Management of Clinically Node-Negative Salivary Gland Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a Medical Oncologist, Director of International Programs for the Cancer Institute and Co-Director of the Sarcoma Program at Cleveland Clinic. Today I'm happy to be joined by Dr. Brian Burkey, Interim Director of the Scully Walsh Cancer Center, Vice Chief of the Integrated Surgical Institute and Division Chair of Otolaryngology Head and Neck Surgery at Cleveland Clinic Florida. He's here today to discuss management of clinically node-negative salivary gland cancer. So welcome.

Brian B. Burkey, MD, MEd: Thanks so much, Dale. Appreciate it.

Dale Shepard, MD, PhD: So give us a little bit of an idea of kind of the things you do here at Cleveland Clinic.

Brian B. Burkey, MD, MEd: I'm an otolaryngologist, but have really focused my entire career on head and neck surgery. That is treatment of tumors, both benign and malignant of really anywhere in the upper aerodigestive tract and also the thyroid and parotid.

Dale Shepard, MD, PhD: Excellent. Well, today we're going to talk about some research that you were involved with, managing clinically node-negative salivary gland cancer. So a lot of different people might be listening in. Could you give us maybe just a little background of what exactly that is?

Brian B. Burkey, MD, MEd: Right. So obviously salivary glands include most commonly the parotid gland, but also the submandibular gland and the minor salivary glands in the oral cavity. And again, they create a wide variety of tumors. Some of the most varied histopathology really in the human body in terms of tumor development occur in the salivary glands. And again, because of the varied types of tissue within the salivary glands, both secretory tissues and ductal tissues, what we're really looking at is when we take these tumors out, they can be malignant, not always malignant. Sometimes we don't know ahead of time how do we deal with the lymph nodes in the neck. Because certainly high-grade malignancies of the salivary gland are frequently associated with lymph node metastases, but benign tumors obviously not, and low-grade tumors very uncommonly. So the ideas on the front end, maybe before you have all the information that you need that you might have at the end of the operation, how do you plan the management?

Dale Shepard, MD, PhD: And so what are some of the factors that lead to the complexity? You mentioned the wide range of histologies, whether it's even a malignancy or not. Is there physical exam difficulties? Is there imaging difficulties? What are some of the biggest factors that lead to the complexity?

Brian B. Burkey, MD, MEd: Well, really it's deciding what disease process do you have going on. And so the biggest issue is benign versus malignant. Certainly physical exam can help with that. Certainly the presence of nodes helps with that. But in a case where there's no nodes, then how do you decide? And so we use a variety of ways to help us. One is fine-needle aspiration, which is very good at determining between benignity versus malignity. And then also imaging, as you mentioned. Benign tumors tend to have very smooth borders. Benign tumors have very smooth borders, whereas malignancies tend to be more invasive, appearing more fuzzy around the edges. And again, on imaging, the presence of enlarged or abnormal lymph nodes goes along with malignancy.

So we try and look at those issues that are associated with it. Size can also be associated with that, but there are certainly very large benign tumors, but tumor growth characteristics in the history can help us decide.

Dale Shepard, MD, PhD: And so as you're approaching a patient, you're thinking about how you're going to manage them. You're thinking about specifically about management of the neck. What are the options that you have when you make those decisions?

Brian B. Burkey, MD, MEd: Well, let's assume that because just for the purpose of this paper, we're dealing only with cancer. Let's assume that we think it's a pretty high risk of cancer. And again, either based on the history of a rapid growth or a very kind of ugly appearing CT scan or MRI scan or a needle biopsy that suggests malignancy, right? In that situation, really then we have to decide should we treat the neck or not. Meaning do we think there's a high enough risk of spread to the neck to warrant the side effects or morbidity of neck radiation or neck dissection?

And so when we look at that on the front end, again, the first step is always to look at imaging. Certainly if there's a nasty appearing node on the scan, really most guidelines would suggest, and we do recommend neck dissection upfront. In the situation of, as this article suggests, a clinically N-0 that is no negative neck, then we try and get a sense, is this a high grade malignancy?

