E09 Frances Wright On Nodal Disease In Melanoma

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Chad Ball  00:15

Welcome to Cold Steel, the Canadian Journal of Surgery podcast, with your hosts Ameer Farooq and Chad Ball. The goal of the CJS podcast is threefold. The first is to highlight the best research currently being completed by Canadian surgeons. Second is to offer educational topics for both surgeons and trainees alike. And most importantly, the third goal is to inspire discussion, thoughts, creativity and career development in all Canadian surgeons, we hope you enjoy it.

Ameer Farooq  00:50

On this episode, we got to talk to Dr. Frances Wright. Dr. Wright is a surgical oncologist at Sunnybrook Hospital in Toronto. She dissected out the topic of nodal disease in melanoma for us. This was a fantastic overview of a topic that I think many residents find confusing. I know I enjoyed it and I hope you will too.  Once again, Dr. Wright, thank you very much for joining us on Cold Steel. We know how busy you are. So we really do appreciate you taking the time to come and speak with us. I wanted to ask you a little bit about your training and your background. Where did you grow up and where did you do residency and the rest of your training?

Frances Wright  01:34

I grew up in the UK, until I was 12. And then we moved to Hamilton, Ontario. I did undergraduate med school at U of T and then I went to Queen’s, which was great for my residencies in general surgery. I then came back to Toronto and did surgical oncology in Toronto. And then I’ve been on staff at Sunnybrook since then.

Ameer Farooq  01:59

Some of us have a little quiz at the end of this year. So, I thought we would use the opportunity to sit down with someone who’s a world expert on melanoma to talk a little bit about melanoma, especially given that you are one of the authors on some of the landmark trials in this area. So, I was hoping that you could talk about MSLT-1 and MSLT-2. Talk a little bit about how those trials were set up. And how that really changed the way that we managed nodes in melanoma.

Frances Wright  02:34

Sure, I certainly talk about that. And thank you very much for asking to have me on, it’s an honor. I was just talking to one of my residents today and he was saying he’d been listening to the podcasts and found them really helpful. So that’s great. So MSLT-1, wide local excision, plus sentinel node biopsy or wide local excision alone, inclusion criteria for that trial. So, melanoma 1.2 to 3.5 mm in gaps and clinically, node negative. And those patients had their surgery, if their sentinel node was positive, then they went on to a completion dissection. And obviously, if their sentinel node was negative, they just had the wide local and central node. In the arm that just had the wide local excision alone, those patients went on to just observation. And if they developed palpable adenopathy, then they had a therapeutic lymph node dissection at that time. So that was the overall setup of the trial. The 10 year follow up from that trial was published in around 2014, in the New England Journal. So, fairly important trial in melanoma world. Of course, just taking a step back, all of the studies beforehand, or the studies beforehand, had looked at whether there was benefit to doing an elective lymph node dissection. So, patients were randomized, in the studies in like the 1990s, they were randomized to either, no surgery or an elective lymph node dissection. So, they either got a full groin or a full axillary dissection, or just watching weight and then deal with any problems that come up. So, in that trial, that trial had no survival benefit. There was some subset analysis with one group of patients maybe having a benefit. I think it was men and they had ulcerated tumors. But after that trial, when patients didn’t get elective lymph node dissections anymore, when they were clinically note negative. And so that came, then Donald Morton came along. And that was when the idea of the sentinel node biopsy came along. And then as we just discussed MSLT-1 was the 10-year follow-up published in 2014. So MSLT-1 was actually a negative trial. There’s some controversy in the skin cancer world, a bit about this. Not really amongst the surgeons, but maybe a little bit more amongst the dermatologists. But for overall, a negative trial. But when you did a subset analysis, which was a plan to subset analysis of the patients that had disease, and in each group, whether you have the sentinel node, or whether you developed palpable adenopathy, about 20% of patients had nodal disease. And when you looked at those patients, so if you had sentinel node positive disease, and then you had your completion dissection, the 10-year survival was around 60% or so. When you looked at the patients who had the therapeutic lymph node dissection, so they had palpable disease, and then you had your groin dissection or axillary dissection, those patients had a 10-year survival of 40%. So, the analysis that the melanoma surgeons took from that was, if you were sentinel node positive, then there was a survival benefit to having a sentinel node done. If the sentinel node was negative, then you got some great information, but we haven’t made you live any longer. So, the landscape’s changed a little bit now. So, the sentinel node is, in addition to being a therapeutic modality if you’re a sentinel node positive, but now, if you’re sentinel node positive and if you have greater than a mm disease, you also are a candidate for adjuvant therapy. So, when we look at adjuvant therapy for melanoma, there are 2 groups. There’s immunotherapy, which any patient can get, whether you’re BRAF positive or BRAF negative. If you’re BRAF positive, which is a marker on the melanoma itself, that about 40% of patients have, then you could potentially get a drug like dabrafenib and trametinib or BRAF MEK inhibitor. And both of those drugs, dabrafenib and trametinib has longer follow-up and there’s a survival benefit to getting those drugs in the adjuvant setting. The immunotherapy, I think it’s just been 1 year follow-up so far. But there’s a recurrence-free survival benefit between patients who got immunotherapy versus placebo. So, the benefit of the sentinel node, just to summarize. #1, if it’s positive, it’s therapeutic. #2, if you’ve got more than 1 mm of disease in your sentinel node, then you’re a candidate for adjuvant therapy. And then of course, it gives you better staging and prognostic information as well. MSLT-2, ask the question, was there a benefit to doing the completion dissection or not? So, patients with the inclusion criteria for MSLT-2 was positive sentinel node. And then, those patients were randomized either to a completion lymph node dissection, or they were randomized to ultrasound monitoring, and only if they developed palpable or only if they develop disease, did they have a completion dissection. We know from the literature, that if you have a positive sentinel node with melanoma, your likelihood of having further disease, if you do a completion dissection, is about 20%. So, we do a completion dissection, or we used to do a completion dissection, on about 80% of patients and they have no disease there.

