CLND in melanoma patients is NOT associated with survival benefit

As effective therapies were developed for melanoma patients, folks began to take a harder look at whether or not the removal of all the lymph nodes in the nodal basin, after a positive sentinel lymph node, provided benefit.  With no effective treatment for melanoma, the argument for CLND made more sense.  These days, as ratties have proved the value of both targeted and immunotherapy as treatment for advanced disease as well as adjuvant (BRAFi and Yervoy were FDA approved for metastatic melanoma in 2011, anti-PD-1 was approved for same in 2014, and nivo was approved for use as adjuvant only in 2017) and are now furthering the examination of NEO-adjuvant treatments, we have learned better.  The research and recommendations have vacillated back and forth over the years and the topic has been more than covered in this space with a zillion articles and discussions.  Here's a brief review of the value and difference between SLNB (sentinel lymph node biopsy) and CLND (complete lymph node dissection) written in 2016:

I have long said that sentinel lymph node removal and testing in melanoma seems like a complete no-brainer to me!!!  It is done when you return for the needed wide excision around the tumor that was removed.  It is minimally invasive considering you're going to have the wide excision anyway.  It is the only way to know what stage you really are.  You may have only cutaneous disease and therefore are categorized as Stage 1 or 2....based on how thick your lesion was, the presence of ulceration, etc.  BUT....if you have a positive node to go with that....you are then Stage 3....and that is a very different place to be.  

1.  It's important to know that's where you are in melanoma land.

2.  It makes a world of difference in recommended follow up.

3.  It makes a world of difference in what insurance companies will cover for your follow-up.

4.  AND....it makes a world of difference in potential treatment options.

NOW....do NOT confuse sentinel node removal and biopsy with a complete lymph node dissection (CLND).  CLND is different.  A CLND is when, usually after having one or more positive nodes, all the lymph nodes are removed from the nodal basin (the area in which the positive node was located).  This IS invasive surgery and has the potential to cause nerve damage and/or lymphedema, among other things.  IF you had a positive sentinel node, this would be one of the things you would have to decide about doing or not.  The science and data surrounding whether this is helpful or not, worth the potential damage or not, is murky.  There are studies that say it helps and others that say is does not.  BUT whichever way you decide to go with this...this is a decision made AFTER the sentinel node dissection and separate from it!!!

The difference between the two procedures and reasons for them remains on point.  And while there are still occasional valid reasons to consider a complete lymph node dissections - now there's this:

Completion lymphadenectomy for a positive sentinel node biopsy in melanoma patients is not associated with a survival benefit.  Kleman, Han, Leong, ..., Sondak, et al.  J Surg Oncol. 2019 Mar 18. 

Completion lymph node dissection (CLND) for sentinel lymph node (SLN) disease in melanoma patients is debated. We evaluated the impact of CLND on survival and assessed for predictors of nonsentinel node metastasis (positive CLND).

Positive SLN melanoma patients were retrospectively identified in the Sentinel Lymph Node Working Group database. Clinicopathological factors were correlated with CLND status, overall survival (OS), and melanoma-specific survival (MSS).

There were 953 positive SLN patients of whom 831 (87%) had CLND. Positive CLND was seen in 141 (17%) cases and was associated with worse OS and MSS . CLND was not performed (No-CLND) in 122 of 953 positive SLN cases (13%), of whom 100 had follow-up and 18 (18%) developed a nodal recurrence (NR). No significant differences in OS and MSS were seen comparing CLND with No-CLND and comparing positive CLND with No-CLND NR patients. Gender, primary site, ulceration, and number of positive SLNs were correlated with nonsentinel node metastasis.

Performance of CLND provides prognostic information but is not associated with a survival benefit. Clinical variables can predict a positive CLND in patients who may be at high risk of recurrence.

In reviewing the records of 953 melanoma peeps with positive SLN, researchers found that there was no impact on overall survival or melanoma-specific survival, no matter if the CLND was done or not.  The usual risk factors of "gender, primary site, ulceration, and number of positive SLNs" were noted to coordinate with metastasis as studies I've reported on previously corroborate.  

As someone who has had two CLND's (to both axilla), the first in 2003 and the second in 2007, yet still progressed to Stage IV in 2010, watching the research on the topic unfold has been interesting to say the least.  However, given the advances in melanoma therapy, it is probably time to move on! - les

CLND - Complete lymph node dissection in melanoma - the whole shmegegge!!!!!!!!!!!

