Treatment Failed? Here's What to Do Next.

Drug resistance, treatment failure, supplements & Q&A with Cancer Drug Designer Dr. Chaplin. #Chemotherapy #cancertreatment #cancerdoctor

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Episode Description:

When your oncologist says the treatment isn't working — do you know what they actually mean?

Because it's not one thing.

And which category you're in changes everything about what comes next.

In our latest live, Dr. Chaplin broke it down:

• Why "stable" cancer can get you dropped by insurance
• The cell mechanism that quietly makes chemo less effective over time
• What to ask before your oncologist switches you to a new drug
• Which supplements interact with this — and how they cut both ways
• The one switch that almost never makes sense (but happens all the time)

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Inquiries: 

info@elevatingcancertreatment.com

https://elevatingcancertreatment.com

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Disclaimer:
The information provided in this podcast is for educational and informational purposes only, and does not constitute medical advice. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have heard or read in this podcast or on this channel.
Reliance on any information provided by Dr. Jay Chaplin or Elevating Cancer Treatment is solely at your own risk. Dr. Jay Chaplin is a scientist and drug developer, not a medical doctor providing patient care. The content presented here reflects general scientific understanding and research, and may not be applicable to your individual health circumstances. Individual medical conditions and treatments vary, and no two situations are exactly alike.
Always consult with your personal healthcare provider before making any decisions about your health or treatment plan.

Transcript

SPEAKER_00 0:00

Hello everyone. Welcome to yet another live. This time we're talking about when treatment fails and what to do next. We'll take a step back and discuss that in just a moment. A few pieces of foundational work before we get started. Again, as almost all of you know, I'm Jay Chaplin. I'm a PhD, not an MD. This is not medical advice. This is medical education. Please discuss these things with your oncologist. So I'm here to answer questions and talk about how we develop resistance to drugs, what resistance means, because often that's poorly defined, what we can do about it. There will be ads periodically throughout this. We don't control when those ads show up or what they will be. So please roll with us through that. My lovely wife and admin goddess and IT guru Pauline is moderating and will be putting things into the comments as we mention them and has pinned the comment for how to get in touch with us if you want to have a meeting. You do, as always, need to be a subscriber in order to comment. So if you're trying to comment and you can't, that's why. In addition, uh we cannot pin it. We can only pin one thing, and that's the contact piece. There is also a free resource, 10 Things to Elevate Your Chemo Journey that's on our website. Uh that can be posted here, and Pauline, if you would post that, that would be great, but it won't be pinned to the top. Um so a few a few things. Um if you have topics for future lives, we've got the next few lives uh set up and we have topics for those. If there are particular topics that you want to see us address in a live meeting, please let us know. We we always try to start with a topic, it generally devolves into answering particular specific questions after a little while, but we'd like to start with a topic. If you have one, please suggest that. Um June 15th. That will be how to make immunotherapy work better for you, supplements, biomarkers, and what your oncologist skips. On July 6th, we will do how to tell what's real and what's not, uh, the science explained behind ivermectin, fenbendazole, and the biggest cancer myths. How to be able to look at what's out there and get a sense for yourself whether it's true and relevant and whether it's worth your time and energy. Uh, we could go on, we've got ones scheduled out on July 20th and August 3rd, but those are somewhat in flux. Um and thank you, Seamus, for leading us off with uh the news. Um the news that's not news. Revolution Medicine is getting massive standing ovations at ASCO right now. ASCO is a premier conference for oncology research, and Revolution Medicine's drug, Diraxon Rasib, that we did an episode about a little while ago, is getting massive notice, as it should. It's a fantastic drug and a fantastic step forward, not just for pancreatic cancer, where it really shines, but it really ought to be a game changer for roughly about 25% of all cancers once it finally gets approved that broadly. Because the pathway that it impacts is core to growth of cells, and it's one of the most commonly hyperactivated pathways in cancer. So this should be a drug that will be of massive benefit to nearly a quarter of all cancer cases. So hang on, this may be something for you, even if it doesn't seem like it right up front. And again, going through and looking at genomics reports, looking at what's mutated, what's hyperactivated, what's upregulated is something that we excel at and can provide some complementary information to educate your oncologist about. You don't have to have a RAS pathway activation or mutation in order to have hyperactivity and benefit from this drug, Diraxon RACIB. Now, Diraxon RAC leads directly into tonight's discussion because while Diraxon RACIB is a spectacular drug, it has fewer side effects than standard of ker chemotherapy, and it's massively more successful, 60 plus percent more successful than standard of care chemotherapy. It does still have a problem with resistance. Even some of the people who are currently in the clinical trials are developing resistance to it and needing to move on to something else, or as we'll talk about tonight, find other approaches for that. So with that, I'd actually