De-escalation in Cancer Care

Kevin Knopf, MD

Kevin Knopf: In my clinical job I'm the head of haematology oncology at Highland Hospital, which is a safety net hospital. This is a hospital that cares for patients who are uninsured or poorly insured, and I think a lot of my ideas about de-escalation come from my daily work either here or in other settings.

So these are my conflicts of interest. These are actually both startups that are involved in de-escalation of cancer care and I may address Cadex genomics, which is very interesting, during the discussion.

This is a quote that I think embodies de-escalation, not just in cancer care. But in all areas of medicine, which is, we always say less is more, as our mantra and this was just a song that came on the radio as I was driving in the other day. 

We've had an evolution of nomenclature, certainly, since I've been trained in oncology in the twentieth century we talked about patterns and quality of care and evidence-based medicine, and I originally started studying cost-effectiveness at a branch at the NCI with the health economist, then in the  21st century we developed new names. Value based cancer care, which is just applying cost effectiveness to cancer care and our parent organization, oncology talked about the choosing wisely campaign as a subset of all internal medicine. De-escalation is a term, I think I heard after that, and then financial toxicity is a term that was coined by an oncologist at Duke about 5 years ago to describe the side effects of treatment that affect patients financially.

This is a definition of de-escalation. It's my working definition, which is the idea of eliminating treatment above and beyond that which is most useful to the cancer patients. So in medicine in general, we tend in America to do too much to do. Too many tests to do too many things to the patient that may not help them so de-escalation to me means returning to the level of treatment which is optimal for them without excess, treatment or toxicity to maximize the time without symptoms or toxicity and there's a metric for quality of life that we know about, Q-Twist, which I don't see used very often, but I think really embodies that, and I keep that in my mind when I'm thinking about things clinically, and I think that that de-escalation is a return to normalcy, that things should not be escalated and that we should strive to get back to what's proper for the patients next. There are 2 things that we are taught. We can do as physicians and caregivers for patients. One is to make them live longer, and 2 is to make them feel better. So these are sort of our mental goals. When we're seeing a patient in clinic and thinking about what to do. Things that are beyond this may not actually achieve one of these 2 goals, and that may be friction in the medical system, for the patients, things that don't really help them.

There are 2 main reasons for de-escalation in cancer care. The first is basically the principle of medicine that we all try and follow, which is to first do no harm, and that we want to focus on the patient who is in front of us at clinic, or in the hospital and treat them in an optimal way which is not to treat them with tests or medicines that don't help them or that hurt them. There's a second larger reason which is related to public health, that of distributive social justice and health equity focusing on all patients If you think about the whole country, and that's where my interest in health economics, I think, plays out

De-escalation is important for many reasons. Most important reason, I think, is, it's in the patient’s best interest to have optimal care. To have as precise a care as possible and we talk about precision medicine. But one definition of that is treating the patient with only things that help them at minimizing toxicity and side effects. We want to avoid unnecessary toxic treatments, and one of the principles we think about when treating patients is that we'd want to be treating the patients as if we were the victims ourselves, and we wouldn't want extra things done that didn't really help us. Much of clinical oncology, like other medicine, is about trade-offs between true advocacy and things that are helpful and true toxicity, and we try and maximize and optimize that ratio.

Medical care takes time from patients that often can take hours spent waiting for tests or appointments. A PET scan takes probably a half a day for a patient, and I had a good friend who went through treatment for cancer, who would spend basically a day at a centre to have a scan and see a physician for 15 minutes. This is particularly important when patients have limited time left that we do not spend too much time on things that don't help. Unnecessary care can come with risk and adverse events. The iatrogenic events and things that hurt the patient, and then the patient's own toxicity, financial toxicity, which was coined by a physician at Duke, Aaron Mitchell wrote a nice essay that we should be treating that with Curative intent, which is quite a bold statement, this is what patients pay out of pocket for their medical care and medical debt has become a huge problem in the United States.