Pros and cons of whether or not to do a complete lymph node dissection (CLND) are varied.  Here is a post addressing both (with many links within):  Sentinel lymph node disection ~ "important diagnostic procedure and might be of therapeutic benefit re: DFS and OS!"

If you prefer the links following that one in a list - here they are:
Feb 2016:  "Patients with microscopically negative/PCR+ SLN have increased risk for nodal recurrence that was mitigated by CLND"!
Also Feb 2016:  Sunbelt Melanoma Trial Final Results: No survival benefit for interferon or complete lymph node dissection in patients with a single positive SLN!
Still Feb 2016, a little tangential...but addresses effect of positive SLN:  Women and melanoma risk
Post covering several reports from 2014:  With melanoma: You can never be too rich or too thin! But, you can be too young!!!
And this huge study from Faries et al in 2014:  Lymph node removal after superficial melanoma lesions...to do or not to do????

So....it is absolutely clear (at least to me) that removal of the sentinel node after a melanoma lesion is crucial to staging and treatment if nothing else.  Complete lymph node dissection in the area of that sentinel node is more complicated.

Now there's this:

Timing of completion lymphadenectomy after positive sentinel node biopsy in patients with melanoma. Oude, van Akkooi, Rutowski, et al. Br J Surg. 2017 Feb 20.

Nodal staging with sentinel node biopsy (SNB) and completion lymph node dissection (CLND) provides prognostic information to patients with melanoma and their physicians. It is not known whether the timing of CLND is associated with survival outcome and/or CLND tumour load. This study investigated whether CLND timing is associated with CLND tumour load, disease-free survival (DFS) and/or melanoma-specific survival (MSS).

A retrospective cohort of patients with SNB-positive melanoma from nine European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group centres undergoing surgery between 1993 and 2009 were examined. Patients were selected based on availability of CLND and follow-up data. The CLND interval was defined as the number of days between diagnosis and CLND. Patient and tumour characteristics were collected. Five-year DFS and MSS rates were calculated. Cox and logistic regression analysis were performed, adjusting for known prognostic/predictive indicators.

A total of 784 patients were included in the study. Their median age was 51 years, and 418 patients (53·3%) were men. Median Breslow thickness was 3·0 mm, and 148 patients (18·9%) had a residual tumour load. Median CLND interval was 84 days. Five-year DFS and MSS rates were not significantly different for patients operated on with a median CLND interval of less than 84 days and those with an interval of at least 84 days. In a multivariable Cox model, CLND interval was not a significant prognostic indicator. CLND interval was negatively correlated with identification of positive non-sentinel nodes, but following adjustment for known risk factors this effect was no longer found.

The time interval between diagnosis of melanoma and CLND did not influence CLND tumour load, DFS or MSS.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. Faries, Thompson, Cochran, Andtbacka, et al.  N Engl J Med. 2017 Jun 10.

Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. 
In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence. Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. 
Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases.

So...if you note the 2014 study linked above, Faries has been looking at this stuff for a long time.  In this latest report, again, it is clear that sentinel lymph node biopsy is "associated with melanoma specific survival."  In this study, they placed patients with a positive sentinel node, randomly in either an immediate completion lymph-node dissection group or a nodal observation group that were followed with ultrasound. The group with the immediate CLND was "NOT associated with increased melanoma-specific survival".  The 3 year rate of survival was similar in the dissection and observation groups.  "The rate of disease free survival was slightly higher in the dissection group (68%) vs the observation group (63%) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92% vs 77%); these results must be interpreted with caution."  (Not sure why the caution unless they don't feel it was really a statistically significant finding.)

An interesting notation is that lymphedema was found in 24% of the folks with the CLND.  We already knew (mostly from breast cancer patients) that lymphedema is more common in older, heavier patients and more common in inguinal dissections than in those to the upper extremities. 

As Faries has done, we all need to move where the data and truth takes us.  I do not regret my two CLND's done to bilateral axilla in 2003 and 2007.  It is probably easier to take that stance since, despite some weird nerve stuff to my right (have had three surgeries there over the years!!!) I luckily, have not developed lymphedema. Additionally, back then we did not have the study results we have now...nor effective melanoma therapies.  Great strides have been made in understanding and treating melanoma in just the past 5-7 years.  For too many, however, it is not nearly enough. Keep pushing, researchers!!!  Keep pushing!