Ameer Farooq  09:41

Right. In other words, the sentinel node biopsy got all the disease.

Frances Wright  09:45

That’s correct, for 80% of the patients, exactly right. So, in MSLT-2, again, the question is, does completion lymph node dissection improve survival for patients with a positive sentinel node? Patients were randomized to either just the surgery, and in this study, it included patients with head, neck melanoma, and then extremity, and truncal melanoma. Or they were randomized to ultrasound follow-up. It was a pretty intensive follow-up. So they got ultrasounds every 4 months for 2 years, then every 6 months of 3 to 5 years, and then they just got clinical follow-up from years 6 to 10. If, at any point in the ultrasound follow-up, there was an abnormal lymph node, either that was palpated or was seen on ultrasound, then the patient got a biopsy. If it showed melanoma, then they got a metastatic workup. And then, depending on what the metastatic workup showed, a completion dissection. So, if you were in the observation arm, getting your ultrasounds, something looks bad, you do a biopsy, it shows melanoma, metastatic workup’s negative, then you went on to a completion dissection. So that was the observation or the study arm, I guess. And then everyone else got immediate completion lymph node dissection.

Ameer Farooq  11:25

Right.

Frances Wright  11:25

Make sense?

Ameer Farooq  11:26

Makes right. Yep.

Frances Wright  11:28

Okay. So, that study was reported in 2017. There were about 1940 patients. And the median follow-up was about 3 years. And what that showed was that there was no survival benefit to doing the completion dissection, which is a big deal. Because it’s a lot less morbidity for patients to not have, especially, a growing dissection. Axillary dissection has morbidity as well, but the groin dissection has a lot of morbidity with it. So, no survival difference between the two, between the immediate dissection arm, and between the group of patients who were in observation. They did some subset analyses and there were no subsets of patients that benefited from a completion dissection. So, whether the sentinel lymph node metastases was bigger or smaller, whether you had more than 1 or greater than 3. So, no patients seem to benefit from doing the completion dissection.

