Osteosarcoma Q+A with Dr. Matteo Trucco

Osteosarcoma Q+A with Dr. Matteo Trucco
Matteo Trucco, MD is Director Children's Cancer Innovative Therapy Program Associate Staff, Peds Hematology-Oncology & BMT at Cleveland Clinic . He received his training in Pediatric Hematology/Oncology from Johns Hopkins University and the National Cancer Institute and has focused his career primarily on Pediatric Sarcomas and the development of new therapies.

Ann Graham: Welcome to OsteoBites, everybody. My name is Ann Graham, I'm an Osteo Warrior and Executive Director of MIB agents. Today on OsteoBites, we are talking with Dr. Matteo Trucco of Cleveland Clinic. He will be answering your osteosarcoma questions. He'll be doing this along with Junior Advisory Board Members - Camille Wall, Mia Sandino, Vicky Hoy, and Christina Ip-Toma, our Director of Scientific Programs.

Dr. Matteo Trucco is the Director of The Children's Cancer Innovative Therapy Program and is Associate Staff of the Pediatric Hematology-Oncology and Bone Marrow Transplant Program at Cleveland Clinic. He received his training in pediatric hematology/oncology from Johns Hopkins and the National Cancer Institute. He is focused primarily on pediatric sarcomas and the development of new therapies. He is also a big part of MIB Agents. We're incredibly grateful to have Dr. Trucco lead our Scientific Advisory Board. He co-chairs our annual FACTOR conference. He's on our board of directors and he is the co-lead along with Christina Ip-Toma of TURBO, which is the MIB Agents Osteosarcoma Tumor Board. We keep him busy.

I also need to say I'm so glad you're here. But when we're done, if you would go outbid osteosarcoma, that would be super too. Outbidding osteosarcoma is our annual online auction. It started this morning and it runs through Sunday night. I just looked at it before coming on and items are really going fast. So, please jump on. You can bid on really cool items that directly impact the lives and kids of families fighting osteosarcoma. It's an easy way for your community to support you and, also, you get really cool stuff too. The virtual auction is hosted on a trusted platform and is user-friendly, you don't have to provide a payment to bid. Just bid and every bid that you send through enters you in for a chance to win a 500-dollar Amazon gift card. So, the more bids you make, the more chances you get to when your auction item and win the Amazon gift card.

The event is too good to ignore. There are luxury hotels. There's art. There are experiences like, well, one of my favorites is five-star chef, Nathan Rich, coming to your house to cook for you, your family, and I think up to ten friends. Hyundai car racing donated an event in California that includes hotel as well as the VIP tickets and just in, we got a night at Rancho Bernardo Inn, where a FACTOR conference is being held in June. So much stuff, so, please find the auction link on our social media or on our website and we'll also drop it in the chat.

Also, please know that this episode is sponsored by BTG Specialty Pharmaceuticals. BTG provides rescue medicines typically used in emergency rooms and intensive care units to treat patients for whom there are limited treatment options. They are dedicated to delivering quality medicines that make a real difference to patients and their families. They do this through the development, manufacture, and commercialization of pharmaceutical products. Their current portfolio of antidotes counteracts certain snake venoms, the toxicity associated with some heart and cancer medications, and their drug, Voraxaze, which is for a high dose methotrexate toxicity. So, thank you to BTG and thank you to Dr. Trucco.

Would you introduce yourself, please, Dr. Trucco? Anything I missed.

Dr. Matteo Trucco: Yeah. Thank you, Ann. No, I actually think you covered it all. It is an honor to be here. I'm a Pediatric Oncologist. I also am involved in clinical trials here mostly focusing on sarcomas as Ann said. I've had the honor of working with MIB since 2016 doing the FACTOR Conference helping with the OsteoBites, the outsmarting osteosarcoma, and just yesterday, we launched TURBO, which I think was a great success discussing some challenging cases with oncologists, surgeons, a great panel of experts who were attending that. So, always an honor to be here on OsteoBites doing anything within MIB. I hope this is a helpful session with everybody.

Mia Sandino: Wow. I am Mia Sandino, the Vice President of the Junior Advisory Board for 2022. I'm very happy to be here today. I live in sunny Los Angeles and I have been undergoing treatment for osteosarcoma since 2018. I am 23 and currently attending the University of California in Santa Barbara.

Camille: Hi, everyone. My name is Camille Wall. I'm 19 years old. I live in Boston, Massachusetts and I'm currently a freshman at Boston University. I am a seven-time Osteo Warrior and a member of MIB's Junior Advisory Board.

Vicky: Hi, everyone. My name is Vicky Hoy. I live just outside of New York City, was diagnosed with osteosarcoma past July, so I'm still undergoing treatment, but plan to attend Villanova University in the fall once I beat osteosarcoma.