like to take a step back. I have been, boy, it's only been five minutes. It feels like half an hour already. I have been talking and I'd love to get some feedback from you. When when you think about drug resistance and needing to switch from one drug regimen to another, one chemo regimen to another, something like that. What do you think about? And the reason I ask this, I'll sort of jump the gun a bit. The reason I ask this is there are multiple things that can cause treatment failure. Treatment failure can occur because of intolerably severe side effects. Treatment failure can occur because the treatment is controlling the cancer, but you're not making any progress, and everything remains the same for a long period of time, and eventually your insurance kicks you off for treatment failure because it's not doing anything more than just containing the cancer? Or treatment failure can occur when the cancer starts to progress and you actually get growth of tumors or increases in biomarkers while you're on treatment. So for those of you who have had to deal with this, which one of those did you think we were talking about tonight and which ones are the most interesting to you? Please put something down in the in the comments. While you're doing that, and I haven't seen anything yet, um while that's occurring, again, those are sort of the the general yeah, multiple immune-related adverse events is definitely a failure. Um again, that's that's essentially in that first bucket of intolerable side effects. So when we think about treatment failure, in most cases, your oncologist will talk about that in the sense of progression while under treatment. So the drugs are not containing the cancer anymore. But again, there are multiple different categories here, and those do need to be treated differently. Um I I see you and hear you loud and clear, loud streams. It it everything is a cost-to-benefit analysis for insurance. And for instance, being on uh an expensive drug like in Hair2 for years and years and years, when it's just keeping things contained, often people will get kicked off after a period of time because that is that is not improvement. That is just containment. And if you're going to get just containment, they would prefer you to be on a cheaper therapy. That's that's the nature of the medical care system that we're under here in the United States. Good insurance won't do that, but most insurance will do that. Um just something to be aware of. So again, taking that step back with intolerable side effects, whether that's from classic chemotherapy, let's say a platin drug causing neuropathy, or um immune-related adverse events from an immune checkpoint inhibitor like ketruda or opdevo or uruvoi? The the name of the game there is mitigating the side effects, because if the drugs are containing the cancer and you can find a way to reduce those adverse events, then you can maintain use of that drug and go back on it. The question is, are those adverse events truly severe enough that they can't be mitigated downward to a point where they are tolerable? Or do you really need to switch to something else? And that is that is a bigger deal with the immunotherapies. When immunotherapies really go sideways, not a rash, not some GI effects, but severe immune-related adverse events, then you pretty much have to stop. You have to do something else because once your immune system is primed, it retains memory. But for classical chemotherapy, a lot of times if it's intolerable side effects, you can pause for a bit and put into place other approaches to mitigate those side effects. We've talked about a number of them. Um apigenin, which is something that will come up multiple times tonight for multiple different reasons. That can be useful for mitigating side effects of multiple chemotherapy drugs, the platin class, um, doxorubicin, etc., um, also 5 fluoro uracil and the prodrug cape cytabine, it's very useful there. Um, glutamine for offsetting GI effects. For immune-related adverse events, you can help prevent them when restarting therapy by taking high-dose vitamin D3 andor curcumin or resveratrol in high doses. Those are all mildly immunosuppressive. You take those right around the dosing window to mitigate the side effects. A lot of times you can actually restart an immunotherapy with mild to moderate immune-related adverse events and have a good second round through that. Um does that make sense? So there's that. Um first line came has not failed yet. Fulferoenox, then full fury. But if it fails, it would be worrisome. Pancreatic cancer, I I hear you there. And uh so pancreatic cancer with K Ras G12C. We already have drugs for KRAS G12C. Um, so I would I would look toward those with Diraxon Rasib in the background, but we'll come back to that. Um for the for the lack of benefit category, or what insurance would call lack of benefit, when when your therapy is keeping the cancer in check, but you're not getting improvement, that often comes down to a condition that most oncologists don't really grasp or or discuss appropriately. That is not a case where the cancer has evolved around the therapy and is no longer touched by the therapy. For instance, um, with breast cancer, if you are taking an aromatase inhibitor to squash down estrogen levels, and your estrogen receptor mutates and develops the one of the always-on mutations, it will signal all day and signal growth to your cancer, regardless of whether there is estrogen there. A cancer with that feature will grow and grow and grow at its maximum rate, even without estrogen, and that is a complete treatment failure, not a it is being contained. What is happening in most of the situations where a cancer is being contained by therapy, but no longer getting better, is that the cancer is not truly resistant to the drug treatment. But what's happened is the cancer has gotten better at expelling the drug and not taking up a toxic concentration of it or a concentration of it that is fully effective. There are multiple