Health care frequently escalates, probably the first thing that happens to most patients when they wake up in the hospital is somebody wakes them up at 5am and draws a CBC and a conference of metabolic panel. I've been a patient myself over the past decade about  30 days in the hospital, and when they do this for me, and they come in at 5am, I chase them away, and I don't think patients know that they can refuse tests. But I don't think these tests are helpful for me, so I tell them to go away, and there's a little bit of friction. When we order these tests, we're waking up patients who are having trouble sleeping. And with the Cbc and the Cmp we can have a cascade of unnecessary tests down the road. The costs, for these tests are about $1000 a day or more. So when I teach residents, I try and instil this in them but this is really a tyrannical situation. I think it's most hospitals will do this on most patients most of the time. So we're starting off the day behind the  ball in terms of de-escalation.

If economics is the dismal science, then I like to say that health economics is the most dismal science in America, and also that is a zero-sum game, that if we spend money, for example, on daily labs that we didn't need we don't have that money for prenatal care for another patient where the money might go to a higher return on investment in improving health care.

This is a graph that a lot of American physicians show, because it doesn't show us in a very good light. We seem to be spending more and more money per patient each year, but our benefits are not accruing. Part of that is that 90% of health care is actually due to the social determinants of health rather than the 10% that we do as clinicians. But another part of it is the economic inefficiency of our health care system in the United States compared to other countries.

These are some elements of financial toxicity that have been published in many articles and talked about at many conferences in the past couple of years. It's interesting that in the US more than half of the dollar is diverted for profit, so things that don't really help the patient. We're already working at less than half efficiency there. A recent study showed that a third of Medicare patients can't afford to fill their oral chemotherapy drugs. More than half of Californians actually get their insurance through public insurance. So, although the US Is very interested in the private market and managed competition, most insurance is actually public. 42% of newly diagnosed cancer patients go bankrupt within 2 years of diagnosis, which is a real financial toxicity and half of women who are battling metastatic breast cancer are being pursued by debt collectors. Our efficiency ranks is about number 50 in health care overall. Part of this may be economic friction.

Why do we escalate? I think this is the first and most important question. I think on oncologists tend to be optimist, and they want to believe that the next treatment they have will be the one that really helps the patient. We want to feel that the treatments we have at our armamentarium are effective and do a great job, and we feel like we can continue to help the patient. So it's natural optimism that on colleges have, we order a lot of tests because of a fear of missing something and if a test gives you more granular information, there's a fear that if you don't order that test you'll miss some important bit of information which may not actually matter clinically. And then this is just become the fashion. So if everybody around you is ordering a PET scan for a patient remission, you feel out of sorts if you don't do that, so you feel sort of a peer pressure to act as others, and it can affect referral patterns if you're in a situation where you're in a competition for patients and you're the one outlier who doesn't do things a certain way, it can affect your own financial livelihood next.

It's much harder to sit and talk to a patient about why you're not going to do something then to just do that. I've had conversations with patients about why we're not going to get a PET scan, and it takes a lot more time out of the day than it does to just click a button and order it. Time is a precious commodity for all physicians so not all of them will take the time to explain why treatment might not work, or why a scan isn't needed than it is to just try it. It's very hard to have the end of life conversations with patients emotionally. It's much easier to offer another line of therapy, and then we have some misaligned economic incentives in America.

This is a slide from an old video game called SIM Hospital. On the top are the 2 perspectives that that I was taught are the most important. The perspective of the patient in the perspective of society. But we have many elements in American health care that are involved in healthcare, including health tech and startups here in Silicon Valley, where I live nearby: physicians, medical groups, hospitals, pharmaceutical companies. If a patient is not having active treatment or having scans done, and you’re monitoring them, then you're not generating any revenue within this web. So there's this sort of element that may influence how things are done.