Christina Ip-Toma: Super exciting. And I'm Christina Ip-Toma. I'm a mom to Osteo Angel Dylan, and the Director of Scientific Programs for MIB agents, and welcome, everyone. Today is a little bit different from our other OsteoBites in that it's really a free flow Q&A. So, if you have any questions, please put them in the Q&A in the Zoom function, and we'll go ahead and get started.

I'm going to throw out the first question to Dr. Trucco, which is - I think everyone knows that the standard frontline chemo for Osteo is MAP but if there's relapse after that first line chemo, is there a standard second, third line chemo that most oncologists will turn to or what are the different options there?

Dr. Trucco: Thank you, Christina, for that question. And by all means, call me on it if I start using medical jargon or saying stuff that people don't, you know if I'm not speaking English and speaking doctor-ish, I apologize in advance. Yeah, you're right. MAP is the traditional therapy upfront for pediatrics, actually. Adults tend to use adriamycin and cisplatin, doxorubicin and cisplatin, skip the methotrexate so they might save that for the second line. Usually, people will reach for something containing ifosfamide as a second line, it's a very active agent. Historically, we've been doing it with ifosfamide at etoposide just because people don't like using single-agent chemotherapy, but no one's tested ifosfamide alone against ifosfamide and etoposide.

And then there may be some reasons that people don't want to use ifosfamide because it's toxic to the kidneys or after 28 weeks of MAP, it's kind of rough. So, other regimens like gemcitabine-based therapies exist, usually, jumping out at docetaxel, recently tyrosine kinase inhibitors have become more popular and show some activity. So those may be other agents. Sometimes people reuse, re-challenge with some of the prior drugs, Doxil, for example, as a way of giving more doxorubicin in a relatively safe way. So, the short answer is something with ifosfamide, the more complicated answer is that we try to tailor the therapy to the patient as best as possible.

And then in the midst of all that, clinical trials are always to be considered. Some people, there are two schools of thought, wait until you've exhausted all the standard regimens and then go to trials. Other people say, hop on the trial when you can when you're healthy enough that you always have that stuff on the shelf waiting for it.

Mia: Great. And then I had a good question come in that's very similar. What targeted therapies or TKIs are currently used for osteosarcoma, which I know you just kind of went over, but are there any kind of up-and-coming treatments that you know about right now?

Dr. Trucco: Yeah, there's a few that we use. Kind of the newest one is Regorafenib, which is a TKI that seems to be pretty active against osteosarcoma, and by pretty active, I mean, we're not saying 100% of patients respond, but maybe 20 or 30%. It's got its own toxicities even though it's not chemo, your hair won't necessarily fall out, it can affect blood counts, can affect the liver, and have other side effects. Cabozantinib - we love these complicated names that no one can pronounce. Cabozantinib is another one that similarly has some efficacy against osteosarcoma.

Before those two emerged, pazopanib was one that we used. That one's claim to fame is that it turns your hair white. It doesn't fall out, but it turns white. Back in the day, people use sorafenib usually combined with an mTOR inhibitor like everolimus. There's a clinical trial that showed some efficacy there. I don't remember the last time I've actually used that combo but technically, that's a TKI, technically, it is a regiment people use.

Camille: All right. I have the next question. What are your thoughts on treatment for unresectable lung disease that can't be removed with surgery and what do you think about interventional radiology options for lung nodules?

Dr. Trucco: I think lung nodules that can't be removed suck. I am against them. That's my feeling about that. What I tell my patients is, with osteosarcoma, you need to do two things - get rid of all the tumors that you see and get rid of all the tumors that you don't see. So the systemic therapy, you are killing the cells that are floating around that you don't see. Yeah, they may shrink the tumor, but you're really killing those cells that are floating around that setup new metastasis.

At the same time, you need to remove that macroscopic, that visible nodule, that visible tumor in the bone, and when you can't surgically remove it, your options, you still need to hit it somehow. So, newer approaches to radiation enable you to do that. It all depends on the size and where it's located. A specific technique called SBRT is being used with more and more frequency and successfully. And then there's Interventional Radiology Techniques like ablating it somehow, and you can either ablate it by freezing it, it's called cryoablation. So you stick a little probe in there literally. I think they have liquid nitrogen flowing through it to freeze it. You can see the ice ball form, try to encapsulate the tumor.

The limitation there is the size, again, what other structure is close to how easily they can stick a probe into the tumor. Then there's radiofrequency ablation, radio waves, high-frequency ultrasound is now a new technique and they all have their advantages, disadvantages. A lot of it is operator-dependent so you want someone with experience doing it and know that that's location, location, location. If it's next to a vital structure and there's no way to make sure you're hitting just the tumor and not the vital structure, then that limits your options.

Vicky: All right. The next question is - are there any drugs today that will help minimize ototoxicity from cisplatin?