transporter proteins that essentially are designed evolutionarily to pick up stuff that is weird and doesn't really belong here and pump it back out of the cell. And that works on all sorts of things. That works on uh Advil or Tylenol that you take for your headache, that works with excess vitamins, that works with chemotherapy drugs. And so when you have a situation where your cancer is still being contained by a chemotherapeutic or a targeted therapy, but not getting better, it's not resistant per se, but it's no longer fully sensitive either. And that's that's because of these drug, excuse me, drug efflux pumps. The biggest one of them is something called PGP, that's a capital P hyphen lowercase GP, PGP, P glycoprotein. And this is a common drug transporting protein. It's on the membrane of every cell in your body. Some have more than others, every cell in your body, and again, it pumps out foreign stuff or things that are overrepresented. If there's too much inside of a cell, it will also kick it out in order to try and maintain balance and homeostasis. It's also what makes up the blood-brain barrier. We think of the blood-brain barrier as something static, like a filter that only lets certain things through. That's not what's happening. What's happening is things get out of the bloodstream, they go into your brain, they go through this layer of cells that have very high concentrations of PGP. Anything that doesn't belong gets pumped back into your bloodstream, away from the brain, back into your bloodstream. So PGP is active all over the body. It turns out that if you are in this case, there are drugs and also over-the-counter materials that can bind to PGP and either shut it down temporarily or compete for binding with PGP and sort of block it, like a revolving door. Um, Pauline and I were just up in Boston over the weekend, and you know, a revolving door can only take so much. If there's a crush of people trying to get in there, it will back up because there's only so many people who will fit into one compartment of a revolving door. And if you take something that is bound by PGP and pumped out by PGP, that will take up space and lead to an accumulation of chemotherapy inside of your cancer cells, which will make them more sensitive. You can use this to re-sitize cancers that are still responding but not improving under treatment. So, in terms, and we should talk about the side effects of that, because there are side effects of that. Um, viropamil will do that. That is a prescription drug. Your oncologist should know about that, but might not know about that. That is known to block PGP and can resensitize tumors to drugs that are still working but not working optimally. And you can also do things. So a number of over-the-counter compounds, uh, nutritional supplements also bind PGP and will compete for those spaces. So high doses of the vitamin-like substance, coenzyme Q10, will bind and partially block PGP. That is useful. Very high doses of curcumin will do that, very high doses of apigenin will do that, very high doses of resveratrol will all do that. The downside of all of these is that while they will make your chemotherapy more potent and may tip the balance toward actually causing improvement with the with the drugs that currently are just containing things and keeping them level, it may make them more potent. They will also make you more sensitive throughout your entire body. Your side effect profile will go up. It will exacerbate any and all drugs that get pumped out through that PGP system. So again, if you are taking large amounts of coenzyme Q10 or large amounts of curcumin or resveratrol, if you're taking Tylenol, you may have to adjust how often you take it or how much you take it. With your chemotherapy, it will make it more potent, but you will feel the side effects more. Okay. So that's that static piece. What about when the cancer has developed resistance and it's starting to rapidly progress again? There are actually ways to re-sensitize for several different chemotherapy drugs and targeted kinase inhibitors, that kind of thing. And again, there's a name here that keeps coming up, and I do want to acknowledge it, and it's one of the reasons why I talk about it so often. Umstreams. Um, I will come back to that time after time again. Apigenin is a compound that is useful for preventing side effects. So that first category, preventing intolerable side effects, it's good for blocking PGP and increasing the potency of the doses that you have. And because apigenin blocks several key growth pathways within cancer cells, it can actually resensitize cancers that have developed classical resistance and make them sensitive to the chemotherapy again. So, again, this is not everything is holding steady. This is your cancer has developed resistance and is starting to grow. Apigenin can shut down certain cell pathways for a number of different compounds, for ariniticin, for five fluoruricil, cape cytobean, uh doxorubicin. Resistance to any and all of those has been shown to be reversible in many cases with apigenin. Um and there are there are several other compounds that fit into that category. Um lab streams the adjusting chemo doses is an interesting topic in and of itself because traditional chemotherapy is really given at maximum tolerated doses in general, and then it is stepped down on the basis of side effects. Rarely do they go back up because the the general clinical concept is once you have had a bad side effect, you will still be sensitive to that. But but there is often little discussion about ways to mitigate those side effects and be able to bring those doses back up again. You don't really go above the maximum tolerated dose because those are those are circumstances under which you can cause permanent lifelong damage. So they they try and avoid that. But again, adjusting chemotherapy is usually down and very rarely up, almost never up. And again, that that is an entirely different discussion because many oncology drugs are dosed at