This is a rubric for value based analysis. And we always want to be on the right side of the curve where we're getting more benefit rather than less. If we can spend less and get more. That's fantastic that you know. That's an easy decision to make. If we spend more and get more that's where we might talk about cost effectiveness or utility and that's very hard to do clinically but we don't want to spend less and get less. And actually, if we follow this rubric where we eliminated things on the left side, which is basically cost minimization, we probably have a lot more money to care for patients a lot better.

These are the 3 goals of cancer care that we were taught in fellowship. One is to cure, when possible, with minimal long term side effects. So sometimes you can have toxicity in the short run like a bone marrow transplant If you're going to cure somebody and restore them to their natural state of health. The second one is to prolong overall survival and improve quality of life, and then, third is pure palliation. And one of the reasons for escalation is that there's discordance between what the reality of the situation is and what the wishes are and patients may often think that they're curable when they're not because of communication and the lack of understanding about what the goal of care actually is.

How to de-escalate. This is by Dr. Goldstein. Scientific and medical rigor, coupled with respectful and apathic communication. It requires really thinking through the situation in front of you, analysis of what goal you have and what you need to achieve, and thinking about each modality that you have to offer a patient, and then choosing wisely. This is general de-escalation strategies, and I thank Dr. Gyawali for pointing this out, with chemotherapy and immunotherapy would be to treat fewer patients by selecting patients better for treatment, to lower the dose of therapy to that needed to achieve the goal, to decrease the frequency of the therapy to that needed for the goal and duration of the treatment, to optimize the goal.

The fatal attraction of testing is a very interesting essay by a Dr Godwin, and I checked his website, he's a very interesting person with a lot of very interesting quotes. It turns out, if you have ovarian cancer patients in remission, and you were to watch them and wait for them to have symptoms or not, they would do just as well as the current fashion of checking a tumour marker CA-125 every 3 months, to try and identify a recurrence earlier and this is a classic lead time bias problem and it probably does not help the patient to do this but I think across America everybody does CA-125 in patients in remission. Part of it may be the patient says they want to know they're still in remission, and they don't like the uncertainty of not knowing but to stop doing this would be basically unthinkable. I think the issue will fade away, as he says, it's too compelling to test in this manner.

ASCO came up with 10 choosing wisely elements, as did all other sub-specialties when earlier we were talking about de-escalation, over-treatment, and some of them are very good, some of them should go with saying but we don't want to give chemo to patients with poor performance status. Use of PET-CT In early stage breast and prostate cancer is actually done a fair bit. And there's some escalation of this with a new scan called a PSMA scan in prostate cancer. And here they say, no surveillance tumour markers or imaging in breast cancer patients are in remission and asymptomatic, we do this in ovarian cancer. And it's considered choosing wisely when we do it, but if we don't do it in breast cancer, that would be considered choosing wisely. And this is still done 33 to 44% of the time using medicines to stimulate the bone marrow when they're not needed, is one of our choosing wisely.

The next slide will have the next 5 choosing wisely. Minimizing antiemetics is good, I think the second point there most oncologists are following that one. They avoid using PET/CT scans in follow-up of patients is done very frequently. I've been in several practice situations, and I see it done a lot, even though it's one of our choosing wisely. The PSA testing for prostate cancer has changed a lot in the past 2 years. And then surprising the last one. Don't use a targeted agent unless the patient has a target. United help did a survey, and they found that a third of patients who were receiving Herceptin did not have the target of that drug which is overexpression of HER2. So that is something we definitely should be choosing wisely on.

Why don't we choose wisely? There was an article with this title about radiation oncologists, and why they were giving 2 fractions of radiation for bone metastasis when one would do just as well. The 2 main reasons were misperception of patients about prognosis and goal of treatment and then there were correlations with who chose 10 rather than one having to do with practicing in the South. High volume practices and years from training. Interestingly, there was a study showing that credit ratings in the South are lower than in North. This has to do with medical debt.