Dr. Trucco: There is a medication called sodium something. I got to look it up and get back to you guys. There is a drug that's felt that if you give it around the time of cisplatin, it protects the hearing. Thank you. Sodium thiosulfate. My officemate helped me out. There's some concern that maybe, as with anything that protects from side effects, there are concerns that it might interfere with the efficacy of the drug. So we've used it a little bit more in younger kids that are at a higher risk for ototoxicity, especially with other tumors. There's a liver tumor that we use a lot of cisplatin for. That liver tumor happens with really young kids. So, they're at a crazy high level for losing their hearing.

I can't say it's been used a ton in osteosarcoma. But we all kind of know about it. Most of us actually remember what it's called but not me. For example, where I've used it is we've had a patient who was blind and the last thing we want to do is knock out his hearing too. And so that was one patient where we certainly use sodium thiosulfate. So, yeah, I don't know of any newer ones. I'm not saying they don't exist just haven't heard of any.

Christina: Dr. Trucco, last week we had a speaker who is a nutritionist. And so, we had a lot of questions around supplements and particularly, I know as a caregiver and as a patient, you're always trying to figure out how to - your counts up and just kind of stay healthy to get you through treatment and would love your perspective as a pediatric oncologist on supplements. Like during chemo, is that okay before and after surgery?

Dr. Trucco: My take on it is that these are horrible cancers and anything we can do to improve the outcome or the tolerability of the treatment, I'm all for it, provided it's safe and it doesn't interfere with the treatment. And it's those last two that we don't always know the answer to. I'd say at least half of my patients are taking some mushroom or something on the side, and what I've always asked them is just let me know what it is, let me check it with my pharmacists, make sure it doesn't interfere with the drugs. And then, yeah, try it.

If there was a supplement that made doxorubicin tolerable, I think we know about it a little bit more. If there was some herb that made osteosarcoma melt away, we'd know it by now, so I am a little hesitant with some of the stuff I've heard out there. My favorite was when I was talking to a doc who was talking with my patient about some supplements and he said, "Oh, well, you know, we can give massive doses of vitamin C," and I'm like, "Well, yeah, but vitamin C is an antioxidant, the chemo and the radiation that we use works by oxidizing and so you don't want to give an antioxidant." He was like, "Oh, well, in that matter, we can give super high doses and it becomes an oxidant." I'm like, "That makes no sense whatsoever to me." Maybe there's proof for it. But that's the thing. There's just not concrete proof for a lot of these things, at least not concrete proof that I've seen. I have to admit I don't read up on the naturopathic or nutrition literature.

But, again, I do think there's some value to some of it. Ginger is a known antiemetic, does it work as well as Zofran? I don't think so. But, you know, hey, why not? And, again, I'm not against trying it, heaven forbid, ten years from now we hear that "Oh, yes, Chaga roots or whatever actually did help," I don't want to deprive my patients of something that might help before we know that it really does. I just don't want to cause harm.

Ann: Is there anything that you know of that causes harm? Is there anything that really should be avoided?

Dr. Trucco: I can tell you a patient of mine approached me about taking mistletoe and when we kind of looked at its side effects and its interaction with some drugs, we asked them not to take mistletoe. Just leave it at that. So, it's stuff like that. When you're getting Methotrexate, you should not be taking folic acid because Methotrexate works by blocking folic acid. So there is some kind of basic ones like that. And some of these things where they ask you to mortgage your house to buy some supplements, I can't say they're dangerous per se, but it's always a little iffy when someone says, "Well, I would publish my results but then they would steal it," well, that doesn't really happen. "They're afraid of me publishing my results because I would revolutionize the field," no, trust me if you would cure osteosarcoma, it would be helpful. I want to be out of a job. I think most of us feel that way.

Ann: Yeah. I have a follow-up question. After chemotherapy, what about that after chemotherapy space? I remember somebody told me to take magnesium because you're low in magnesium after you go through all of the surgeries and the treatment and everything. And I still take magnesium. I like it. It really makes me feel better. It actually helps me sleep better. I'm a fan of magnesium.

Dr. Trucco: Right. So, specific to osteosarcoma, the cisplatin makes you dump magnesium. So, not only does it make you puke, it makes your hair fall out, and knocks out your hearing, it also hurts the kidneys. And so, if you're ever getting chemo or remember back to your chemo, and you've looked at the fluids they had running, there was tons of magnesium in there because cisplatin makes you dump magnesium. In some patients, that effect kind of lingers after the cisplatin and so you keep dumping if you can't hold onto magnesium, so you need to take more. Now, whether all of us should be taking more magnesium because we're all magnesium deficient, I don't know. I haven't heard that but specific to cisplatin, that happens.

Ann: Anything else you'd like to add?

Dr. Trucco: I mean, afterward, I'm a little more open with my patients at least like if you have to have it, just don't hurt yourself, in a sense. I mean, the jury's still out on whether Vitamin D supplementation should help or doesn't help. We live in a place that's gray half the year and so all of our Vitamin D levels are in the toilet, so, some of us take supplements, some of us don't but none of that's ever really panned out. People haven't really, really, really studied some of these things, so I don't know if anyone who would say, by all means, you should all be taking supplements.