maximum tolerated dose. There are a number of drugs, CDK46 inhibitors, others that I can think of that kinase inhibitors that are dosed at say level X, and then they have a step down where you reduce the dose by a quarter or a third, and then they'll have another step down if you're still having side effects and you'll go down another quarter or another third. Let's say it's a third step. So on that second step down, you are now taking one-third of the drug that you began with. There, there's an example I'm thinking of, and I've talked about it with some clients, for a particular drug, that one-third dose has essentially exactly the same clinical benefit. It has the exact same efficacy at preventing cancer recurrence as the maximum tolerated dose. But because it's one-third of the dose, it has dramatically fewer side effects. So, so again, the dosing conversation tends to be unidirectional, always down, and it tends to start high, unreasonably high in many cases, to provide that ability to step down. But in many cases, you could start at a lower level and get the full benefit and reduce the chances of having. Having intolerable side effects at the beginning. So these are again some of the things that we talk with clients about, making sure that the doses are optimal for you, not just following the NCCN guidelines or exactly what the what the prescription standard is, but what does the clinical data say where you should go? There's a lot to discuss here. Tammy, if you do the fasting regimen before and after infusion, will that lessen the increase of chemotherapy side effects? So fasting immediately before and during infusions generally does help with side effects for most types of classical chemotherapy drugs. It doesn't really help for kinase inhibitors, but again, most of those are pills. The classical chemotherapy drugs that do direct damage to both healthy cells and cancer cells, your uh DNA damaging compounds like five flora uracil or temazolamide or phosamide, your microtubule inhibitors like uh taxol, etc. All of those. Fasting definitely helps with those. Fasting does not really help with kinase inhibitors. It helps a little bit with the immunotherapies, but not really nearly as much as again taking some mild, short-lived immunosuppressants like high-dose vitamin D or curcumin or resveratrol right at infusion. But yes, fasting can really help. I would not fast for extended periods of time. Um, I would try and have a very protein-heavy diet. Uh, many cancers, not all, prostate cancer is one example. There are a few others. There are a few cancers that are not very glucose intensive, but most cancers are glucose intensive. If you can keep blood sugar low, either through fasting or dietary control, or if you're diabetic with metformin, etc., that can be helpful. It won't starve cancer, but it will slow down the growth. Those are definitely useful, and it does, around infusion time, slow down the growth and activity of most of your normal healthy cells, which will partially protect them from damage from the chemo as well. Um, how long to take apigenin? So, so apigenin, again, is one of those things that I come back to because I keep finding it has clinical benefit in multiple different formats. Apigenin, if you're taking it specifically for the effect of blocking side effects or potentiating chemotherapy drugs, really what you're looking for is taking that, again, that sort of like the fasting, the day before the infusion, the day of the infusion, and perhaps a day or two after. You don't have to take it continuously. Now, if you're taking apigenin andor low-dose aspirin, for the immunomodulatory effect to try and increase immune function, particularly in combination with immune checkpoint inhibitors like ketruda and optivo, for that you really do want to be taking it consistently because those drugs are in your system consistently. But most of the chemotherapy drugs given by infusion have a very, very short half-life. They are they're in your system for 12 to 48 hours from the time of infusion and then they're gone. Okay. So I know that there will probably be more questions. I will try and get to them. Um, and I'll talk about the neutropenia there. Um, I do want to say one other thing about this issue with resistance, because we we've sort of talked about how to deal with resistance, how to reverse it. What do you do if you can't reverse it? And and I can't believe I have to say this, but I've I've talked with multiple clients who have been in this position, and frankly, it makes absolutely no sense. If you have actual treatment resistance, if let's say you're on dosataxal, which is a form of taxol, if you're on doseataxil and your cancer has become resistant, it's continuing to grow, you've tried a few things, it's not working, your cancer is growing, it's clearly coming back, and your doctor switches you to a braxane. Ask them why. Seriously, ask them why or find another doctor. Because why? A braxane is a different form of taxol. It's the same drug with a different delivery system. If you have become resistant to dose of taxol, that is taxol with one delivery system. And your oncologist as a solution puts you on the same drug, taxol, in a different delivery system. That's not going to be any better. It's the same drug delivered in a different way. That is not a solution. And yet, that is something that I fairly frequently hear from clients and from people that I'm on calls with, that oncologists will substitute either the exact same drug with a different delivery mechanism, or very, very, very similar drugs. For instance, all of these drugs come in classes. If you truly have a resistance against a drug in a class, please don't let your oncologist switch you to something that is very similar and in the same class. If you have a resistance to taxol, it's not a guarantee, but it's fairly likely that you will also not respond very well to vincristine or venblastine or any of the other microtubule inhibitors. You might be sensitive, but you probably