Some successes of de-escalation, active surveillance for low-grade prostate cancer has really come around in the United States and that's helped a lot of patients. There's a lot of work on minimizing overtreatment of ductal carcinoma (DCIS) which is not actually cancer and papillary thyroid cancer, which has a very indolent course. Shortening the duration of chemotherapy. Shortening the total length of chemotherapy in breast cancer. There's a project that of UCSF looking at tailoring mammography to the risk. A lot of people asking if one year of immunotherapy is as good as 2. There's been some really good work in head and neck cancer with de-escalation of treatment in patients who may not need as high a dose in HPV Positive head and neck cancer in orbital maltoma which is rare they've discovered that 2 fractions work as well as 12. This boom boom is being adopted at many medical centres.

De-escalation of imaging. We know that follow up imaging in Hodgkin’s disease, and non-hodgkin lymphoma in remission does not help the patient. It's lead time bias and if the patients are asymptomatic, it should not be done, this is not one that's followed 100% of the time, but it's one that is out there in the literature and so it's a great opportunity for de-escalation. Patients don't need a scan. They don't need to give up their day to have a scan. There's some radiation to a scan. There's fear and anxiety to what the scan might show, and it ends up being lead time bias which we'd like to avoid. This is something I've thought about, de-escalating, imaging. So when we develop PET/CT scan suddenly oncologists started ordering them a lot more but, in my clinic, the other day I see a patient with lung cancer who's on a steady dose of an oral medicine and doing fine, and I'm following him with history and physical and chest X-ray and a tumour marker whereas my colleagues the physicians I hired would probably use a PET CT to follow this type of patient. Again lead time bias is the reason why that might not be a wise thing to do.

This has been a success story, de-escalation of breast cancer radiation used to be 6 weeks for all patients, then they developed the three-week external beam regiment and one week external bean regiment. There's a great invention by Dr. Michael Baumann out of London about intraoperative radiation therapy, where the patient can have a half-hour treatment after surgery. This is not uniformly used in the United States for various reasons, but could de-escalate, and then some recent work on identifying patients who are low risk for local recurrence, who could safely emit post labectomy radiation.

One of the problems with de-escalation is when it's discordant with our commonly accepted guidelines, because this is a harder thing, for we oncologists to do. It requires a careful analysis of the clinical evidence focusing on meaningful endpoints. It requires some extra education on how to read a clinical trial and statistics which is not really taught in medical school sensitivity, specificity, Bayesian analysis. For me these are things I learned during my masters in epidemiology and by reading, but they're not taught very well in general training, and then the last one, which is questioning of the endpoints that are being used in clinical trials, and whether they're meaningful to the patient.


These are some withdrawn accelerated approvals that may make people ponder, whether giving the drug is in the patient's best interest. If it's going to be withdrawn in a couple of years. These are all haematology, oncology, drugs that were approved, based on accelerated approval but then follow-up studies didn't show them to be effective. While they were approved and were used widely, but then they were withdrawn, and we get really confusing evidence with the PD-1 inhibitors where one company's drug might have a positive trial on another company's drug might have a negative trial based on patients’ selection and that's becomes a moving target. But it does give you pause about when you use medicine that's just newly approved via accelerated approval.

These are some interesting ones that happened recently, the 2 PIK3 inhibitors in non-Hodgkin’s lymphoma were really used a lot before they were withdrawn, or orlatumab

 sarcoma. Somebody calculated that the US Spent 500 million dollars on this drug while it was approved without any benefit to the patients, and then the story of a Avastin and breast cancer has been written a lot about. That it was approved for metastatic breast cancer and widely used until it was withdrawn. Even after it was withdrawn it remained on our professional guidelines and it could still be used, and we don't think any patient really benefited from the use of that medicine.