Hang in there, ratties!!! - c

Melanoma - All things adjuvant

I have kicked and screamed about the need for adjuvant treatment for so many years (especially the more effective anti-PD-1 products vs ipi) that it was almost unbelievable when they were finally FDA approved for adjuvant use in 2017 (Opdivo) and 2019 (Keytruda).  Sadly, recent trial results for the ipi/nivo combo as adjuvant did not prove more effective - providing instead only a greater side effect profile.  Here's a history of adjuvant care in melanoma - ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....   At this point, targeted therapy in the form of BRAF/MEKi combo's, for BRAF positive patients, and NEO-adjuvant treatments are also available for melanoma patients in need of such care.  Here are zillions of adjuvant related reports - Adjuvant care in melanoma

Now, there are these (my comments in red as ever):

Adjuvant Therapy is Effective for Melanoma Patients with a Positive Sentinel Lymph Node Biopsy Who Forego Completion Lymphadenectomy.  Farrow, Raman, Williams, et al.  Ann Surg Oncol, 2020 Dec 27.

Background: Multiple adjuvant therapies for melanoma have been approved since 2015 based on randomized trials demonstrating improvements in recurrence-free survival (RFS) with adjuvant therapy after surgical resection of high-risk disease. Inclusion criteria for these trials required performance of a completion lymph node dissection (CLND) for positive sentinel lymph node (pSLN) disease.

Objective: We aimed to describe current practice for adjuvant therapies in patients with pSLN without CLND (active surveillance [AS]), and to evaluate recurrence in these patients.

Methods: Melanoma patients with pSLN between 2016 and 2019 were identified at two institutions. Demographic information, disease and treatment characteristics, and recurrence details were reviewed retrospectively. Patients were stratified by recurrence and patient-, treatment- and tumor-related characteristics were compared using Fisher's exact test and t test for categorical and continuous variables, respectively.

Results: Overall, 245 SLN biopsies were performed, of which 36 (14.7%) were pSLN. Of 36 pSLN, 4 underwent CLND and 32 underwent AS, of whom 22 (68.8%) received adjuvant therapy with the anti-programmed death-1 (PD1) inhibitor nivolumab (16/22), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (3/22), or BRAF/MEK inhibitors (3/22). At a median follow up of 13.3 months, 7/32 (21.9%) patients on AS recurred, including 4/22 (18.2%) who received adjuvant therapy and 3/10 (30.0%) who did not. Tumor ulceration was significantly associated with recurrence. While not significant, acral lentiginous subtype appeared more common among those with recurrence.

Conclusion: The majority (68.8%) of patients with pSLN managed without CLND were treated with adjuvant therapy. The 1-year RFS for patients managed with adjuvant therapy without CLND was 82%, which is similar to modern adjuvant therapy trials requiring CLND.

Back in the day, including when I was first diagnosed in 2003 and when I recurred in 2007, patients were routinely treated with a complete lymphadenectomy (CLND) of the area around a positive lymph node.  I went through it twice, to both axilla.  Times have changed and the process of CLND is no longer recommended.  In fact, NEO -adjuvant treatment is being studied to see if starting treatment with the positive node in place provides better results and the data is looking positive.  In this report, researchers were looking for differences between melanoma peeps who had a complete lymphadenectomy and those who simply had the positive node removed and started adjuvant treatment.  Of 245 sentinel node biopsies they examined - 36 were positive.  Of those, 4 patients had CLND and 32 had only the positive node removed.  22 were given adjuvant treatment - 16 were treated with nivo, 3 with ipi, and 3 with BRAF/MEK.  At 13.3 months of follow-up - 7 of the 32 patients had recurred - 4 of whom had been treated with adjuvant therapy (abstract does not note which) and 3 had not.  Tumor ulceration was significantly associated with recurrence (which is not news).  Overall, the patients who had adjuvant treatment after a positive node, but NO CLND had a recurrence free survival rate of 82% which is similar to patients who were given a CLND and adjuvant therapy.  Again, this is no longer news, rather confirmation of what we have understood for some years now.

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  2020 Nov.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up.

Patients and methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual, stage IIIA (at least one lymph node metastasis greater than 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.

Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status.

Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups

At three years follow up, Stage III patients of all stripes did better after treatment with Pembro than those treated with placebo - demonstrating a recurrence free survival rate of 63.7% for those treated with pembro vs 44.1% for those given placebo.  YEP.

Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management.  Rauwerdink, Molina, Tompers, et al.  Ann Surg Oncol.  2020 Dec.

Background: The management of patients with resected stage 3 melanoma has changed significantly due to adoption of the Multicenter Selective Lymphadenectomy Trial (MSLT)-2 guidelines and to the survival benefit of adjuvant anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy. Data are scarce regarding recurrence patterns, adjuvant therapy responses, and therapy-associated adverse events (AEs) in the modern era.

Methods: This single-institution, retrospective study analyzed surgically resected stage 3 and oligometastatic stage 4 patients who received anti-PD-1, BRAF/MEKi, or surgery with active surveillance only. The primary end point of the study was recurrence-free survival (RFS). The secondary end points were the location and clinical characteristics of recurrence and therapy-associated AEs.

Results: From a cohort of 137 patients, the study enrolled 102 patients treated with adjuvant anti-PD-1 (n = 46), adjuvant BRAF/MEKi (n = 3), or surgery alone (n = 26). During a mean follow-up period of 17 months, 20% of the ani-PD-1 patients, 13% of the BRAF/MEKi patients, and 42% of the surgery-only patients experienced recurrence. Log-rank testing showed a significantly longer RFS for the patients treated with anti-PD-1 [15.3 months; interquartile range (IQR), 8.2-23.2 months] or BRAF/MEKi (17.9 months; IQR, 12.5-23 months) than for those treated with surgery alone (11.9 months; IQR, 7.0-17.6 months). In the anti-PD-1 group, AEs occurred less frequently than in the BRAF/MEKi group (54% vs 80%).

Conclusions: Adjuvant anti-PD-1 and BRAF/MEKi were associated with significantly improved RFS for the patients with resected stage 3 or 4 melanoma. The BRAF/MEKi group had significantly more AEs than the anti-PD-1 group. This is the first study to characterize real-world recurrence in the modern era of adjuvant therapy for melanoma.

This study looked at 102 resected Stage III and Stage IV patients. (Stage III patients whose positive node was removed as well as Stage IV like me when I entered my Phase 1 Nivo trial in 2010, whose metastatic disease had been removed.)  46 were given adjuvant anti-PD-1.  3 were given BRAF/MEKi.  26 had surgery alone.  At 17 months 20% of those treated with anti-PD-1, 13% treated with targeted therapy, and 42% of the surgery-only patients had recurred.  Recurrence free survival lasted an average of15 months for anti-PD-1 patients, 18 months for the BRAF/Meki group, and only 12 months for those given surgery alone.   {While this type of data analysis of outcomes of adjuvant therapy is much needed - TAKE THESE NUMBERS WITH A HUGE GRAIN OF SALT!!!!!  THE 46 patients treated with anti-PD-1 and 26 given surgery only -is barely sufficient to make valid statistical analysis possible; the THREE treated with BRAF/MEKi does NOT!!!!!!!!!!!!!!!!!!!!}

The data presented in the reports included in this October 2020 post New follow-up data confirms effectiveness for targeted and immunotherapy as adjuvant in melanoma patients!!! is much better! To whit ~ 

From Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.  Drummer, Hauschild, Saninami, et al.  New England Journal of Medicine.  September 17, 2020.  

870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos.  At 5 years, the percentage of patients who were alive without relapse was 52% with dabrafenib plus trametinib and 36% with placebo.

From Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  September 18, 2020.

1,019 patients with complete lymph node dissection ofcutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity.   3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively.

From Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.  Ascierto, Del Vecchio, Mandala, et al.  Lancet Oncol.  September 18, 2020.

906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months with nivolumab and 50·9 months with ipilimumab; 4-year recurrence-free survival was 51·7% in the nivolumab group and 41·2% in the ipilimumab group. With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths, 4-year overall survival was 77·9% with nivolumab and 76·6% with ipilimumab.

NOW - even with all this - it is hard to compare THESE numbers! (Though they are clearly more statistically valid than those noted in the article I started with and also demonstrate the falseness of the claim those authors purport in the last sentence of their abstract!!!!!)  To that end,  I noted when I published them - 

So, there you go.  ALL of these adjuvant therapies provided Stage III/IV melanoma patients whose obvious disease was removed via surgery or radiation better results - no matter if they were treated with ipi, nivo, pembro or the dabrafinib/trametinib combo - than when they were left untreated.  Per these reports, here's how things panned out ~

Dabrafinib/trametinib - at 5 years, stage III melanoma patients alive without relapse was 52% with treatment vs 36% with placebo.