won't. And if you are resistant to vincristine, you're going to be resistant to vinblastine. It is a sister molecule, just the way that dosataxol and abraxane are essentially the exact same thing. Please don't let your doctor give you, because a resistance to A gives you a different form of A. It makes no sense. Switch to something different. Now, now where that begins to fall apart is many of the targeted drugs. If you're talking about, say, uh tyrosine kinase inhibitors, those can be very, very different from one to another. They can have very different mechanisms. So don't get hung up on that. But in terms of the classic chemotherapy drugs, if you're resistant to five-fluor uracil, giving you capecidabine, which is a pro drug that turns into five-fluorauracil in your system won't do you any good. If you're resistant to five-fluorauracil, taking something that becomes five-fluorous, you're just getting more of what you're already resistant to. And yet again, that that is something that we see frequently. If you truly have resistance, move to a different class. Move to an entirely different class of drugs if you can. Even if it's a temporary thing, give your cancer some time to readjust. Cancers are continually mutating, they're continually changing, they're continually adapting. In many cases, they are upregulating or downregulating genes on little snippets of circular DNA called extra chromosomal DNA. Even if you can take a break for two to three months and then switch back to a drug, you may find that a large chunk of that resistance has gone away and you can get a treatment bump from it. But but don't let your oncologist just move you to more of the same thing. All right. Umutropenia is one of those things that that falls into that first bucket of intolerable side effects. If you have very, very, very low neutrophil counts, that is it's a dangerous zone. It is easier to prevent that than it is to fix that. And it, even though it's one of the things that comes back the fastest, that is a lagging indicator. What you do today will have an effect a week from now. Um, it depends on what your chemotherapy is, there are generally very good ways to prevent that up front. Um, we should talk about that and and see if there are ways for your particular chemotherapy to help with that. Again, the names that come to mind for for most traditional chemotherapy approaches are the apigenin and glutamine, but it depends quite a bit on exactly what drugs you're taking and how they interface with each other. Um, right there. Phase one, carboplatin, and paclataxyl with ketruda. So the ketruda is going to be bringing up your lymphocyte counts, but it's not going to do anything for the neutrophil counts. And taking ketruda with carboplatin, paclataxyl is kind of dangerous. You have holy moly, and then doxorubicin and cytoxin, which is um doxirubicin, adriomycin, they're the same thing. Uh, those are what they call the red devil. That's a that's an anthracycline, and it's very, very potent. And then following that with cyclophosphamide, which is activated by the liver. Um that that's pretty intense. You've got a lot of stuff going on, Tammy. We should talk about that offline. Def definitely click on that link, the pinned link at the top, and set up a free consult meeting so we can discuss that because we we want to make sure to map all of that well. Um Judith stepped up the monoclonal antibody. Mm, okay. Six months' time, and that was okay. If you're on any of the immunotherapies, they tend to be very, very, very similar. And we we should talk about it again, that that would probably be offline, but the vast majority of the immunotherapies, with with the exception of Urvoy and Relatlamab and Bispecifics, essentially all of the others are PD1, PDL ones, and those tend to carry um cross-relationships of immune priming problems. If you've overprimed your immune system and you're getting immune-related adverse events with ketruda, you'll also get it with Opdevo, you'll also get it with all the PDL1 blockers to some extent or another. Again, it it's more an issue of not so much switching from one immune checkpoint inhibitor to another. It's more a matter of taking a break, possibly having a steroid taper to calm everything down, and then once you reintroduce, reintroducing carefully, slowly, and adding in on the days of infusion and for a couple of days afterwards, mild, short-lived immunosuppressants to again dampen down the side effects. The side effects that you get from most immunotherapies tend to be triggered on the day of infusion or the day after, when the drug concentration in the serum is by far the highest, but they don't show up for days to weeks afterward. But if you can block that day to two days right around the infusion window, you can usually prevent most of the truly bad immune-related adverse events. Um glofinimab is a bi-specific, and so that that does fall into a different sort of category. The the reason that you would do a step up with Glofidimab is is for potency reasons. As long as you're not getting cytokine release syndrome, you can step up with that, and they will always start you low to try and make sure that you don't have cytokine release syndrome. Cytokine release syndrome used to be something that was hard to reverse. It was hard to reverse it quickly enough to keep patients safe. And so they would start low and move high. That's that has not been the case for the past five years or so, but it's it's still something that is in the clinical space. Um, that's not what you get with traditional chemo or with immune checkpoint inhibitors, those tend to go down rather than up. The by-specifics, CARTs, they tend to go low and then come up. It's a slightly different scenario. Um stable, no shrinkage on CT with contrast after three months mean ketruda linvima failure. It doesn't necessarily mean that it's a ketruda linvima failure, but again, if that persists for a long period of time, insurance is likely to start categorizing it as such. I would start