Ann: Yeah. Yeah. You know what though? I wonder if we should be thinking about as a disease community like post-treatment doing one of those panels that look at - What are you deficient in? What do you have too much of? Just like short-term, just when you hit survivorship or at least get through first-line treatment to have that panel that looks at those things. I think that would be kind of helpful.

Dr. Trucco: Yeah. And I will say, most of the naturopaths and holistic people that I've interacted with do something like that. It's funny because they usually ask us to draw their labs which is funny in some of them. The high sensitivity CRP is specific for heart issues and yet they asked us to draw it. I don't know how they interpret that. So, and another thing I've seen, and again, maybe I'm just dealing with weird ones, but it's like, "Oh, your magnesium is two." That's like, "Okay. Yeah, it's nice and in the normal range." They're like, "No. No. No, it's two. Yeah, your normal range says, it's supposed to be two, but my normal range says it should be more." And so would give supplements for what essentially is normal magnesium.

But, I mean, let's face it. This is a poison that we're using to get rid of a worse evil. So, many patients have side effects and they linger. We catch many of them, the ones we know about. There is one advantage to having treatments that are 40 years old as we have a lot of experience using them but there may be other things that we just don't know because I've got to admit we're not very good at looking at things like nutritional deficits and stuff like that long term.

Ann: Yeah. Thank you.

Mia: Going off of lab values, I kind of have a little bit of a niche question. This didn't happen to me, but one of my close friends because I looked at my values for this too after she and her mom noticed this trend. Whenever she would have more growths, more osteosarcoma growths, her alkaline phosphatase would go up and I just want to know if you've heard of that connection before and if you have any input on it.

Dr. Trucco: Yeah, we use alkaline phosphatases kind of like a poor man's biomarker. Not everybody who has osteosarcoma has an elevated alkaline phosphatase. Not everybody with an elevated alkaline phosphatase has osteosarcoma. It's also complicated by the fact that the liver makes alkaline phosphatase and the bones make alkaline phosphatase. You can fractionate it I guess but extra testing just for the sake of knowing I'm not sure is necessarily worth it.

But that being said, alkaline phosphatase goes up when your bone is turning over. And so, when you have osteosarcoma, there's a lot of bone turnover and so it could be really high. And as you start treating a patient you could kind of see it trickling down. Now, it may bump up because the patient just got Methotrexate. Methotrexate irritates the liver and so you have the liver alkaline phosphatase going up. And so, it's not the most sensitive and the most specific marker. But generally speaking, you could see trends, just because it goes up, doesn't mean you're relapsing. But in the context of other things, it's something that you can look at, follow, be a little bit reassured if it goes down, concerned if it goes up.

Vicky: My next question is based on a personal experience I had. In 2021, I had two small lung nodules grow, and I only had one thoracotomy and SBRT to treat it, so, I'm just wondering what your thoughts are on local control and no systemic chemotherapy or treatment for small lung nodules in patients with multiple relapse osteosarcoma.

Ann: Good question.

Dr. Trucco: Yeah. Osteosarcoma is the one tumor that I deal with where that can't work and we don't really know why. But like Ewing's rhabdomyosarcoma, we don't typically go after the lung nodules, but in osteosarcoma, we certainly do. And some patients have beautiful disease-free intervals and it becomes more of a discussion with the patients especially if you've relapsed multiple times. You guys know a heck of a lot, you might not know as much about osteosarcoma as the doc, but you know more about your osteosarcoma than the doc and so it becomes a discussion about - do I want to go to IV stuff again? Do I need another port placed because I don't have a port because I had it taken out? So, I don't want to get another port and do IV stuff again.

Maybe we look at some of the oral stuff. Maybe we just do surgery. Maybe we just do SBRT. It becomes more nuanced. My colleague and I like to say, yes, you can follow a recipe in a cookbook or you can learn how to cook. And I think deciding stuff like SBRT surgical resection without chemo or other places, let's do a couple of cycles of chemo before we were expected to see if it's responding at that plan, again, we just pull these numbers sort of out of our butts, six months of therapy, or did six months after. I don't know. Seems like a good number. I wish there was more to it necessarily than that. Sometimes, there's not. But those are the kind of nuances and the tailoring of therapy that is the advantage of having folks that just focus on sarcomas and you're at a Sarcoma Center.

Camille: I was wondering what are the chances of osteosarcoma relapse depending on each year there's no evidence of disease. Or like whether it's a like one year out or five years out, ten years out.

Dr. Trucco: If you look at the charts, we have these things called Kaplan-Meier Graphs. It's like you start here, a hundred percent of patients are disease-free and then that number goes down, and then it kind of flattens out and usually, the place where it flattens out, meaning, not a lot of patients are relapsing is around five years.