Ameer Farooq  12:56

One thing I noticed is that one of the planned subgroups was, having a positive node on PCR. I think that’s not normally how we look for nodes. Was that to see if that would give us an indication as to who would benefit from a completion dissection?

Frances Wright  13:16

Yeah. So, I must admit, I don’t look at that data particularly a lot. But the PCR was used because there was a trial, the Sunbelt Melanoma Trial, and they used PCR in that study to identify really, really tiny amounts of disease in lymph nodes. So, there was a move in the melanoma world around that time to assess and see whether, if we identified really tiny amounts of melanoma in lymph nodes with PCR, if that was important or not. And it didn’t show in MSLT-2 that it was important to do.

Ameer Farooq  14:06

So this trial made it a lot harder for residents to get completion node dissections under their belt.

Frances Wright  14:16

Yes, it did. But much better for patients.

Ameer Farooq  14:20

Absolutely. Which is, obviously, what matters more. I have a couple of questions related to this. Who are you still doing a completion node dissection on? For example, the patient that comes in with clinically positive nodes. Are you still doing a completion node dissection on those folks?

Frances Wright  14:38

That’s not a completion node dissection patient. So, I think, who presents with nodal disease now? Because the majority of patients have a sentinel node biopsy, right? So, the indications for sentinel node are, most patients, greater than 0.8 mm in depth. That’s when we’ll start offering sentinel nodes to patients. When it’s between 0.8 mm and 4 mm in depth, that has a survival benefit always. Or that’s what we assumed from MSLT-1, just because we expanded the inclusion criteria a little bit. If a patient has a melanoma greater than 4 mm in depth, then that patient, because they’ve got a higher rate of hematogenous spread, you’re just doing a sentinel node for them for local control. You’re not going to make them live longer, because from the sentinel node, mainly because they’ve got a higher risk of the disease spreading hematogenously. So, the patients who now present with nodal disease, and we do dissections on, tend to be patients, either melanoma unknown primary, which is a well-recognized phenomenon in the melanoma world. The assumption is they had a primary, the body’s immune system dealt with it and saw the little cells escaped and went to the nodes, but we never find the primary lesion. So melanoma unknown primary, patients who had a really thin melanoma, like less than 0.8 mm, and then they develop nodal disease. And that happens about 2% to 3% of the time, with patients with a less than 0.8 mm melanoma. If someone had a false negative with a sentinel node biopsy, if someone recurred after having a sentinel node that was positive and they’re on observation, those are the main scenarios. Or, someone was older and we offer sentinel node now to patients, as long as they’re reasonably medically well up to the age of 80. But if someone’s like 82, or 83, then we don’t usually, but sometimes those patients will come in with palpable nodal disease. So, someone comes in with palpable nodal disease, we will do a metastatic workup, often with a PET scan and an MRI brain, as long as they don’t have metastatic disease, then those patients are the ones who will get a therapeutic lymph node dissection. I do not typically offer patients who’ve had a positive sentinel node, and have no other evidence, like a clinically node negative, I typically offer all of those patients’ observation. I don’t do a completion dissection on them.

Ameer Farooq  17:57

That segues nicely into the next question I was gonna ask you. How do you frame this discussion in the office with patients? Are you following them the way that patients were followed in MSLT-2 or are you stretching out that observation period?

Frances Wright  18:14

That’s a great question. So the way I frame it to patients is, I say to them, “you’ve had a positive sentinel node.” I tell them the next steps in treatment, which is, we typically do CT scans as a staging workup, I tell them their likelihood of us finding distant metastatic disease with just a positive sentinel node, it’s very tiny. I tell them, they’re going to see the medical oncologist and if they’ve got more than 1 mm of disease in their sentinel node, that they’re going to be a candidate for adjuvant therapy. And then from a surgical point of view, I tell them that we don’t operate on patients with positive sentinel nodes. I say, “you’ve got a chance of the disease coming back there, but we will follow you closely with ultrasound and we will deal with any problems that come up”. And I tell them we’ve got 2 big randomized control trials where it does not show a survival benefit to removing the lymph nodes right now. The other trial in addition to MSLT-2 was the DeCOG-SLT trial, which is a German trial, which essentially had the same design as MSLT-2, but with about a quarter of the patients. But it showed the same thing.