Pembrolizumab (Keytruda) - at 3 years, Stage III melanoma patients with recurrence free survival was 63.7% when treated with pembro, vs 44.1% for placebo.

Ipilimumab (Yervoy) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 41.2%.  4 year overall survival was 76.6%.

Nivolumab (Opdivo) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 51.7%.  4 year overall survival was 77.9%.

My thoughts:

The fact that Stage IV patients were included in the study looking at adjuvant ipi and nivo (CheckMate 238 trial) is HUGE!!!!!!  It makes comparison to the studies using pembro and the dabrafinib/trametinib combo as adjuvant in Stage III peeps ONLY, difficult to say the least.   I would really like to see an adjuvant study in Stage III melanoma patients where Keytruda and Opdivo are compared head to head, using the exact same result parameters and time frames.  I doubt there would be any significant difference in results as that has already been found to be the case when those agents are used in treatment of Stage IV melanoma patients - but still.  And finally, while the numbers for adjuvant ipi weren't that bad, and certainly much better than placebo, the side effects were greater - so I don't find ipi as a single agent a good choice for adjuvant therapy given the other options.

FYI - Time frames of follow-up matter.  As time goes on, more peeps have a chance to progress.  So data at three years is often better than outcomes reported at five years.

For instance in this article:  2017 - Nivo better than ipi as adjuvant  The data (drawn from Stage III AND Stage IV melanoma patients who took the drugs as adjuvant) demonstrates this:

Recurrence free survival at 12 months:

70.5% for nivo                    60.8% for ipi

Recurrence free survival at 18 months:

66.4% for nivo                    52.7% for ipi

That is why it is important to compare apples to apples in all aspects.  c

"Patients with microscopically negative/PCR+ SLN have increased risk for nodal recurrence that was mitigated by CLND"!

Molecular Staging of Sentinel Lymph Nodes Identifies Melanoma Patients at Increased Risk of Nodal Recurrence.  Kimbrough, Egger, McMasters, et al. J Am Coll Surg. 2016 Jan 14.

Molecular staging of sentinel lymph nodes (SLNs) may identify patients who are node-negative by standard microscopic staging but are at increased risk for regional nodal recurrence; such patients may benefit from completion lymph node dissection (CLND).

In a multicenter, randomized clinical trial, patients with tumor-negative SLNs by standard pathology (hematoxylin and eosin [H and E] serial sections and immunohistochemistry [IHC]) underwent reverse transcriptase polymerase chain reaction (PCR) analysis of SLNs for melanoma-specific mRNA. Microscopically negative/PCR+ patients were randomized to observation, CLND, or CLND with high-dose interferon (HDI). For this post-hoc analysis, clinicopathologic features and survival outcomes, including overall survival (OS) and disease-free survival (DFS), were compared between PCR+ patients who underwent CLND vs observation. Microscopic and molecular node-negative (PCR-) patients were included for comparison.

A total of 556 patients were PCR+: 180 underwent observation, and 376 underwent CLND. An additional 908 PCR- patients were observed. Median follow-up was 72 months. Disease-free survival (DFS) was significantly better for PCR+ patients who underwent CLND compared with observation. No statistically significant differences in OS or distant disease-free survival (DDFS) were seen. Regional lymph node recurrence-free survival (LNRFS) was improved in PCR+ patients with CLND compared to observation. The PCR+ patients in the observation group had the worst DFS; those with CLND had similar DFS to that in the PCR- group. 

Patients with microscopically negative/PCR+ SLN have an increased risk of nodal recurrence that was mitigated by CLND. Although CLND did not affect OS, these data suggest that molecular detection of melanoma-specific mRNA in the SLN predicts a greater risk of nodal recurrence and deserves further study.

Hmmm....as ever....in melanoma, decisions are not simple - especially when this study is juxtaposed against the recent release of the Sunbelt Melanoma Trial final report: Sunbelt Melanoma trial final results  I still have to believe that getting that S#!T out of there has got to be a good thing!  But, messing with lymph nodes can be a painful, miserable proposition with the significant risk of lymphedema.  So....could robots do that job better?

Robotic-Assisted Transperitoneal Pelvic Lymphadenectomy for Metastatic Melanoma: Early Outcomes Compared with Open Pelvic Lymphadenectomy.  Dossett, Castner, Pow-Sang, Sondak, et al.  J Am Coll Surg. 2016 Jan 14.