Now, I've had patients relapse ten years after, it's like what the heck? So, never say never but most of those relapses probably don't happen on active therapy, some do, but not when you're getting MAP. But, usually, by two years, that's where you're going to start maybe seeing more relapses, and then again by five years that line kind of flattens out. And then, yeah, a couple of patients may relapse later on that but the rate of relapse drops after five years. And that's why we usually use a five-year survival as the measurement for clinical trials because you can just say survival because you have to wait years to see if a patient's going to survive. So, we use the five-year mark. That's why the five-year mark is usually is.

Christina: We have a question from the audience about the lung nodule close to the edge of the lung. So, if there's a nodule at the edge of the lung along the pleura, is there a risk of contaminating the pleura and then also just thoughts towards reading that.

Dr. Trucco: Yes, there's certainly a risk for contaminating the pleura and that becomes challenging especially if there's what's called a pleural effusion of fluid between the lung and the chest wall. You almost have to assume all that fluid, which is caused by the tumor is full of cancer cells. And so, now, the whole pleura all the way up and down, has the potential of having cancer, cancers pop up there, and that becomes quite challenging.

We actually have a clinical trial going on right now. Thanks in large part to the FACTOR conference and MIB where they're seeing whether or not the traditional old-school way of dealing with lung nodules is thoracotomies, a big old scar. They open you up. They feel around and surgically remove any nodules they feel versus what's called VATS, which is basically a little hole, putting in a camera and just kind of plucking out the tumor that way, and see, for tumors where you could go either way, is VATS inferior to traditional, open to thoracotomy. Obviously, a much less invasive procedure, they can go home much quicker, which is generally better tolerated. You can't do that for something in the middle, so it's over at the edge. But, yes, those are some options.

Mia: Circling back to cryogenic ablation and radiofrequency ablation, I'm actually having my 13th cryogenic ablation next Wednesday, and I've also had one radiofrequency ablation of a 6mm growth in my sacrum. I know a little bit of the answer but how would you explain to patients who are considering the Interventional Radiology route and the ablation route, how would you describe the difference between radiofrequency in cryogenic in terms of which would be better for treating a lung nodule versus a nodule, for example, in my case, in my scapula, or my sacrum?

Dr. Trucco: I mean, my answer is very simplistic, actually. You can either burn it or freeze it. Again, that's where having an interventional radiologist who's experienced and knows the advantages and disadvantages of either comes into play. There are some size limitations. Usually, 3 cm is about the cutoff for cryo. If you're close to a blood vessel, freezing might actually be okay because the blood is flowing so fast that it keeps the vessel from freezing while radiofrequency ablation might burn it. So, there's kind of nuances like that. And again, if you got a guy who's really, really, really good at cryoablation, that might be the better option. If you have a doc who's really, really, really, really good at radiofrequency ablation, that might be the better option. And someone who's good at both, again, it's kind of a discussion.

Ann: Mia, can I ask you a question?

Mia: Absolutely.

Ann: How does one feel versus the other for you? Which one do you prefer?

Mia: It really depends. So, I've only had cryogenically done on my lungs and my scapula, whereas the only one that I had ablated via radio frequency was in my sacrum. My scapula was the most painful, but that was predominantly the second one because he had to remove a chunk of the bone for the biopsy. So that when hurt but only for about two weeks and what's truly lovely about the ablations is I'll get to the hospital around 5:30 or 6:00 in the morning and granted, I live nine miles from my hospital, but I'll be home by 2:30 or 3:00 that afternoon. They're generally outpatient procedures, which is lovely. But I had very, very little pain which is surprising. I thought I was going to be in a decent amount of pain because, your sacrum, there are a lot of nerves that are in that general area.

It was quite an interesting procedure that my interventional radiologist said he was expecting it to only be about 45 minutes, it ended up taking two and a half hours because there was some nerve or blood vessel, I can't remember at the moment, that was really close by so he's very very precise. But he did radiofrequency in that instance specifically because of the location, whereas cryogenic is more peripheral in my lungs, at least. And really I haven't coughed up blood. It's just been great in my opinion. But, yeah, I do really, really prefer cryogenic in my opinion.

Ann: Thanks.

Christina: My next question is from the audience. It is - do you have any recommendations for minimizing liver toxicity from chemo?

Dr. Trucco: Just keeping an eye on it usually is the most important thing. It can sort of sneak up on you. Something like Methotrexate, we know just makes all the liver enzymes go through the roof, but they should come down. For instance, I had a patient just recently get Methotrexate, I'm not sure why they checked it, the inpatient team. They checked his liver enzymes and they were like 400 something, usually, it's supposed to be less than 40, and they were worried. I'm like, "Well, let's give him Methotrexate." It's going to be through the roof. And when he came back the next week for follow-up, we checked that and it's back down to normal. So, that happens.