Ameer Farooq  19:43

So are you following them, maybe I missed this, every 4 months for the first year and then every 6 months?

Frances Wright  19:50

Yeah, probably not that much. So typically, I follow them every 6 months for a couple of years, with ultrasound. Usually on the same days the clinic visit. They also get CT scans as well, often every 6 months, to check for metastatic disease, which is why I feel okay with not doing the ultrasounds every 4 months, because they get a lot of imaging in the first few years. And then sometimes, if they had a lot of nodal volume, like sentinel nodal volume of disease, then I’ll follow them maybe for 3 years, for 6 months, like for another 6 months. But usually after that, I’ll switch to yearly. And again, they’re usually getting CTs every year as well, until 5 years.

Ameer Farooq  20:40

And if they come back, let’s say, with clinically palpable nodes, are you repeating their PET scan? Or if something comes up in ultrasound?

Frances Wright  20:52

Yeah, I do. Because, the number of times that patients have isolated nodal disease, at least in the study, is quite low, it’s about 7% or 8%. My personal experience is that it’s higher than that. Because often, we’re still picking up disease quite early. So, sometimes it will just be picked up on ultrasound and I won’t be able to feel anything, or I’ll pick up something in clinic that’s maybe 1 or 2 cm in size, or the patients will. They’ll call and say, “Hey, I feel something in my groin, on my armpit. I need to come in,” we instruct the patients on what to look for. So, we do a biopsy of the lymph node, either in clinical radiology does it if it’s too small for me to feel, and then I repeat the metastatic workup. Because you need to make sure they don’t have metastatic disease.

Ameer Farooq  21:59

I know you were an author on MSLT-2. What was it like to be a part of such a big, multi-centered, practice changing trial? How did that get set up? How did you get involved? And what was it like being part of that trial?

Frances Wright  22:17

Doing these multi-institutional trials, firstly, it’s a really important way for surgical, or really all of medicine, to move forward. I think I really started appreciating clinical trials when one of my partners was Jean-Francois Boileau, who’s in McGill. And he is a huge advocate of clinical trials. He worked at Sunnybrook for a while, and he was awesome. Was so enthusiastic about clinical trials. So that really changed my outlook. So, I do think that practice changing, like you say, is very important. I think what I did, was, I think I emailed Donald Morton and said I was interested in joining the trial. They sent me all of the information. Then, it took a long time for the lawyers and the REB to agree to it at our site, we had to get an external review. I think it was Dave McCready that did it. Because the REB wasn’t sure that this was an appropriate trial because the standard was to do the completion dissection. But eventually, we did get it going. It’s super rewarding. First of all, I think it’s important that patients have access to these trials, our own patients. And then, just from connecting you with your other clinicians around the world who are interested in the same question, the same disease, it’s really great for meeting colleagues and networking, I guess. But really highly recommended. I was fortunate MSLT-2 had funds that they could send internationally. So, it was partially funded by Donald Morton and his funding agency. And then my medical oncologist lead, Teresa Petrella, also supported the trial as well. So that was very fortuitous.

Ameer Farooq  24:36

How did you know that Donald Morton was doing MSLT-2? How did you hear about it?

Frances Wright  24:41

I think it was at the meetings, people talked about it at the meetings. Like the FSO and other meetings. You knew it was going on, it was recruiting, I think, for 10 years. It was a long time period. Yeah.

Ameer Farooq  24:59

That sounds painful. In terms of the REB and all that, kind of, setup.

