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Sue Yom: Hi, everybody. As they say on the Monty Python show, “And now for something completely different.” I do appreciate the engagement of patient concerns, and I will try to discuss the management of dry mouth from a clinical perspective. These are my disclosures.

Active and commercial are listed in black. But the most important disclosure is I’m a head and neck cancer radiation oncologist. And I’m really happy to be here and learn from all of you. And I really appreciate the effort of the organizers to engage the head and neck community in the discussion of PSMA.

So there are a lot of different kinds of saliva. They come from different kinds of glands. And the parotid, submandibular, and sublingual glands go from superior to inferior.

And as you go more inferior and anterior, the saliva becomes more mucinous. Mucins are very important because that’s what gives you your resting sensation of wetness and hydration, and are important for nighttime and daytime comfort.

When these glands become dysfunctional for any reason, you get consequences of dry mouth—or what we call, in doctor speak, xerostomia. This is things like poor sleep, daytime bother, needing to carry a water bottle around, difficulty chewing, swallowing, speaking, susceptibility to infections of all kinds, impaired taste, enamel erosion, and dental caries.

In severe cases, you can get this very classic butterfly lesion, which is a very unique type of xerostomia-related caries that involves the root of the teeth, as you see in this picture. Gingivitis and periodontitis from infection and resulting poor nutrition.

So the salivary glands do express PSMA—specifically in the lumen of the acinar epithelium. As you can see, the lumen is quite important to the function of the gland. And this area is very sensitive to ionizing radiation and unfortunately has poor regenerative capacity. And there are kind of a lot of different mechanisms, but they all sort of relate around this family of glutamate carboxypeptidase.

And so basically, salivary glands express PSMA highly, and that is how you get the mechanism of dysfunction. We do know from the external beam radiotherapy community that there’s a dose-response that creates xerostomia at around 40 Gy. From this long history of detailed dosimetric evaluations from external beam, we know that a mean dose of 40 Gy to the parotid gland confers a 50% risk of reducing flow by 75% at one year.

And we usually use, when we're talking about external beam planning, a mean dose to the parotid of around 26 Gy, which confers something like a 25% risk of reducing flow by 75%. So just by way of perspective, the VISION trial reported a cumulative absorbed dose of about 28 Gy to the salivary glands, which is just about or over the limit that we often talk about.

And this is an interesting paper that I really like to look at when I think about patient experience in terms of the recovery from radiation therapy. So if we’re talking about at least the very well-characterized experience of external beam—and I say it’s much less so for RLT—but anyway, very well characterized, you usually see recovery of dry mouth, the major component of that happening around 12 months or one year.

And so you can look at the curve here. This is a huge study of patient-reported outcomes—their experience of dry mouth. And you can see at about 12 months is where you get the major proportion of your recovery. And then it stabilizes but continues to improve—this is important—over the course of the next 3 to 4 years.

We know that PSMA therapy definitely does result in xerostomia. And I’ve highlighted here for you what I think is a really nice, very short review paper—it’s easy to read—which appeared in Practical Radiation Oncology, one of our major external beam journals. And as you see here, in the VISION trial and the WARMTH ACT trial, which are two signature trials, of course, the level of xerostomia was significant—something like 40% to 60%, or even 80%. And interestingly, of course, the WARMTH ACT trial actually has quite frequent.

So now I’m going to go into the practical point—a whole bunch of stuff really quickly. I can’t cover anything in detail, but this is just a compilation or smorgasbord of all different kinds of things.

Cooling—ice packs have been tried, where they put them on the right parotid and replace them every 30 minutes for four hours. That sounds like a lot of work. And then they found that the right parotid had decreased uptake.

And then this is obviously the mechanism of vasoconstriction, which also could apply to this botulinum injection technique, where they also showed decreased uptake. And then there was a trial of oral ingestion of monosodium glutamate. And there’s this Chinese food syndrome where you get pretty high concentrations of MSG in your body. And if you do that, you will decrease your uptake of PSMA by 33%, but you will also reduce it in the tumor.

In the external beam community, we have looked at something called amifostine for a long time, which is a radioprotectant. This is now actually no longer favored or used in head and neck radiation because even though it does have proven efficacy, it’s very difficult to administer.

It has to be given within 30 minutes of the radiation delivery. It causes nausea and hypotension, and there are ongoing concerns still to this day about protection of tumor.

There are a number of other radioprotectants, but mostly these have been aimed at mucositis. And unfortunately, none have actually gotten to cross that bar of FDA approval for use with radiotherapy. So this remains experimental. And there are some new developing ones in early phases that are oral or subcutaneous injection, which could be more promising in the future.

Here are some other simpler prevention strategies: oral ingestion of vitamin C. We just gave you a few options there. That’s not hard to do, and obviously it’s kind of simple to think about in a clinic. But these are pretty low-level interventions.