looking at things that you can do again to tip the balance in favor of efficacy. I know that I know that we've been talking about some of those, but we should discuss particulars that fit your specific situation. Um with Ketruda, the the Ketruda Lenvima combination is particularly good. There's a nice synergy there, they work together very well. Uh, the linvima does tend to modify the space around the tumor, the tumor microenvironment, and make quietruda more effective. Um so that is an excellent combination, but you can bump up the efficacy there. Um, I would have to take a look at that variant of RCC and see whether it would make the most sense to go with a CD8 positive or or killer T cell route or a natural killer cell route. There's two different approaches to work with there, but I would look at increasing the efficacy of the ketrudic component of that as long as the side effects, again, remain tolerable. We we don't want to be pushing on the immunotherapy aspect if you still have persistent immune-related adverse events, and I know that that's been an issue. Um glutamine I hope that helped. Uh glutamine taken before and after aren't infusion, or do you suggest long-term use? So you you've got a couple of things tied together there. Um sorry, I'm just now remembering something my lovely wife said after the last live. I should be repeating the questions. I haven't been doing that. All right, so the question: should glutamine be taken a day before and after arena T can infusion, or do you suggest long-term use? So, so again, this goes back to mitigating intolerable side effects and one of the categories of um the resistance and having to change drugs. So, glutamine is very useful for offsetting the side effects of many of the traditional chemotherapy drugs, particularly the ones used for colorectal cancer, bifluor, uracil, cape cytopine, uh oxaliplatin, all the platinum class drugs, um, arinat can in particular. So, so in terms of glutamine, there are multiple things that happen here. In general, even if you're not receiving chemotherapy, even if you're just in palliative land and just being made comfortable, glutamine has value. It it reduces wasting, it reduces muscle loss, it reduces uh some of the tissue dysregulation that uh tumors can cause. Glutamine is helpful in general just by itself. And so I would recommend a low dose of glutamine constantly, as long as it's the taste doesn't bother you. Some people find glutamine to be bitter and unpalatable. I'm I'm very sorry if that's the case. There is clear clinical benefit. If you can take 10 grams a day, that is a great thing on an ongoing basis. 10 grams is not really enough to offset full fox or full fury or any of those types of things. And Arinateacan is very harsh on the GI system and is helped quite a bit by glutamine. If you're taking full fox or fulfillory or KOX, anything like that, it's very helpful to take higher doses of glutamine the day before your infusions, the day of your infusion, and the day after your infusion. And for those we're looking at more like 30 to 40 grams of glutamine, it's a much higher dose to help offset that. Because the, again, I've said this before, and apologies for the disturbing visual, um, the nausea, the diarrhea, the cramping, all of that that people experience with those regimens, full fox, full fury, k-pox, etc., are due to essentially losing the entire lining of your intestines and having your intestines be an open sore. So of course you will feel nauseous, of course, you will want to vomit, of course, there will be diarrhea when your intestines are an open sore and needing to heal. That is very, very rough on the body. Glutamine helps both prevent that damage and also speeds the healing of it. And so it reduces the duration of those effects and it reduces the intensity of those effects, but only if you have very large doses. So again, I would look at 10 grams daily to offset wasting and to provide resources for your body to fight back against the cancer, and higher doses of 30 to 40 grams right around the infusion to hit that. Does that answer your question? And and I apologize for being um less than utterly clear on on some of these questions. Uh again, we start to get into uh details that require knowing the entirety of the scope, and and it's it's hard to come back with a quick, simple, broad answer for people when when it's about interaction of drugs. Um does Nacetylcysteine help produce glutamine? So so there's uh there's a confusion there. So glutamine, just by itself, glutamine is an amino acid. You're probably thinking of glutathione. Glutathione is a three-amino acid mini protein made from cysteine, which is the component of Nacetylcysteine. N-acetylcysteine is just a more bioavailable form of cysteine. You you can take cysteine, you can take Nacetylcysteine, they're all absorbed. Um, so that's used in making glutathione, but it's not used in making glutamine. So glutamine is also one of the components of glutathione, and and glutathione is useful in general for maintaining redox balance and and keeping the inside of cells with the environment that they like to be in, a healthy environment. But excess glutathione can also. Actually, counteract certain types of chemotherapy. Just the way that with platinum class drugs, you would not want to take high doses of antioxidants, vitamin C, vitamin A, vitamin E. You also don't want to take large amounts of glutathione or anything that produces lots of glutathione. So I would not take glutathione during full fox or full fury. I would take glutamine because your body uses it for many things, but I would not take excess Nacetylcysteine or cysteine or directly glutathione. You can buy glutathione supplements. It's not something I would take during that time. I hope that helps. We are 45 minutes into the hour-long live. I am shocked that time is flying like this. Um have these things been helpful? Have these discussions been useful to you? And did the overall piece about the different types of drug