Immunotherapy or Observation only for Stage IIIa ‘micro metastatic’ diagnosis?

Hi Mark,

I am sorry that you and your wife are dealing with this.  Melanoma sucks!!!  BUT!  There is a lot of hope.  Targeted and immunotherapy have radically changed melanoma treatment and outcomes for the better just since 2011.  It can be hard to find Stage IIIa specific data, but it is out there.

Here is just one such report:
<p style=”font-weight: 400;”><u>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.</u>  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  September 18, 2020.</p>
<p style=”font-weight: 400;”>We conducted the phase III double-blind European Organization 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.</p>
<p style=”font-weight: 400;”>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.</p>
<p style=”font-weight: 400;”>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😉 and in the PD-L1-positive tumor subgroup. The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status.</p>
<p style=”font-weight: 400;”>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.</p>
Here is a primer that I put together that may help you in looking at treatment options so as to better understand the lingo.  Both targeted and immunotherapy have been approved for use as adjuvant.

https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2017/08/melanoma-intel-primer-for-current.html

An important thing to note here – the ipi/nivo combo (ipilimumab/Yervoy and Nivolumab/opdivo) is NOT approved for adjuvant patients.  There was a trial and high hopes that the combo would improved the outcomes for adjuvant patients, as it is the immunotherapy treatment that provides the best results in Stage IV melanoma patients.  However, it did not have outcomes any better than anti-PD-1 (Nivo or pembrolizumab/keytruda) alone.  On the good side, however – ipi is the bad boy of side effects.  Either anti-PD-1 agent is much more tolerable as a single agent.

Here are a ZILLION articles on adjuvant treatment in melanoma:  https://chaoticallypreciselifeloveandmelanoma.blogspot.com/search?q=adjuvant

On a personal note – In 2003 I was diagnosed with melanoma.  I had a 0.61 mm lesion to my back.  Back in the day, a complete lymph node dissection was  done of my right axilla with three sentinel nodes found.  One of those was positive for micro-mets of melanoma and I was categorized as Stage IIIb.  Back then there was NO effective treatment for melanoma.  (You can read about interferon in the primer.)  So we watched and waited.  In 2007, I developed another lesion to my left forearm (0.5mm).  The jury remains out as to whether it was a met or a second primary.  Anyhow, given the times and my history, another complete lymphadenectomy was done of my left axilla.  No nodes were positive.  In 2010, on a routine chest x-ray (melanoma follow-up was far from standardized back in the day) “something” was seen in my bronchus.  As an asthma patient, it was thought to be related to that since “melanoma never looks like that”.  After 6 months of watching, a bronchoscopy and biopsy was done.  Melanoma can indeed look like that.  Follow-up PET and MRI of the brain showed a brain met as well.  Surgery to remove the right upper lobe of my lung and SRS to my brain met were my next steps.  No targeted or immunotherapy were FDA approved for melanoma at that time, though some were in trials, but required measurable disease – something I had just gone to a great deal of trouble to remove!!!  Finally, in December of that year, I gained a place in a phase 1 nivo trial, in the adjuvant arm, albeit Stage IV.  The other arm was Stage IV patients with active disease.  We did well!!!!  (Considering it is melanoma we’re talking about!!!)  I took nivo for 2 1/2 years (we have since learned you needn’t take it that long) and though it wasn’t fun, it was manageable.  I worked 12 hour shifts 3 days a week throughout.  Some folks have a more difficult time, but that was my experience.  Most importantly, I have been NED for melanoma ever since.

One other thing you might consider though attaining it might be difficult – I have been screaming about it for years ~ ctDNA.  The information attained by that test may aid in your decision making.  Here’s a report:  https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2019/03/circulating-tumor-dna-ctdna-as-way-to.html

The choices we make in our melanoma care are intensely personal.  Are you a gambler?  Your wife’s odds may indicate that she could be disease free forever, or even for many years, then be treated as a stage IV and survive.  On the other hand, I have walked in melanoma world for a LOOOOONG time.  It is a beast!  It can get away from us and do things that docs never expect.  When I was first diagnosed, in the middle of a master’s program with a 10 and 12 year old – I was desperate for a treatment that did not exist.  And even though my tale is one of the incredibly lucky ones, if I were in my 2003 shoes today – and I could have taken nivo THEN – I absolutely would have.