Frances Wright  25:05

Yeah, no, eventually it worked out. It’s easier now. I think now, they’re just more accepting of the surgical trials. We have a trial that we’ll be opening in Canada now, called MelMarT, which we participated in the pilot, again, from this network of international surgeons who are interested in melanoma. And it’s taking patients with stage 2 melanoma. So clinically, no negative, either greater than 1 mm melanoma, ulcerated, or just greater than 2 mm. And it’s comparing a 1 versus 2 cm wide local acquisition for those patients, which will reduce their extensive surgery. But again, that came from leading up with this network of surgeons. They’d meet at least once a year at the Society of Surgical Oncology meeting and usually like 6 AM, very early. But you go and meet, and they talk about some of the next trials that were coming up and see if people are interested.

Ameer Farooq  26:14

That’s so cool. That’s awesome. I think I saw you put a tweet out about that. And I’ll link to it in the show notes. I wanted to switch gears a little bit and talk a little bit about IL-2 injections. I know you’re sort of a pioneer and pushing this modality. Can you talk to us a little bit about how you got interested in this and a little bit about IL-2 injections? Which patients to use them on? And how does that fit into your practice?

Frances Wright  26:49

Sure. I started using IL-2 probably around 2009. I think it was predominantly… the melanoma practice at Sunnybrook was really starting to grow, had really grown by that point. So, we were starting to get patients who had in-transit disease. So, recurrence of their melanoma between the primary site and the nearest nodal base. So, we needed an option to treat these patients. I had heard of Claire Temple-Oberle, who then worked in London, but now works in Calgary. And Claire, she’d used limb perfusion for a number of years, but had found it had been quite morbid in terms of patient outcomes and she started using IL-2. So, I talked to Claire and she was very generous. She shared her protocols and, kind of, provided email advice on what to do with patients. And essentially, I just started doing it so that we could provide the service to our patients. At that point in time, there was really no adjuvant therapy for melanoma. The adjuvant therapy was interferon, which had a 3% survival benefit. And there was really nothing effective in terms of metastatic treatment for melanoma in the system or nothing that was effective systemically. So there were very, very, limited options for these patients. Limb infusion or perfusion, we could send people down to the US to do it. A few people went down. But, again, it was morbid. One of the patients came back and she had a compartment syndrome from the limb infusion. So, essentially, I talked to Claire and started using interleukin-2. The drug company, Novartis, supplied the IL-2 free, until about 2014 or so. After that, it didn’t supply it for free and the patients had to pay. So at that point, I put in an application to the pan-Canadian Drug Review or pCODR. And with the support of Cancer Care Ontario and Teresa Petrella helped us as well with that, we got it approved across Canada. And then each province had to approve it, so that the patients didn’t have to pay. So now it’s on the formulary and IL-2 is being used in, probably, about 6 or 7 centres across Ontario.

Ameer Farooq  30:01

That is super cool. I didn’t realize there was a Calgary connection. That’s awesome.

Frances Wright  30:06

Yeah, no, Claire’s fantastic. I’m not sure where Claire heard about it. There are a number of papers from Europe, I think, Germany and the UK, a bit being used in the 1990s and the early 2000s. So, I’m not sure if she read it in papers or if she actually went and saw it done. But she was actually the first person who started it in Canada. What I do now is, I inject patients with IL-2 and then one of my dermatology colleagues, and I, also give the patients their retinoid and aloe vera cream. And so, they kind of get a triple therapy. And that increases the complete pathological response rate. So, it’s just getting that, hopefully, published soon. And with the triple therapy, the complete response rate is about 58%. And with IL-2 alone, it varies between 40% and 50%.

Ameer Farooq  31:19

Wow.

Frances Wright  31:19

So, it’s pretty effective. We do it in the office, and patients generally do pretty well on them.

Ameer Farooq  31:30

And this is in conjunction with other adjuvant therapies, or is this by itself?

Frances Wright  31:35

No, this is just with creams. So, aloe vera and retinoid cream. That, along with the IL-2, essentially they’re immunotherapies. They upregulate the immune system. So, you’re doing a local therapy that’s upregulating the immune system.