For osteosarcoma, specifically, chemo doesn't usually cause toxicity. I know adults sometimes doxorubicin can but not something we typically see. And then if you're radiating, it somehow kind of catching some of the liver, yeah, they're trying to shield it from radiation is the best way to do it yet having an experienced radiation doctor certainly helps. Sometimes, something like proton therapy, which is the same concept of radiations just delivered in a different way, so that you have the cup, but you don't get right behind the cup can sometimes prevent stuff like that.

Yeah, livers are not usually the ones I'm too too worried about, at least with upfront therapy. Some of the TKIs can affect the liver though. And again, you just got to keep an eye on it and let the liver heal.

Christina: I have a question based on personal experience. I can't remember the exact name of it but it was one of the side effects. Is there any way you can prevent gastrointestinal acculturation and other gastrointestinal issues that come from the chemos?

Dr. Trucco: So the doxorubicin, for example, causes mucositis. It's what we call these sores you can have in your mouth, anything you can have in your mouth, you can have basically in your entire GI tract. So, a couple of things. One, in the mouth, oral hygiene, like keeping the bacteria low. So brushing your teeth frequently, mouthwashes, stuff like that helps. Specifically, the stomach antacids like Pepcid, Axia, take your pick, can help with that.

Then, actually, eating is usually a good thing. Even if you're nauseous, even if you're just sick, having something going through your GI tract is usually a good thing. And then we use a lot of what's called Helios here. It's amino acid glutamine, which my colleague who's sitting next to me, helped develop and it protects the lining of the intestines from the mouth all the way down. In my experience, it helps some people amazingly. Other people just doesn't. I don't know why it works for some people and some people, it doesn't work for them. But those are some strategies we've used.

There are other medicines that kind of coat the stomach, for example, there's a medicine called Carafate which, if you ever saw those Pepto-Bismol commercials where the pink stuff goes down in the stomach, that concept. Pepto-Bismol is a different medicine, Carafate, though, kind of generally does the same thing. And then there's some more. So there's BMX, which is a mouthwash, which is like Benadryl Maalox Xylocaine. So, it's the xylocaine that melts in the mouth. So, you rinse and spit that before eating and everything, but at least it doesn't hurt.

Then, usually, when your counts recover, those sores go away. That helps. And then there's a medicine called Palifermin. So what it does is it's a growth factor basically for the cells that line your mouth and your intestines. Everyone's a little hesitant to give a growth factor to someone who has cancer but I've had patients where the mucositis was just so horrendous. We could not get the [inaudible] to her. We gave her Palifermin three days before the chemo, and it's funny, you could almost see her lips swell up from a factor, and she tolerated the chemo better, not perfect.

Getting approval for that is not always the easiest thing, it was designed for transplant patients, but those are some of the tricks we have up our sleeves to try to deal with it.

Some people also, an old-school trick is to place ice in your mouth while you're getting the infusion with the thinking that it constricts the blood vessels so not as much chemo is going to your mouth, but obviously, it's hard to keep ice in the entire GI tract during an hour infusion. You're stealing all my tricks.

Christina: Dr. Trucco, I have a question about just considerations when you are doing multimodal therapy like chemo, radiation, surgery, and some of the standard guidelines are around. I know that there are some compatibility issues with certain chemos and radiation. So if maybe you can elaborate on that and then also just, the healings, absolutely, an issue for spacing out chemo and surgery and so kind of what are the general guidelines around that?

Dr. Trucco: I mean, there are some hard and fast rules. You don't give doxorubicin and radiation at the same time. You can give doxorubicin on the first day of radiation, but then no more afterward. And again, we don't use radiation quite as much in osteosarcoma as other tumors mostly because osteosarcoma just isn't as sensitive to radiation as other tumors, and maybe some molecular biologist knows why. I don't know why. I just know that it's not.

So, those are kind of hard and fast rules. But other than that, we certainly combine them, and there's some thinking, and I think there's some validity to it even though it hasn't been thoroughly tested, that really the combination of radiation with chemo works better than either one alone. And so there are some drugs that sensitize the tumor to radiation that exists. I can't say there's a lot of data for it specifically in osteosarcoma but we try to extrapolate some things from other tumors. And then, this is where having a team, that sarcoma team that works well together, they talk to each other, and if you're going to radiate the esophagus or something, maybe not give something that causes myositis right away or don't hit the kidneys while you're giving [inaudible]. So there's a discussion that way.

As far as healing from surgery, it's always, actually, a battle of sorts. So, you give your MAP, and we doxo-cisplatin two weeks later, Methotrexate, Methotrexate, doxo-cisplatin two weeks later, Methotrexate, Methotrexate, and then surgery. And part of the reason for that is Methotrexate doesn't drop your blood counts as much so you could probably go to surgery pretty quickly after that and we can get into the whole why surgery as techniques out, that's a separate topic.

