in patients after a CLND versus 6% in the observation group). In addition, patients in the observation group who developed clinically enlarged, positive lymph nodes by ultrasound were still candidates for CLND at the time of discovery, and this delay to additional surgery did not appear to impact overall survival.

As a result, clinical observation with frequent physical exams and ultrasonography has become a reasonable and recommended option for certain patients with a positive SLNB. However, it is crucial for clinicians to realize that this may not be achievable for all individuals. A patient must be reliable and able to undergo visits at least every 4 months with an ultrasound; those unable to travel or unable to keep this schedule will need to be considered for CLND. In addition, imaging and follow-up must be performed at a center with the clinical expertise to adequately identify if any lymph nodes appear abnormal on ultrasound and as a result treat as necessary. If intensive follow-up is not possible for a patient, CLND must be considered and offered.

Furthermore, most patients in MSLT-II had only one positive sentinel lymph node identified or had a low burden of disease (< 1mm sentinel node tumor deposit); as such, these findings may not be applicable to high-risk patients who have multiple positive sentinel lymph nodes or a high sentinel tumor burden, defined as a deposit > 1 mm in diameter. As such, caution should be used when recommending ultrasound surveillance in this group.

Finally, national approval has been given in recent years to several systemic therapies to be used in the adjuvant setting for stage III melanoma. These immunotherapies were not evaluated in this trial and may have an impact in the decision of whether or not to offer a CLND in certain patient populations. Consultation with a medical oncologist who specializes in melanoma care is recommended in these situations.

In conclusion, MSLT-II has changed the surgical paradigm for patients with melanoma and a positive sentinel lymph node biopsy, allowing for observation with frequent physical exams and ultrasonography. It is important to understand the limitations of this trial to determine if a patient can forego completion lymph node dissection.

_References:

_{1. What is melanoma skin cancer? American Cancer Society. Accessed April 27, 2022. https://bit.ly/38u55gQ}

_{2. Siegel, RL, Miller, KD, Fuchs, HE, Jemal, A. Cancer statistics, 2022. CA Cancer J Clin. 2022. doi:10.3322/caac.21708}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: cutaneous; version 3.2022. Accessed April 28, 2022. https://bit.ly/3OLPhXx}

_{4. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609. doi:10.1056/NEJMoa1310460}

_{5. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211-2222. doi:10.1056/NEJMoa1613210}