There's a great article by the ESMO group. Bishal was the first author, and I think Nathan Cherney was the last author that basically shows over the biases in the clinical trial, and how to analyze the clinical trial with some great examples and I try and share this paper widely, because it really crystallizes how to think about a cancer clinical trial to deconstruct it and figure out whether there's a role for de-escalation based on the way the trial was done and these are complicated topics that are well covered in the paper. Some more that are well covered in the paper, and it's probably the paper I read most often. It's on my desk, and I refer to it a lot when I'm reading a trial.

These are some other biases, mortal time bias, I think, was in that paper, lead time bias and length time bias have a lot to do, not just in cancer screening, but in deciding treatment, and when to treat and imaging, and when to image. And then there's always this fitness bias that patients who are enrolled on clinical trials are much fitter with less co-morbid illnesses than the patients we see, for example, at a county hospital who may have heart disease and lung disease at the same time, and so one should always sort of read the clinical trial and try and say, is the patient in front of me close enough to the patient in the clinical trial that makes sense, and that's a very hard and timely thing to do. And there are other biases and a great website called catalog of bias that has those listed for people to look at.

What does this surrogate endpoint mean? I think there's been several talks on Consilium that really cover this well, to me it's confusion, because cancer growth can follow nonlinear dynamics and when I trained in oncology we had overall survival and quality of life as our endpoints so these newer ones, which are used for drug approvals and in clinical trials, are hard to interpret and we don't actually tell the patient per se that this drug will make your X-ray or your cat scan look better for an extra 2 months but you won't live any longer from it, because it's sort of obfuscated, particularly if it's like a myeloma trial where all it does is keep the protein at a lower level for an extra 3 months. It's very hard to translate that in our minds, and it's very hard to explain that to the patients particularly if we have limited time with the patient or limited time to read and analyse the trial carefully.

Surrogate endpoints are ubiquitous.80% of registration trials use progression-free survival as an endpoint And this is the 60,000$ question: is progression free survival a good surrogate for overall survival or quality of life. Much of the time. It's not, and that makes a de-escalation very challenging. Somebody described maintenance strategy as eating every 5 minutes, so that you're not hungry at lunch, except that eating can be a toxic chemotherapy drug and so questioning maintenance strategies is a wise thing to do. I think the first one I saw was maintenance tax on ovarian cancer which made patients have a lot of toxicity from neuropathy but didn't make them live longer. Maintenance Rituximab in follicular NHL was very popular for a while. It seems to have de-escalated and so it's a question about who benefits from maintenance therapy, including the toxicity and the cost. There's a lot being branded about a trial of using adjuvant Osimertinib in lung cancer that doesn't seem to improve the overall survival or curated patients which is the goal of adjuvant therapy and even now we haven't seen any improvement in overall survival from that drug, so that might be an opportunity to deescalate.

This is a challenging one. When I read these trials I was myself sceptical because there was no improvement in overall survival, and using these drugs that have side effects without an improvement in overall survival in a patient with metastatic breast cancer is widely done. We're told to look for the target for the first drug and so to not do these you're going against the grain and then there was a great article by Dr. Tannock that came out in 2022 , that really went over how this happened, and his quote is here: “a drug that causes net harm should be withdrawn from market”. Well, that is probably the right opinion about that but this drug is used widely and it's considered sort of a marker of quality of care that you check for the marker for that drug. Interestingly, the 2 drugs for lymphoma, that target that marker were withdrawn after accelerated approval and Everolimus is still widely used in this setting, second line.

This is a recent trial that's baffling a little bit. This is a great drug in the sense that we have a target, a K-ras mutation, and a targeted drug, and that's appealing because we saw such great results with the mat and it chronic myelogenous leukaemia. It's oral, but it does not approve overall survival, and it has side effects. So it's hard to make a lot of a surrogate endpoint even though this drug is guideline listed and FDA approved at this point.

