Backed by a mountain of evidence, Dr. Zitelli walked us through the new and changing role of sentinel lymph node biopsy for melanoma in a riveting 20-minute talk presented at the 16th annual ODAC conference. Here are the highlights.
“Let’s separate what’s really evidence based from what you’ve been told.”
Before delving in, Dr. Zitelli skillfully laid the framework for his lecture. The crux of sentinel lymph node biopsy is based on the theory of orderly progression, in which malignant melanoma cells leave the tumor and preferentially enter the lymphatics and the first lymph node. This theory is rivaled by the anatomic pathway, in which malignant melanoma cells may enter the lymphatics or the blood stream, resulting in simultaneous dissemination.
Which theory is correct?
The overwhelming preponderance of evidence supports the latter anatomic theory – melanoma cells may enter the blood stream directly or the lymphatics, potentially bypassing the sentinel node. This anatomic theory is evidence based. It refutes the theory of orderly progression that the concept of sentinel lymph node biopsy is based on. Another common misconception is that lymph nodes are filters – they are not. Lymph nodes are sampling organs, sampling antigens in order to initiate an immune response.
With the groundwork laid, Dr. Zitelli went on to summarize the emerging evidence for sentinel lymph node biopsy. “This is what you need to know when you counsel a patient in order to obtain true informed consent.”
ONE
What you’ve been told: Sentinel lymph node biopsy improves survival
What the evidence shows: There is not a single solid tumor for which sentinel lymph node biopsy has been shown to provide a survival benefit.
We’ve been told that sentinel lymph node biopsy improves survival in intermediate thickness melanoma, because subclinical deposits are removed from the lymph nodes before they can grow. In fact, 33% of patients who underwent sentinel lymph node biopsy, did so because they thought it would improve their survival. Yet, there is not a single solid tumor – melanoma, gastric, renal, thyroid or otherwise – where electively removing normal lymph nodes, even in the case of microscopic involvement, has shown a survival benefit.
A cornerstone trial, the Multicenter Selective Lymphadenectomy Trial (MSLT-1), set out to prove the survival benefit of sentinel lymph node biopsy in melanoma. However, sentinel lymph node biopsy failed to improve melanoma specific survival. Subsequently, MSLT-2 looked at whether removing positive lymph nodes further down the line would improve survival in patients who had positive sentinel lymph nodes – this was also a negative study.
TWO
What you’ve been told: Sentinel lymph node biopsy is the best prognostic test
What the evidence shows: MSLT-1 concluded that sentinel lymph node status was the strongest predictor of death in melanoma – this was statistical error.
We’ve been told that sentinel lymph node biopsy is the best prognostic test, informing patients how likely they are to die from their melanoma. But let’s take a closer look, 70% of patients are not even eligible for sentinel lymph node biopsy because their melanomas are less than a millimeter thick. Of those who are eligible, many choose not to undergo the procedure. How useful is a test if over 70% of people do not have it? What’s more concerning is where sentinel lymph node biopsy falls short. Sentinel lymph node biopsy only identifies 1/3 of people who will eventually die from melanoma. In fact, twice as many people who have a negative sentinel lymph node die, compared to those who have a positive sentinel lymph node.
How did this word even get out? MSLT-1 dubbed sentinel lymph node status the strongest predictor of death in melanoma, with a hazard ratio 2.4. However, the same study found a hazard ratio of 1.59 per every 1 mm incremental increase in Breslow depth. Most important is the “per every 1 mm.” Therefore, if we compare a 1 mm thick melanoma to 3 mm thick melanoma, the hazard ratio becomes 2.52, and if we compare a 1 mm thick melanoma to a 4 mm thick melanoma, the hazard ratio is greater than 4. The conclusion made by MSLT-1 stating that sentinel lymph node status is the strongest predictor of death based on hazard ratio, is statistical error.
More recent studies show that Breslow’s thickness and other clinicopathologic features have much better prognostic value than sentinel lymph node biopsy alone. Dr. Zitelli – “If we know Breslow’s thickness, any additional information gained from sentinel lymph node status – either positive or negative – is not statistically significant.” Better tools include web-based models that factor Breslow thickness and other clinicopathologic data, as well as gene expression profile tests.
THREE
What you’ve been told: Sentinel lymph node biopsy avoids the long-term complications of complete lymph node dissection
What the evidence shows: Sending patients for sentinel lymph node biopsy does not avoid long term complications.
We’ve been told that sentinel lymph node biopsy helps avoid the long-term complications of a complete lymph node dissection by removing positive nodes. However, MSLT-2 showed that it is not beneficial to remove lymph nodes. To further illustrate his point, Dr. Zitelli walked the audience through a sample cohort of 1000 patients, based on established complication rates.
If we take 1000 patients and only perform lymph node dissection for palpable disease, we would expect 39 major complications such as lymphedema and nerve damage. But if we took the same 1000 patients and performed sentinel lymph node biopsies on the entire cohort, we would encounter complication rates for sentinel lymph node biopsy with negative nodes, positive nodes, as well as complication rates for those who go on to have complete lymph node dissection – in this case, the total the number of complications we would expect is 58. Sending patients for sentinel lymph node biopsy does not avoid long term complications.
FOUR
What you’ve been told: Sentinel lymph node biopsy identifies patients who will benefit from adjuvant therapy
What the evidence shows: Sentinel lymph node biopsy doesn’t identify patients who will benefit from adjuvant therapy, yet
We’ve been told that we should send patients with melanoma for sentinel lymph node biopsy in order to determine whether or not they would benefit from adjuvant therapy. Context is important. Most studies of Sentinel Lymph Node Biopsy, Melanoma, Prognosis have been performed on patients who have far advanced unresectable disease. Thus, the dramatic results from these studies may not be generalizable to many of the patients we see.
However, some studies of adjuvant agents included patients without clinically evident lymph node disease:
- Stage IIIA patients: no palpable lymph nodes, but positive sentinel lymph node biopsy
- Stage IIIB patients: ulcerated primary, no palpable lymph nodes, but positive sentinel node biopsy
- Stage IIIC patients: no palpable nodes but with satellite lesions
Studies of ipilimumab included stage IIIA and IIIB patients. In subgroup analyses authors found no survival benefit for stage IIIA patients, but a potential survival benefit for more advanced stage IIIB patients. For BRAF inhibitors, stage IIIA and IIIB patients did not show a survival benefit. Nivolumab did not offer recurrence free survival in stage IIIB patients. Venurafenib showed no significant reduction in stage IIIA and IIIB patients Adjuvant PD1 inhibitors did not show recurrence free survival benefit in stage III melanoma patients.
In summary – we don’t know. In practice, Dr. Zitelli considers adjuvant therapy in patients with an ulcerated primary and positive node. He advises us to be on the lookout for clinical trials in our area for interested patients. Of note, the costs of these agents may be prohibitive and side effect profiles should be carefully considered.
This information was presented by Dr. John Zitelli at the 16th Annual ODAC Dermatology, Aesthetics and Surgical Conference held January 18th-21st, 2019 in Orlando, FL. The above highlights from his lecture were written and compiled by Dr. Ramone Faith Williams. Dr. Williams was one of the 5 residents selected to participate in the Sun Resident Career Mentorship Program (a program supported by an educational grant from Sun Pharmaceutical Industries, Inc.). Dr. Williams is the academic chief resident in dermatology at Albert Einstein/Montefiore.