In the absence of iliac or obturator nodal involvement, the role of pelvic lymphadenectomy (PLND) for melanoma is controversial, but for select patients, long-term survival can be achieved with the combination of superficial inguinal (inguinofemoral) and PLND. Open PLND (oPLND) is often limited in visual exposure and can be associated with considerable postoperative pain. Robotic PLND (rPLND) is a minimally invasive technique that provides excellent visualization of the iliac and obturator nodes. Outcomes comparing the open and robotic techniques have not been reported previously for patients with melanoma.

We reviewed our experience with rPLND for melanoma and compared clinical and pathologic results with oPLND. We evaluated operative times, nodal yield, and short-term oncologic outcomes.

Thirteen rPLND (2013 to 2015) (15 attempted, 87% success rate) and 25 oPLND (2010 to 2015) consecutive cases were completed. Pelvic lymphadenectomy was combined with an open inguinofemoral dissection in 8 of 13 (62%) robotic and 17 of 25 (68%) open cases. Median length of stay was shorter in the rPLND group, with 1.0 vs 3.5 days for pelvic-only cases and 2.5 vs 4.0 days for combined ilioinguinal cases. Median operative time (227 vs 230 minutes;) and nodal yield (11 vs 10 nodes) were not different between rPLND and oPLND.

Robotic PLND offers a safe, effective, minimally invasive approach to resect the pelvic lymph nodes in patients with melanoma, with no significant difference in nodal yield or operative times, but a shorter length of stay compared with oPLND.

Well, hmmmmm....again.  No impressive increase in the number nodes removed nor significant decrease in time on the operating table...but a decrease in length of hospital stay.  Perhaps over time we will find that that will contribute to the development of fewer side effects like nerve damage and lymphedema.  Have to wait to see what the ratties tell us.

Hang in there - c

SLNB and CLND....in melanoma patients!! Again!

The topics of sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) have been more than covered here!!  But, melanoma is a scary world to say the least, and folks are most frightened right at the time they are having to make these decisions! So, there was this:

SLN biopsy. Delay of 40 days = WHAT???? (Plus some general guidelines)

And this:

CLND - Complete lymph node dissection in melanoma - the whole shmegegge!!!!!!!!!!!

Now there's this:

Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations. Verver, van Klaveren, van Akkooi, et al. Eur J Cancer. 2018 Apr 13.

In light of the evolving landscape of adjuvant therapy in melanoma and the recently confirmed absent survival benefit of completion lymph node dissection (CLND), it becomes important to explore possible consequences of omitting CLND, and whether it is possible to adequately stratify positive sentinel node (SN) patients solely based on information retrieved from the melanoma up to the sentinel lymph node biopsy (SLNB).

A retrospective cohort from nine European Organization for Research and Treatment of Cancer Melanoma Group centres was used. Patients were staged based on SLNB and CLND result according to the American Joint Committee on Cancer (AJCC) criteria and stratified by ulceration and SN tumour burden. These were incorporated in Cox regression models. Predictive ability was assessed using Harrell's concordance index (c-index) and the Akaike information criterion (AIC).

In total, 1015 patients were eligible. CLND led to upstaging in N-category in 19% and in AJCC stage in 5-6%. The model incorporating only ulceration and SN tumour burden performed equally well as the model incorporating substages after CLND. The model incorporating substages based on SLNB had the lowest predictive ability. Stratifying by ulceration and SN tumour burden resulted in four positive SN groups from which low-, intermediate- and high-risk prognostic classes could be derived.

Adequate stratification of positive SN patients was possible based on ulceration and SN tumour burden category. The identification of low-, intermediate- and high-risk patients could guide adjuvant therapy in clinical practice. Omitting CLND seems to have little consequences.  

This report simply reiterates what prior studies have shown.  SLNB is important for staging.  And looking at what the sentinel node shows as far as tumor burden, esp when you consider whether or not the initial lesion was ulcerated,  can be very helpful in evaluating risk and decision making regarding adjuvant treatment.  CLND did not really impact results.

Good luck, ratties!  You can do this! - c

Sunbelt Melanoma Trial Final Results: No survival benefit for interferon or complete lymph node dissection in patients with a single positive SLN!

Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy.  McMasters, Egger, Edwards, et al.  J Clin Oncol.  2016 Feb 8.