Ameer Farooq  31:54

Gotcha. That’s super cool. I did want to ask about one of your other research interests, as well, which is the patient perspective on their cancer experience. In particular, I loved the paper that you recently published in CJS, looking at the impact of hernias on cancer patient experience. How did you get interested in the patient experience side of things? And where do you see us going with that type of research, especially as PROMs, and other patient reported outcome measures, really start to take off.

Frances Wright  32:33

So, that particular study was predominantly done by Rahima Nenshi, who’s now in Hamilton. That study was looking at patients with giant hernias and essentially looking at their experience while they waited to have surgery. So, it was a qualitative study, which really gives you an in depth look at a phenomenon. So, the phenomenon here was the patient’s experience with having hernias. So, I got interested in qualitative research when I was getting my masters of education. Then I was fortunate, when I first started practice, to have some mentors, PhD mentors, who helped me do further qualitative research. So really, it’s not in depth understanding of the phenomenon. Other research we’ve done is, we’ve looked at patient experience with having a pelvic exent or having a sacrectomy. Andrea Covelli looked at why women choose to have a contralateral prophylactic mastectomy, and really trying to understand that phenomenon. So qualitative, it’s fairly different from a lot of the scales that people use, and I sometimes use them as well. I’m not as familiar with them. But when you look at things like a HAT scale, or a patient satisfaction scale, that gives you numbers about how someone’s feeling. And you can track how they’re feeling and doing over time, but it doesn’t give you that in depth understanding of phenomenon or why something is happening.

Ameer Farooq  34:36

Awesome.

Chad Ball  34:38

That’s amazing, that’s right. Thank you very much. As someone, obviously, who lives in the surgical oncology world, but certainly HPV, I haven’t thought much about melanoma in a very long period of time. Except on the odd patient with mets that’s referred to us, maybe indirectly. But, yeah, that was tremendous. What would you say to the average general surgeon, that maybe works in a community practice, in regards to, not so much assessing these patients upfront, but in particular, pitfalls and referral patterns. Who should they be sending? Should that be everybody? Should that be some? What’s your advice on that?

Frances Wright  35:25

General surgeons are absolutely able to do, obviously, biopsy of melanoma. No question with that. They’re general surgeons as well, I think in a patient who’s clinically node negative. And we have lots of general surgeons in the province who provide excellent wide local excision and sentinel node surgery. Lots of people, lots of providers across the province do that. I think, palpable lymphadenopathy, just as Ameer was saying, I think the experience that trainees have now, with taking out big bulky nodal disease from the axillary or groin is, in residency, it’s fairly limited. I think those patients should be sent into a surgical oncologist or someone who’s got experience with that. There’s also some interesting things we can do with those patients. We just had a trial that closed at Sunnybrook. But if those patients have that melanoma marker, the BRAF marker, then you can sometimes treat those patients neoadjuvantly. So, they can go on dabrafenib and trametinib for about 4 months or so, they can have their surgery, and then they can finish up their DABRTRAM. But that kind of approach with the neoadjuvant, you need a medical oncologist to get the drugs and deal with the side effects, which can be quite significant. So, I would say the palpable adenopathy should go into a cancer center. I think if a patient presents with in transit disease, most of those patients end up coming into the cancer centers as well. It’s not a super common scenario. There’s about 7% of patients who’ve had a melanoma greater than 1 mm. I also think if a patient’s got metastatic melanoma, then those patients should be discussed at a tumor board. Like if they’ve got a lung met, or if they’ve got a liver met or small bowel met. Those patients should be discussed so you can figure out, is surgery the right thing? Should they have systemic therapy first or after the surgery? Do they need radiation? Those are the patients that I think should definitely come into the cancer center.

Chad Ball  37:59

Frances, we can’t thank you enough for doing this with us. Thank you so much.

Frances Wright  38:03

My pleasure.

Ameer Farooq  38:14

You’ve been listening to Cold Steel, the official podcast of the Canadian Journal of Surgery. If you’ve liked what you’ve been listening to, please leave us a review on iTunes. We’d love to hear your comments and feedback.  So, feel free to email us at podcast.cjs@gmail.com, or connect with us on Twitter @CanJSurg. Thanks again.