This is a relatively rare disease, but it illustrates the problem in that when I treat these patients I will give them Bendamustine-Rituximab and see how long their intermission, and you can use a Ibrutinib second line. The trial, showed no difference on overall survival quality of life by using this maintenance strategy of this drug which does have risks of a-fib, sudden cardiac death bleeding and rash and we could easily de-escalate to just spend a Bendamustine or rituximab and delay starting ibrutinib until progression with actually helping the patient out. So it's going against the grain to see this trial published in the journal of medicine, and then question it and do something different.

Provenge is a really interesting drug. When trial came out I wrote an editorial about it because it did not lower the PSA or shrink anything, but it seemed to improve the overall survival patients with prostate cancer. And it turned out to be a problem with control arm being put on a dummy drug for 4 months that delayed the time until they got an effective drug Docetaxel so the overall survival may be just a spurious event, and an oncologist would be perhaps in the right question using this drug, which cost 300,000$, and doesn't seem to help the patient, but it is a widely used therapy. This trial has been critiqued by several oncologists in that patients were responding to a standard regimen, and then in the Placebo arm, that regimen was stopped, and in the treatment arm they were given a targeted drug. Again, targeted drugs are very interesting molecularly because we're identifying the target. In the placebo arm there was almost 10% response rate and if you look at the Kaplan-Meyer plot, it crosses at several points, which means it's probably not interpretable but this is now a standard guideline to test for this mutation. In all these patients and have this therapy waiting in the wings to offer them.

The choosing wisely has a economic and societal goal of de-escalation to diminish financial toxicity and some areas of research, such as interventional pharma-economics are focused on this. This is a great natural history of this drug. This is the Martha Stewart drug a monoclonal antibody for colon cancer. At first we gave this drug to all patients, and we saw responses very infrequently. Then we found out that there was a mutation, and the patients who had that mutation would not respond. That research was done in France, and when it  was implemented  30 million euros a year was saved, and it took about 3 or 4 years until we started applying those results in the United States. Then we figured out that patients with certain mutations were un-responsive, and that the side of the colon mattered, and that a rare HER2 overexpression. So now we're treating only 15% of the patients down from 100%. But our response rate is 85%, so this is a real success story in precision oncology by making the treatment more precise, minimizing toxicity, and can maximizing efficacy. This is a real win over time next.

Treatment holidays. There's some literature on this in colon cancer and refractory cancer. This may actually prolong overall several patients by giving holidays, I don't know all this literature that well, 2 patients I saw on this week one with metastatic cervical cancer and one with metastatic endometrial cancer. Their scans look good, and I said let's stop treatment and see what happens and they're both about a year and a half out, with no treatment which I think has improved their quality of life. If I had given them stereotypic radio surgery, I might have said that did it, but I didn't in either case, and I have a cohort of patients like this where I try to give them treatment holidays and I think it's a very good strategy to investigate further.

De-escalation in chronic myelogenous leukaemia. This is in the divida textbook actually, that first line Imatinib which is generic, maybe 17$ a month, works as well as the second line therapies, which are more potent, and that appropriate patients can stop their medicine completely and 40% and will be disease free again, that's a study that I think came out of France and England and then Dr. Kentarjian is talking about how you can reduce the dose of these second generation medicines which will reduce the cost and toxicity. Not an incredibly common cancer but one where we could really optimize care by d-escalating to using a generic drug first line.

Biosimilar substitution. I've written some articles where you would think that a 100% substitution would happen because the drug works, just as well at a lower cost but it's not a 100%. It varies a lot from that, even in European countries we're not up to yet 100%, but this would be a huge opportunity for cost savings with keeping the patient outcome exactly the same, and we could use that money for other things, including low and middle income countries perhaps.

This is a great group of interventional pharmaco-economics, Dan Goldstein and some others who were looking at things. Some of the things that they've come out with have to do with doses. The use of Abiraterone with a low-fat meal to lower the dose by 75% and save 75% of money. Weight-based Keytruda dosing one of the PD1 inhibitors can be given every 6 weeks so that saves 25% and it saves the patient an extra visit to the clinic by going for every 3  weeks to every 6 weeks. A trial that's getting a lot of press is very low dose use of Pd1 Inhibitors, with a great result in India. It turns out these drugs don't have a dose response curve that 0.1 milligrams per kilogram works as well as much higher dose. And the dose that we use now, which is fixed dosing is somewhat arbitrary. So there's a great opportunity here for dose de-escalation if we want it.