“The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy.

Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS).

In the Protocol A intention-to-treat analysis, there were no significant differences in DFS  or OS  for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS  or OS  across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months.

No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.”

Interesting.  Not really news in the case of interferon!  Can we finally be done with that "treatment" already???!!!!  As far as the complete lymph node dissection, I guess there remains one (at least) question...and that is....What about folks with obvious tumor in their sentinel lymph node?  This study reports that in these patients with sentinel nodes that were "negative by conventional pathology, but WITH melanoma detected via RT-PCR" testing, there was no overall survival benefit to the complete lymph node dissection.  Hmmm.... This study result does stand in contrast to data showing benefit from CLND in the 2,000 patients randomly studied by Balch and Faries in their 1994-2014 study where patients were observed OR treated with lymphadenectomy if a positive node was found.  On a personal note:  My initial primary lesion was only 0.61mm thick with no ulceration.  However, a sentinel node was positive for micrometastasis. I did elect to have a complete lymph node dissection of the area but declined interferon.  Still, I developed a second thin primary in another location 4 years later (removed, negative SLN, CLND), but advanced to Stage IV with brain and lung mets 3 years after that.  Still more we have yet to figure out...but we've come a long way baby!!!  Thanks, ratties! - c

SLN biopsy. Delay of 40 days = WHAT???? (Plus some general guidelines)

While there is controversy around whether or not to do a complete lymph node dissection - with newer research indicating little to no increase in overall survival with the procedure - sentinel lymph node biopsy remains an essential part of diagnosis and thereby treatment!!!  How would you know you were Stage III (or not) if no sentinel node(s) evaluation was done after a cutaneous lesion is removed?????  How would you know what treatment and course of observation you would need to pursue????  Furthermore, insurance companies balk at covering anything!  When you don't have the argument of proof of metastasis to a node very few, if any, will cover important follow-up scans.
Here's a post covering a great deal of recent research on both SNL biopsy and CLND:

CLND - Complete lymph node dissection in melanoma - the whole shmegegge!!!!!!!!!!!

Now...there's this:

The intriguing effect of delay time to sentinel lymph node biopsy on survival: a propensity score matching study on a cohort of melanoma patients. Tejera-Vaquerizo, Descalzo-Gallego, Traves, et al. Eur J Dermatol. 2017 Sep 23. 

Time between primary melanoma excision and sentinel lymph node biopsy (SLNB) has not been sufficiently studied as an independent predictor of survival in cutaneous melanoma.

We used propensity score matching to evaluate whether early SLNB (performed  less than/= to 40 days from excisional biopsy) is associated with higher mortality in patients with cutaneous melanoma.

A retrospective cohort study at a tertiary melanoma referral centre. We included 787 consecutive patients from the melanoma database of the Instituto Valenciano de Oncología who underwent a SLNB between 1^st January 2000 and 31^st December 2015, of whom 350 were matched into pairs using propensity score matching. The variable of interest was the time between primary melanoma excision and SLNB (less than/= to 40 days vs greater than 40 days). The study outcomes were disease-free survival (DFS), melanoma-specific survival (MSS), and overall survival (OS).  

A delay time of 40 days or less was associated with worse DFS, and OS. Other variables associated with shorter MSS were age, tumour location and thickness, mitotic rate, and SLN status.  Early SLNB was associated with worse survival in patients with cutaneous melanoma after adjusting for classic prognostic factors. A delay time of over 40 days was not associated with higher mortality.

While this sounds a bit counter intuitive....in that leaving the positive node in place for 40 plus days...garners BETTER responses than removing the same node in 40 or fewer days in regard to disease free survival and overall survival.  However, the rational for this phenomenon is the idea that those positive lymph nodes are needed for the body to process the antigens in the melanoma cells that are present in the node(s) in order to facilitate the body's immune response.  If the immune response is never launched, the chance of persistent disease is greater.

Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. Wong, Fariers, Kennedy, Agarawala, et al. Ann Surg Oncol, 2017 Dec 13.

To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma.  An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma.

Nine new observational studies, two systematic reviews and an updated randomized controlled trial (RCT) of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included.

Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions less than 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or less than 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of greater than1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; greater than 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors, and details of the reference patient populations are included within the guideline.

So...not really much new here...but might be edifying for folks looking at making this decision.