Ask more questions as you have the need.  There are many smart and caring peeps on this forum.  I wish you and your wife my best.  Yours, celeste

PS – Having worked with docs since the age of 18 and seen more than my share as a patient, I can assure you that in all realms of that experience – surgeons and radiologists are far more cavalier than subspecialists and ALL of them more cavalier than any patient!!!!!  For what it’s worth.  c

 

hi Mark, I will let Celeste answer your questions, I would just like to give you a couple of article to help you put things together. First link is to checkmate 238 adjuvant trial with nivo vs Ipi for stage 3b,c and stage 4 non resectable. second link is to keynote 054 pembro vs placebo adjuvant 3a,b,c. Both of these trial started before new 8th edition of staging came out, with the new 3a,b,c,d staging classification. https://www.nejm.org/doi/full/10.1056/nejmoa1709030. https://www.nejm.org/doi/full/10.1056/nejmoa1802357

Mark there is also a pretty good series on Onclive from 2019 when adjuvant trial data was coming in and how this data changed how oncologist treated their patients. also in this series they talk about targeted therapy trials for those patients with Braf+ status ( not sure what is going on with Braf status with your wife). https://www.onclive.com/view/stage-iii-melanoma-adjuvant-therapy-trials  https://www.youtube.com/watch?v=vskLWHO7gb8&t=34s

You are absolutely correct, Mark.  The less melanoma present – the less risk.  For everyone.  Tumor burden is a huge prognostic indicator even for Stage IV patients.  We have learned that immunotherapy works best for all patients when the tumor burden is low.  That is why it is such a boon as an adjuvant.  I mean – you can hardly have less disease than then, when dealing with a melanoma diagnosis, can you?  It is absolutely certain that lots and lots of Stage I and II melanoma patients, after the requisite and understandable panic attack, never have to be bothered with melanoma again.  Things are a bit more murky for Stage III patients, but even there – the smaller the tumor, the better they do.  It has been definitively proven that tumor size and ulceration of the initial lesion play a huge role in prognosis.  I am a bit of an outlier having had a small lesion with no ulceration and micromets to one node.  Still, lots of Stage III patients do well for years and years with no treatment beyond excision.

After writing my initial response, I realized you had not mentioned any particulars regarding your wife or her lesion – which is totally fine – but remembered this post, which you may find interesting.  It is a bit old – more pertinent to a time when researchers were trying to determine who needed sentinel node biopsy, who did not and what it meant. Interestingly, I would not have been recommended to have one under current guidelines, but would have been sitting there unaware of my positive node!!!!  At any rate, you may find this interesting:  https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/04/with-melanoma-you-can-never-be-too-rich.html 

I’ll take a look at your report in a bit and give you my thoughts.  For whatever they are worth!  HA!!  best, c

Okay, Mark. I read your report. Here’s my take –

This is a pathologist’s view of melanoma using what can be seen under the microscope to predict the risk of recurrence and survival.  Pathologists use tumor volume, tumor location or a combination of those factors to define that risk.  Clearly, less tumor volume is best.  It is also best when the tumor cells have not invaded the interior of the lymph node, nor disrupted the structures of the node (within or without).  They note that ulceration and mytosis of the initial lesion are independent factors.  Other studies corroborate this as well.

The real question is – Whether a lymph node with minimal involvement, once removed. has the same risk for recurrence or death as a negative node?  The answer is – YES! – sometimes.  The caveat is that in melanoma, the risk is not zero.  Rather, it is likely between 5 and 10% over 75 months per this study.

To back up a step – I am not sure about what you mean when you say “there was an intrusion of 0.03mm in her extracted node” and see the definition of Stage IIIA in the paper I shared (defined as at least one lymph  node metastasis greater than 1 mm) as a 30 fold increase.  It depends.  It depends on how good a job the pathologist did evaluating your wife’s node generally.  It depends specifically on – the actual location of the invading cells, their characteristics and total tumor volume within the node, though from what you have said, it sounds as though there was only micrometastatic involvement.  Then, in order to gain the most complete picture regarding total risk, that information has to be combined with risk factors present in the patient generally as well as those in the initial lesion itself.

So – you and your wife face a difficult risk benefit analysis in order to make your best decision regarding further treatment.  This article by Weber (my physician) and some other serious Melanoma Big Dogs describes the risk of nivolumab as a single agent – https://pubmed.ncbi.nlm.nih.gov/28068177/

I have many posts regarding side effects of immunotherapy on my blog.  The risks are real.  However, you have to be sure you are looking at risks from anti-PD-1 as a single agent.  The addition of ipi/Yervoy or even ipi alone (also categorized in some papers as ‘immunotherapy’)  has a much worse side effect profile than either anti-PD-1 product as monotherapy.  Further, as more oncologists have become familiar with treating melanoma patients with immunotherapy, they have become much better at recognizing and treating side effects – leading to much better outcomes for patients.  Another point you should consider that Ed broached is your wife’s BRAF status.  This should have already been run and be available to you.  Targeted therapy for BRAF positive patients is also available as an adjuvant treatment – though that treatment has potential side effects as well.

Finally, be sure that your wife is being seen by a melanoma specialist, or at the very least an oncologist who treats a lot of melanoma patients.  That level of expertise can make a real difference in outcomes.

I hope this helps.  You wife is very lucky to have you searching for information and learning as much as you can on her behalf.  I was lucky that way as well.  Your wife will have to walk this path alone, but your support will be more valuable than you will ever know.  I wish you both my very best with whatever choice your wife makes.  c