So one of the things that suggests that we should do a neck dissection, is it a high grade malignancy or not? And high grade malignancies are things like squamous cell carcinoma, salivary duct carcinoma. Those are very high-grade malignancies with very high rates of neck metastases. We tend to choose around the 20% range of risk of spread to the neck to decide if we should do a neck dissection. So again, there's no magic to 20%, but we think that when the risk of spread to the neck is less than 20%, we probably don't want to put the patient through elective neck treatment. And if that number is higher than 20%, then we think that the risks warrant the side effects from neck irradiation or neck dissection.

So again, for the higher-grade malignancies, that number is higher than 20%. That includes, again, high-grade malignancies, squamous cell carcinoma, salivary duct carcinoma, some high-grade mucoepidermoid carcinomas, and then the size of the tumor. So T-3 or T-4, and that is tumors greater than four centimeters in size, malignancies greater than four centimeters in size, or those with some sort of involvement in surrounding structures, skin involvement, or for instance, facial nerve paralysis.

So in those situations, we would recommend some sort of treatment of the neck. My own preferred treatment is to do a neck dissection during the removal of the tumor. So parotidectomy, neck dissection. Some surgeons don't, for one reason or another, want to perform an neck dissection at the time. And then in that case, typically they would perform post-op radiation in the neck.

Dale Shepard, MD, PhD: So how did you go about taking a look at our patients and come up with a study to look at outcomes related to how people chose to do management of the neck?

Brian B. Burkey, MD, MEd: Well, as happens in a lot of research, the paper actually started with the idea of trying to determine the real risk of spread to the neck in terms of the tumor type and all that. And because again, of the variety of histopathologies, the number of cases was just not... We were not able to determine that. So what we ended up doing was looking at then with all of our cases of clinically node-negative salivary gland cancers, what's the best treatment for the neck?

So we looked at over 400 cases. And some were treated with observation alone. That is, they just had a parotidectomy or salivary gland resection. I say parotidectomy because the vast majority of these were in fact parotid tumors. So almost half of the patients underwent observation alone, did not have neck dissection or didn't have neck radiation. Around 80 or so, underwent neck dissection alone. About 70, neck irradiation alone. And then about the same number, a little over 90 patients or so underwent both neck dissection and neck irradiation.

So let me go into that just briefly because this is a complex subject. But let's say a patient comes in with, let's just pick a simple case, parotid cancer with what appears to be an N-0 neck on the imaging. If we think they're low risk, for instance, there doesn't appear to be a high grade nature to the tumor, it's less than four centimeters, we might choose observation. And those patients would then, let's say we don't see anything on imaging, as long as it's a low grade tumor on final pathology, then they would undergo parotidectomy alone and that would be kind of the end of the story. We'd observe them, and that's the majority here of patients. And that's because the majority of parotid cancers are in fact low grade.

But then let's say we think they're higher grade. We do a neck dissection, we end up noting either a positive node on neck dissection, or in that case, let's say, then they might have neck dissection. And in a very high grade tumor with a positive lymph node, they'd get post-operative radiation as well. So that's kind of that group.

And then there's that kind of middle group that ends up with let's say a medium grade tumor or high grade tumor that underwent parotidectomy. Then some of those patients might have a neck dissection and not need further radiation. If they only had, let's say a single node or were N-0 ultimately. Or, let's say that they had a parotidectomy, but then you found out later that they had a high grade tumor, then you might want to radiate them post-op. So that's kind of the four groups. I'll stop there. I can go into what we found if you want.

Dale Shepard, MD, PhD: Yeah, I mean I guess that would be good to think about the findings in terms of... You looked at, I guess local recurrence, regional recurrence, distant metastases. What did you find and were you surprised by any of the findings?

Brian B. Burkey, MD, MEd: Yeah. So let me just say that the findings actually suggested that we're doing things the right way as we had decided. In other words, we didn't see one group that did very poorly in comparison. So I'll just go through the results with you briefly.