Hang in there, peeps.  Melanoma-land is a crazy place.  - c

LATE ADDENDUM!
Sometimes I get tired, or lazy, or weary of beating the same old drum over and over.  But, sometimes...important topics NEED repeating, re-visiting, and re-evaluating.  Plus....2 heads are certainly better than one!  That being said, for those of you who don't follow the forum on MPIP, I am adding a discussion of this post that developed there thanks to my dear Edster. I think his points are worth bringing here, as are my thoughts about the "new" guidelines for SNLB which, though I have railed about them on this blog before, are perhaps even more pertinent at this time given the possibility of effective adjuvant care with minimal side effects.  That said, here you go:

Hi Celeste, does that journal article come in English or is it published in spainish? I have a thought about the time frame of the data, starting in 2000 and running to 2015. My thought is if they are looking at overall survival and progression free survival, you would think that the effect of adjuvant therapies and stage 4 therapies that would be available to the group in that time frame(2000-2013) were not very good and would make it hard to transfer finding to what is such a drastic land scape change, even in the last year and a half. Now, if they had data from say, MD Anderson from 2014-2016, with the better stage 4 drugs available to patients and Ipi approved in the adjuvant setting. If these observation held up then I could see the value of their study. I think that I am becoming to critical of research studies and wonder too much about alternative motives of researcher's. I had treatment on Friday #100 and there wasn't even a cake or candles or a marching band!!! I love the way that your blog makes me think and ask questions and how important it has been to so many of us,on our melanoma journey's!!! Hugs from a very cold Canadian!!!Ed

Hey Edster!

I think the questions you pose are good ones.  And as I noted in my comments...the data of better outcomes by delaying SLNB by 40+ days...is certainly counter intuitive.  Alternatively, there has been a good deal of data noting that a delay of 1-2 months before SLNB has not adversely affected outcomes.  I had BOTH my SLNB's within 2-3 weeks of my cutaneous biopsy results back in 2003 and 2007. (Maybe that's why I progressed to Stage IV!!  Ha!  Who knows?)   In theory, one would assume that researchers took the time frame of the patient's diagnosis and treatment changes into account.  However, I can't be sure about that.  One other factor to be considered is that adjuvant treatment for NED Stage III or IV patients is a relatively new thing...and many of these peeps would not have had treatment unless they had active disease.  But....it is still an important point to think about when we know the landscape of melanoma treatment has changed so radically just since 2011.  The complete article is in English if you have a mere $39.95!  Hee hee!  https://link.springer.com/article/10.1684/ejd.2017.3065  

I don't think that this article is enough to change current practice...though it is something researchers should think about.  Mostly, it should be very reassuring to those who find themselves...for whatever reason...going longer than they like before having their SNLB.  I know I wanted the suckers out of there!  I  have worked with many here on this forum and via my blog going nutters about any delay, so this should help provide a bit of prospective.

For another point relative to that post...I don't really agree with the new guidelines for SNLB.  For instance, I would still not technically qualify...as my first primary was only 0.61mm with no ulceration.  Yet, I had a positive node, developed a second primary 4 years later, and developed brain and lung mets 3 years after that.  NOT THAT EVERYONE DOES THIS!!!!!!!!!!!!!!!!   But, the more important point is that the positive node, took me from Stage 1b to Stage IIIa in one fell swoop.  Back then - it didn't matter very much.  There was no treatment.  TODAY, it makes a world of difference, because as you pointed out - ADJUVANT care!!!  Soooooo important and now thankfully exists and is FDA approved.

Additionally, the factors that make a difference for a thin melanoma are younger age (less than 40), mitotic rate (which folks don't really look at any more), higher Clark level, and sex.  Ultimately, guidelines are JUST guidelines.  A framework for a starting point...not the end all be all.  It remains very rare for thin melanomas to have lymph node involvement.  However, with a 5% chance of that positive node, now that we have various adjuvant treatment options...finding out if you are in that 5% makes a bigger difference.  

And as to the most important part of your comment - HAPPY 100th TREATMENT day, to you!!!!  I would totally have baked you a cake and had a Timmy with you!!  Salud!! You rock!!  Love you bunches...from a fairly cold Chatt town.  (Do I get to claim being cold if it's 34 degrees????) - c

Thanks, Edster.  This is important stuff and your attention to it makes the world a much better place for melanoma peeps!  love, c

To read more of this thread with really thought provoking comments from Janner, here's the link:  Discussion of SLNB post on MPIP