resistance, how drug resistance is viewed and seen both by doctors and insurance companies, has that been useful? And have you gotten some tools to deal with that? Um, apigenin doesn't help the efficacy of an ADC. Ah. So apigenin can help with certain kinds of ADCs. So the T can class is benefited from apigenin. Um, because of some of the pathways that apigenin shuts down, it will make cancer cells more sensitive to everything in the T can class. That includes a rhinotcan in fulfillory. It also includes extacan and many of the payloads, uh the monomethyl orostatins uh and the manicides, all of those compounds that mess with how DNA is folded and maintained in cells, and those are usually the payloads on most of the ADCs. So your ADCs, just like arinetic in, will benefit from having apogenin. And by the way, I I know that this is a bit of a side conversation. We recently did an episode about timing of these drugs. Timing makes a difference, timing makes a difference in side effects, it makes a difference in potency, and that's another way that you can deal with having sort of a constant. You can adjust the timing potentially to get more potency and potentially drive the cancer down. Umrina TCAN and all of the TCAN class drugs, so virtually all of the ADCs, are best dosed in the late afternoon, early evening, four o'clock and later ideally, and as close to as close as you can get to that window if you can't get to four o'clock. So try and take apigenin with those and dose them later in the day. Your five-fluor uracils, your alkylating agents, your direct DNA damaging agents, um, temazolamide, iphossamide, five-fluor uracil, cape citabine, those are all early morning agents. All right. Um CP, modified citrus pectin, stay in the body? So so pectisol doesn't really get out of the intestinal tract very well. It stays in the intestines for the most part. And whatever does get into the bloodstream, because it's very small, broken down monomers of the modified citrus pectin, those get cleared very quickly. So pectisol, it does bind galactin 9, and it does have some efficacy, particularly for colorectal cancers, at preventing metastases and preventing regrowth. The amounts necessary to provide that benefit are very, very large. If you go back and look at the clinical studies, they're much higher than most people take. Um, the levels of pectisol that you need to have are 15 grams per dose, a minimum of three doses per day. That's 45 grams of pectisol per day for a relatively modest inhibition of metastases. It is it is real data, it really does help, but that 45 grams a day buys you somewhere around a 9% decrease in in metastases. So useful, but that's a literally a lot to swallow. So think about that. There are often other supplements, other off-label drugs, other approaches, pharmaceutical or or nutraceutical, that have just as much efficacy benefit and are less expensive and easier to tolerate. Um thank you. I'm glad that the discussion on supplements has been helpful. Um Carl? Yep. Awesome. Um 30 grams of pectasol a day. So so you're close. You're two-thirds of the way there. If you can bump it up from 30 to 45, you are at the bottom of the range for clinically proven benefit. Yep. Um, anything that helps or hinders vitamin K2? And is there an optimum way to take K2? Um, powder tablets be open and dissolved in vegetable or fish oil. So I'm assuming that we're talking about the very high-dose vitamin K2 approach that was in one of the episodes recently. Um, so again, this question is about how to take the vitamin K2 and is there an optimum way? So there's a little bit of confusion there. The vitamin K2, vitamin K2 is said to have a very short half-life in the body, and that's not quite true. Vitamin K2 has a very short half-life in the serum, in the bloodstream, but it doesn't stay there for long. It actually is very fatty, it likes to be dissolved in fat, it gets absorbed and redistributed through fat globules throughout your body very quickly. And so it gets cleared out of your bloodstream very quickly and builds up in cells, it builds up in the membranes, the outer membranes and then mitochondrial membranes, and then the inner mitochondrial membrane. And that's where it has the effect. And so with vitamin K2, if we are indeed talking about this very high megadose approach, which works very well for essentially all cancers except for brain cancers, glioblastoma, astrocytoma, um, and for gallbladder cancers for some reason. And it requires a higher dose for breast cancers, but that's still reachable. For vitamin K2, it helps to take it with some fat because that increases absorption, but the amounts are so huge they're going to get in one way or another. You need very large amounts. It really doesn't matter whether you're taking them spread out through the day or all at once, because it's not the dose in your bloodstream that matters. It's building up in your cells the level that it has to build up to that matters. So, so again, whether you spread those for a normal dose, it's three capsules per day. You can take them all at once, you can take them spread out, but you have to take it for a minimum of three days for it to build up enough in your body to have the effect. And three days is the minimum. The maximum is 14. After 14 days, you really do have to stop and take a break because you're running a risk of causing uh long-term impacts on mitochondrial function and producing persistent fatigue and persistent loss of energy, which is not something we want for you. So we we don't know where that boundary is, but we know that 14 days is clearly obviously safe and has a large margin of error. So we'd rather stay on that side than extend it. Some of the clinical trials went up to 90 days. And while no one reported those side effects of persistent fatigue, that also isn't something that they were measuring for. So I really don't want anyone to push it that far. Um, how many scans of no shrink means failure and switch? Uh, that so the question here is for your insurance