The more sort of fancy scientific ideas we’ve heard about now over a couple of talks is the J591 antibody or other types of monoclonal antibodies that would offer more specific binding that wouldn’t affect the apical lumen. But as we know, the major implementation of that—as we've just heard—is with actinium. And actinium, as an alpha particle, has more effects due to its relatively higher biologic effectiveness. And that is why you’re seeing increased xerostomia, at least with this specific manifestation.

The other thing I’ll just put out there as one possible avenue we could think about in terms of prevention is optimization with EBRT, where you’re using the geographic sparing of EBRT in combination with rational use of RLT, for example. Prevention is always the best medicine. But if we can’t get that done, we engage in a lot of supportive care.

So I’m showing you all different kinds of products here that go to the common aim of oral moisturization: xylitol. Just remember, xylitol is really good for your mouth. If you ever have a chance to have some xylitol, go ahead.

Coconut oil, coconut-based products also are really helpful for restoring the pH balance of your mouth, and very positive effects in the dental community. We do sialogogue prescriptions. Pilocarpine is the classic medicine.

It does come with side effects of sweatiness and sometimes dizziness. Important to know if you prescribe this, that it is temporary and has to be used three times a day. And also, there are other secondary options like cevimeline or bethanechol, and it is worth trying more than one because it is very common that a patient will respond to one of these better than the other two.

We did a study in the RTOG—that we participate in heavily at UCSF as well—which was comparing acupuncture to pilocarpine. Because a lot of patients don’t want to take a drug every day, three times a day. And so this was using acupuncture pressure points and doing electronic stimulation to simulate acupuncture therapy to these pressure points.

So you can look at these. And if you push on these, maybe you’ll feel good today. And here’s the patient actually receiving that therapy.

It’s a TENS unit which is hooked up to your acupuncture meridians. And what we found in this study was that the effect of the TENS unit stimulation was similar to pilocarpine. I will say I had an interesting experience on this trial—several of my patients actually bought the machine at the end of the trial and kept doing it.

You can turn it up yourself. You just grab the dial and turn it up as high as you can go. And some of them got pretty good effect because they turned it up pretty high.

We ran a humidification trial at my institution, where we gave patients this handheld humidifier. Humidifiers are often very big and bulky, but this handheld device was nice. We had them use it twice a day, and we actually showed significant improvements in quality of life.

We put all our dry mouth patients on fluoride toothpaste. It’s important to understand that the fluoride toothpaste has to go on twice a day, at least for a few minutes, and then has to be on there for 30 minutes. And the reason is this is an actual chemical reaction with the surface of the teeth, with the enamel.

And it’s also really helpful to add calcium supplementation on top of that, because the fluoride will actually bring the calcium onto the surface of the teeth. And here, what you’re trying to do is counteract the effect of dryness on the enamel.

You may think, well, the oral effect isn’t so bad. And it’s not so long. Maybe we don’t need all this. I will tell you, people’s teeth start to decay within a couple of months after any level of xerostomia. So it is worth thinking about.

We also give them additional calcium supplement through rinsing. And we also try to again keep the oral environment of the mouth stable with baking soda rinses. All of this helps to maintain the oral environment for the teeth.

And I’ll just give you a quote here from a radiation patient who talked about the importance of dental health to patients—that any effect on teeth is terrifying to comprehend. He recommended actually using trays, which is the most effective way to put fluoride on your teeth, and do it during your shower. So you just leave it out by the shower, put the fluoride on. It’s all done by the time you get out, because everyone in America showers for 15 minutes a day.

OK. Here’s the exciting stuff, because I figured you guys would want to hear something exciting to justify my being up here for eight minutes. There is a study out right now. This is based on the new thought of trying to get aquaporin complementary DNA into the salivary gland.

And so this is actually gene therapy–based transfer. Aquaporin is actually a water channel. And so the salivary gland, after it’s been damaged, can actually regenerate that water channel.

This has some really promising early data behind it. Now in a randomized study. And that is through the NIH and the group MIRA.

And then there’s stem cell regenerative therapy for the parotid and submandibular gland. Two labs well known in the radiation oncology community—Randy Kimple, [inaudible]—both investigating different mechanisms for how we could potentially utilize regenerative therapy in the future.

So I’m just going to emphasize the importance of a longitudinal clinic presence for these patients, both for prevention and for support after they receive radiation treatment to their saliva glands. This can be an emotional issue. They do need counseling. They need constant reinforcement of the behaviors.

There needs to be management and coordination with the various services that can help them with dry mouth. We include dental, nursing support, swallowing therapy, and oral medicine for infectious management.

Thank you so much. And if you’re interested in hearing more about this, I love talking about this topic. And as Tom knows, I will talk to you for 10 minutes anytime you call me about it.