So number one, again, the major salivary glands that is parotid or submandibular gland were the most common site. And the most common histologies were, as we thought it might be, mucoepidermoid carcinoma. Actually, adenoid cystic carcinoma crept up to that level too. Adenoid cystic carcinoma is a little less common in general, but I think because we're a referral center, we had a little higher number.

And then the good news was, in terms of loco-regional recurrence, there really was no difference between all four groups. So that is observation, neck dissection, neck irradiation, or combined surgery and post-op radiation. Really there was no difference in loco-regional recurrence, which at first sounds a little weird, but in truth it just says we probably gave the more significant disease more significant treatment to get the same result.

So it kind of suggests that our rationale for how we treat patients is correct, that it is worthwhile being a little bit more aggressive in the high-grade tumors. That is, again, the larger tumors, T3, T4, and high-grade histology, than in the lower-grade cancers. And those with positive lymph nodes probably need both surgery and radiation.

In terms of distant recurrence, what we found not surprisingly, was the patients that had the most amount of therapy had the highest distant recurrence rate. And why is that? Those are clearly the patients that either have really high-grade pathology or have nodal spread. And as we all know, nodal spread is the major risk factor in the head and neck for distant metastases. So in truth, whereas the results at first look kind of confusing, it really just backs up the way we've treated salivary gland cancer for the last 20, 25 years.

Dale Shepard, MD, PhD: But I guess it's good that you went through the explanations of why different therapies were used. I guess it sounds like it's important not to sort of take away a headline that there are four ways you could treat, and it doesn't matter which one, you have similar outcomes. The treatment modality was based on the characteristics that you were identifying.

Brian B. Burkey, MD, MEd: Yeah, that's right. The good thing is we didn't under treat anybody, but it isn't a randomized study for sure. It's very non-randomized. Right.

Dale Shepard, MD, PhD: So where do you see this going next in terms of trying to make these predictions? I guess you mentioned undertreatment, but you have to think about overtreatment and undertreatment. What might be a next step in terms of trying to define groups and who might benefit most from what treatments or with the distant metastases that we see, addition of systemic therapies? Where do you think this goes next?

Brian B. Burkey, MD, MEd: Yeah, I think the first obvious step is that the group that did least well, obviously the patients that developed distant metastases. So option number one, or decision number one, is if we can know those patients, how can we better treat them? And the reality is we kind of know those patients. They're very high grade pathology like salivary duct carcinoma, which is the worst of all potential salivary gland malignancies, and those with nodal spread.

And so interestingly, this group's had a lot of research towards it for years. I was involved in a study along with one of the senior medical oncologists, Dr. Adelstein, up in Cleveland looking at patients with lymph node spread in salivary gland cancers and whether or not the addition of chemotherapy is of any benefit in addition to radiation. And the long and short is that answer is the study was never completed because of low numbers, but it looked like at least the early returns was that routine chemotherapy doesn't make a difference. And so we don't routinely give chemotherapy with radiation in patients with high risk features including nodal spread.

But this was from a couple years ago, and we all know there's a whole bunch of new opportunities, certainly with some of the immuno therapeutic agents. Is there small molecule agents? Is there something potentially we can give other than routine chemotherapy? Interestingly, salivary duct carcinoma, those commonly are hormonally active and so much like breast cancer. And so we think there may be a role, and again, there's several studies ongoing about that. So that's kind of one avenue of looking at this.

The other, I think, avenue of interest in terms of next steps is can we better define on the front end those patients that really would benefit from a neck dissection versus radiation? Again, great debate on which one has less morbidity. Certainly, I think in the age of modern surgery, a routine selective neck dissection has next to no morbidity. So if we could know on the front end that we can treat patients with a neck dissection rather than post-operative radiation, I think there would be a benefit to that. And that's initially what this study was designed to do. It's going to take more numbers, and I think that's the next stage of this particular study.

Dale Shepard, MD, PhD: Well, it looks like you've come up with some interesting data that will help move the field forward in terms of how we think about this and guide future studies. Appreciate you being with us today for some insights.

Brian B. Burkey, MD, MEd: Yeah. No, it's my pleasure. I appreciate it. You've walked through what can be a bit of a confusing topic really well, Dale, and I appreciate your help with this.

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