company, how many scans in a row of stable cancer will it be before your insurance kicks you off? That depends quite a bit. It depends quite a bit on your particular insurance company, and it depends on whether there are any other treatment approaches that they would deem reasonable. If you are on a more expensive drug that is working for you but is holding you steady, and there is some cheaper option, I have seen insurance companies kick people off in as little as three scans with holding stable and no no further improvement. Um on the other hand, I I know of cases where people have gone for up to four years and the insurance companies haven't haven't kicked them off. Um but that tends to be more in the circumstance where there really isn't another accepted therapeutic approach. So that is the last chance, or last chance. There's often something else. Um but again, if if there is a cheaper option available, I've seen it as short as three scans. Well, three scans of no further improvement means four scans in a row with the exact same tumor size and distribution. Hopefully that makes sense. All right. We are, oh my gosh, we're six minutes from the end. So again, um thank you all for coming. I love having these, I love having your questions. I hope these are all useful. Our next live is on June 15th, how to make immunotherapy work better. And and and Rich and Deb, please come back and please let's also talk about immune-related adverse events because that's the other piece. We can talk all day about how to rev up your immune system and get more benefit out of immunotherapy, but the other piece is how to do it safely and not have immune-related adverse events at the same time. Um, so that's the next one, June 15th. Uh, then we're going to be gone for a little bit. We'll come back. Our next live after that is July 6th. How to tell what's real and what's not, how to evaluate the claims that you have out there because the internet is just awash with opinions and everything sounds good and everyone sounds confident. So, how do you tell what's real? How do you tell what's false? Um, I'm happy to weigh in on those conversations, but you can't always lean on me. So, so hopefully that will be a chance to train you a bit on how I think about things, what I look for to tell whether something is reasonable or not reasonable, and whether it's something really worth your time and energy and money. Okay. Um, and Galaxy Cat question coming in under the gun. Does the TXA2, that's thromboxane A2, does the TXA2 pathway only apply if one has PDL1? It does not. It does not. So the thromboxane A2 pathway suppresses T cell activity primarily. And so if your cancer can still be recognized and controlled by killer T cells, CD8 positive T cells, then using aspirin, low dose of aspirin, andor apigenin will be beneficial to you whether or not you have a high PDL1 concentration or not. So aspirin and apigenin can be useful even without using an immune checkpoint inhibitor. If you can use an immune checkpoint inhibitor, in addition to aspirin and apigenin, you will get more benefit out of it. Um there is that. So if your cancer isn't controlled well by killer T cells, but it is controlled by natural killer cells, then aspirin and apigenin make less sense. So I again, this is the kind of thing that we'll be talking about in a lot more depth next time because that's all about immunotherapies. Um Gemsar for six months, mixed results, want my brain back. I completely get that. Gemsar is one of those ones that causes a lot of brain fog. Any suggestions for other possible treatment? Um Hodgkin's lymphoma, lemolidamide, or everolemus. Um Diane, let's talk. Um, there are other things that you can do. There are things that you can do right now, non-pharmaceutical things that will definitely help you with that. So again, let's chat. Um yeah. So Rich's uh the comment here, thank you for all the great information. Rich's treatment has no protocol from NCIS, which kind of helps and keeps all treatment open open when there's no official protocol. That also means that your oncologist really doesn't know what to do and is kind of kind of throwing spaghetti at the wall. Um so it it makes it harder to rationally combine things. So it lets let's explore that some more. Um Carl, thank you. Much appreciated. Um Judith, excellent. Uh anything else? Um I know we're down to the last minute. Um, I try and fit in as much as possible. Anything else in the last last couple of moments? I if not, I do hope you all come back for the next one on the 15th in two weeks from now. Um, immunotherapy is really my thing. I know we talk about chemo, I know we talk about drug interactions, I know we talk about drug stacking, but immunotherapy is really the space that I am most comfortable and happy in. And it is super complex, and I like to be able to explain that and simplify it and try and bring some sense to all of it because it is incredibly powerful when it's used properly, and most oncologists don't know how to use it properly. All right. Uh Galaxy Cat, how can I find out if I have PDL1? Uh, normal tissue is not okay. You do need the tumor. You do need the tumor, and it's not something that usually shows up on a genomics test. Generally, you need a tumor biopsy, and they need to stain for the protein because just because the gene is hyperactivated doesn't mean that you have the protein on the surface. And there's lots of other ways that it can be controlled. So you really need a biopsy sample stained for PDL1. Um, that's the 22C1 antibody staining. It's standard. Um, every every hospital either does that in-house or can send out for it. It's completely normal. I would get that. That's one of three things that you need in order to be. You don't need all three. It's one of three things. If you have any one of them, you are a candidate for immunotherapy. But we'll talk about that next week. Awesome. Thank you all very much. Love that you're coming, love that you're asking questions. I'll see you in two weeks. Thank you.