So let's say you do surgery the week after Methotrexate and then you need some time to heal whether it's surgery and amputation, or what have you. You need platelets, you need red blood cells and you need white blood cells to heal after surgery. If you give chemo right away, you're almost guaranteeing an infection or wound healing stuff like that. So you need to get the wound chance to heal. But you also don't want to go six weeks without chemo because the tumor doesn't care whether you're healed or not, the tumor is just going to grow. And so, usually, we say, two to three weeks after surgery is when we'd like to start chemo.

If it starts becoming four weeks, that's where we start nagging the surgeon, "I need to get chemo. I need to get chemo." By six weeks, I'm telling the surgeon, I'm giving chemo and you're just going to have to deal with the complications, but we're a team. That's kind of the logic behind the time between chemo and surgery. Similarly, you don't want to go into surgery, neutropenic, thrombocytopenic, or anything like that. So, again, in a real lab setting, you don't want to give ifosfamide and that surgery in the next week because you know everything's going to be dropping. So, we space things up.

Vicky: I think it's funny you say that about going two to three weeks out or six weeks out because I can expect the conversation my oncologist and surgeon had when I was six weeks out without any chemo because, like, "You're staying here. You're getting chemo." I was like, "So soon?" And he's like, "We need it right now."

Dr. Trucco: Oh, yeah. I'm sure he was pulling his hair out.

Christina: Can I ask for a quick follow-up to something you mentioned, Dr. Trucco, about the radiation when you were talking about radiation? Like, the difference between SBRT and EBRT and my understanding is SBRT is higher doses and fewer days versus EBRT is a spaced-out lower dose. And so is there any thinking these days of what's more effective for osteo?

Dr. Trucco: I mean, for osteo, and again, our experience, and I am not a radiation oncologist, but SBRT is what we go with. Osteo is not Ewings. Ewing's, kind of your standard approach if you're going to use radiation for local control, it's six weeks of radiation, teeny tiny doses, Monday through Friday for six weeks. SBRT, you're actually trying to jack up the equivalent to radiation dose because we know that 56.4 grays, which might work for Ewing sarcoma will not work for osteosarcoma. So you're actually giving the equivalent of, actually, a higher radiation dose with SBRT. And you do that by giving it over like 5 days or something like that, 15 maybe, but usually, it's a lot less.

And the nice thing, boy, I hope Dr. Murphy's not on this thing, but the way I see it is instead of giving like 1D full dose, your kind of splitting it up into two or three or four Ds. And each one is giving a fraction of the total dose. And so only where all those beams overlap are you getting a full dose. So, you actually are exposing a lot more tissue to radiation, but much lower doses and the tumor is getting the full dose, and that's why we're able to push the doses of SBRT higher than what's normally tolerated by normal tissue because we're splitting up the beams and conforming it in a way that maximizes the amount of radiation to the tumor and minimizes it to the other tissue.

Mia: I have a really really great two-part question come in. See, where's the first part? Okay. Do you know the status of Mepact and if it will be available to patients in the US again soon? And on top of that, would you ever give Mepact again to a patient who has already completed the typical 48 doses?

Dr. Trucco: So, the first one is Mepact, you can get it for patients in the US. It is through compassionate use. The company Takeda, I won't get to all the history of it. But basically, they've tried to get approval here, they didn't. It's approved in Europe, it's approved in Mexico and a few other places. But it is possible to get it for patients. It takes a little bit of leg work from your doctor, but the process is, honestly, not as bad as I thought it was when I first did it. The FDA has made their part a lot easier. Your institution might give you a hard time but usually, those people you just have to say it's a patient with cancer, "By all means," and the drug company, Takeda, has been very good about providing it except when they ran out and it was like a production issue. They just didn't have it. So it's on hold.

Rumor has it that it's available again, so that will help. Whether it will ever be FDA-approved for use in the US, boy, I can tell you, I tried talking to Takeda about opening a clinical trial, combining it with some immunotherapy, and they said that is not a drug in our portfolio that we are interested in reading to the US. Period. And so, it's going to take a little bit of convincing to find a way to get them to bring it to the US, even try to get it approved.

As far as giving it beyond the 40 doses, I never done that. Not saying I'd be close to it, but it has to be a specific context where I really, really, really thought the Mepact did something and I say maybe even the period of time between those administrations would have to be pretty long. But let's say, we got mepact and a patient who we are all convinced was going to relapse didn't for 10 years, but then they relapse again, well, maybe Mepact really did something and I consider giving it again. But, that's a pretty rare patient.

Vicky: My next question is, what, in your opinion, is the most promising drug currently in a clinical trial for osteosarcoma?

Dr. Trucco: That's a good question. I don't necessarily think it's a drug. So, we were so far behind leukemia and a bunch of the adult tumors as far as immunotherapy. And I really think if there's, and this is just my personal opinion. If there was a tumor that should respond to immunotherapy, it should be osteosarcoma. The tumors that respond to immunotherapy, look at their genetics and they're a complete mess. [inaudible] osteosarcoma doesn't have a complete mess of them when you look at their genetics.

That being said, which of the many approaches? I couldn't tell you. I mean, there's the Listeria model that was started first to dogs, and now we have a clinical trial for that seems promising. There are Car-T Cells targeting here, GD2, there's CD47 mixed with a GD2 antibody, which again, seems promising, but the trial is suspended now, so something must have happened.

So, I'm excited about immunotherapy and I think if it's going to work in a solid tumor, probably going to be osteosarcoma, but I can't tell you which one. Some of the other things that I'm looking at with some colleagues, I've mentioned this before and we're close, I swear, but we're using this drug disulfiram which seems to particularly affect osteosarcoma. So it's a drug that blocks an enzyme, you need to process alcohol. It's been around for 70 years now and maybe it blocks the enzymes that osteosarcoma needs or it helps deliver drugs or even we're talking about supplements before, apparently copper seems to be very low in metastatic osteosarcomas. And disulfiram happens to transport copper into cells. So, is that how it's working? So I'm excited about that and the work that Curtwise puts out. It's more interesting. So we're very close to opening a clinical trial for disulfiram and liposomal doxorubicin against osteosarcoma and other sarcomas.

The other thing approved that I'm working with is doing something interesting. It's not a new drug, but a new approach to how we give drugs, and instead of giving your 28 weeks of MAP and then saying, "Bye. We'll follow up," and kind of waiting for you to relapse, the idea is - let's keep cancer on its toes. And in this sense, we're using leukemia as the poster child. If you've ever seen someone treated with pediatric leukemia, ALL, they get four drugs for four weeks then they switch to another handful of drugs for about six weeks, then they switch to another handful of drugs for another six weeks. Then they switch and they get the first combination of drugs again and then they switch to yet another thing and then they have this long maintenance phase and it's like, "Wait a second. You're changing treatment, even though you're responding to it," and that came all by happenstance. But maybe that's exactly what we should be doing. Instead of MAP, MAP, MAP, MAP, MAP.

Maybe we should be doing MAP for a few cycles then bring in the ifosfamide then bring in something else and then bring something else so that the tumor never has a chance to develop resistance. Kind of out there, kind of tricky to test but especially for someone with metastatic osteosarcoma, for example, we know the outcomes are poor, so we got to try something different.

Ann: Okay. I have a one really important burning question that is on, really, I'm sure, everybody's mind. What's with the horse behind you.

Dr. Trucco: I was on a conference call with the board of directors for another foundation that I work with and someone had that fuzzy background except for this bust of a horse. And so, when I was on a meeting again with the docs that I was on that meeting with, I put the horse behind me as a joke and nobody picked up on it. So it's just there.

Ann: Well, we did.

Christina: Did you draw that horse? Because it's a really good horse. I didn't know you had that skill and talent, Dr. Trucco.

Dr. Trucco: Yes. I surprise people all the time.

Ann: Okay. So, Mia has a reference for you, a movie reference. I had a different one. Mia, you go after me, but I was thinking, Italian Doctor Matteo Trucco knows about horseheads, which is just a terrible reference, please, Mia, save us from ourselves over here.

Mia: My favorite Canadian once said about a certain politician that him being in office is like, "There's a horse loose in a hospital. It's never happened before."

Ann: Oh my gosh. We're giving you lots of references for the next time somebody asks you about the horse behind you.

Dr. Trucco: Thank you. I've been meaning to update it, but it's just there.

Ann: Should we go? I don't know. We're going to update it too. Where can you go from a horse? You've hit the pinnacle there. Okay, we better wrap it up because, as usual, Dr. Trucco has been very generous with his time. So, thank you so much, Dr. Trucco. And for everybody, more information on these OsteoBites and all OsteoBites can be found on YouTube, mibagents.org, social media, or your podcast place. If you registered for this OsteoBite session, you'll be emailed the final version of this OsteoBite as well as any links discussed. So, hang on for that, it should be in your inbox tomorrow.

Next week, we will be talking with Dr. Michelle Ghert of McMaster University and Juravinski Cancer Center in Ontario. She's going to be speaking with us about the prophylactic antibiotic regimens in tumor surgery. I have questions for her. If you have questions, I hope you join us, too. That's going to be a really great conversation.

Until then, thank you again, Dr. Trucco, for so many things, for so many things. Thank you. Thank you, Dr. Trucco, including today, and thank you to our panelists, Mia, Vicky, Camille, and, of course, Christina Ip-Toma, our Director of Scientific Programs. And thanks to our sponsor, BTG Specialty Pharmaceutical. Thank you all for joining us today. And please go outbid osteosarcoma today. We need to kick this beast. So, let's have some fun doing it. All right. We'll see you next week, everybody.


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