De-escalation at the end of life. I think in America we don't refer our patients to Hospice early enough, because we don't like to have the end of life conversation, but it really is in the patient's best interest to understand what the goal of care is, and to make informed decisions at the end of life. We see patients who are admitted to the ICU inappropriately in a passway there rather than at home. We see a lot of heroic use of immunotherapy and targeted therapy in the last  days of life, with no benefit. We have a very low average time on Hospice in 5 cancers it was shown in a well study, and the way to do this is to introduce palliative care to patients with metastatic cancer much earlier in their treatment. At my hospital we do this, because we have palliative care clinic in the same clinic as us, and so we can send the patients there, and they can have some of those conversations. But I trained at a time when we didn't have palliative care as a separate discipline, and we needed to have those conversations ourselves and there's a way to do the end of life conversations that's respectful and honourable and optimizes the patient outcome that can be taught.

Paths forward. You know a great opportunity would be designed prospective clinical trials with economic endpoints and quality of life measurements these would probably have to be from the perspective of the pair, from a national insurance platform, a single-party pair, because it's targeted at society as well as the patients. And we don't see very many of these trials and it would be great to have more of them. This is a great opportunity for collaboration between high-income countries and lower-income countries, where many of the chemotherapy drugs that are very, very effective are not available to their patients because of economic issues.

So in conclusion, this is a very difficult topic to grasp, but it's very well worthwhile to do it. To spend some intellect and some psychology thinking about why we escalate care and how de-escalating care will help patients tremendously. It's a growing movement. We see more literature about this, more conferences, more groups focused on this. There are financial reasons to do this as financial pressures continue to mount, and medical debt increases, and the cost curve continues to break, and the health care system continues to suffer. It may become fashionable for financial reasons, and then there's philosophical reasons as Lao Tzu said you only want to use  as much force as necessary. I think philosophically, in treating patients, you only want to treat patients as much as necessary and as much as this talk has been about cancer care, de-escalation applies to sort of all aspects of medical care.

Leeza Osipenko: My first question to you would be, are you aware of any studies comparing Europe and the US on the difference in terms of amount of treatments used for particular tumour types, or that the burden of treatment, how much more the US is doing or has escalation of cancer care been similar across the board, and that we need to de-escalate everywhere.

Kevin Knopf: I'm looking forward to this talk because I've never practiced in Europe, and I know that escalation of care is a huge problem in the United States, and less of a problem in Europe where most of the countries there have a single-party payer that has some sort of economic guardrails, such as NICE, where many drugs we use here are not approved for use in England. So definitely, there's much better de-escalation in European countries than there is in America. There is sort of this fashion of doing what we're doing in America there so for example fixed dose of PD1 inhibitors probably is commonly done in Europe. The studies that are done are not you know, prospect randomized obviously, they're sort of review articles and theme pieces and I'm very interested in how Europe does things, because I think you know, de-escalation is something we should all strive for, and we have a less sufficient healthcare system, because of the way health care is paid for in America that may encourage escalation of care.

Silvia Marsoni: I'm an gastrointestinal oncologist, and I'm well now not anymore in the clinic, but in the research and I'm a Gi girl. I would like to say a couple of things. First of all, I will give you some good example and bad example of de-escalation, and non-de-escalation in GI cancer. In rectal cancer, and at this very moment there is a lot of talking about the non-procedures, meaning no, no surgical management after an escalated chemotherapy, a near-adjuvant chemotherapy. These are really important things, because, as you know, the surgery for rectal cancer is radical, and there are several trials going on including one of mine, but the results are really very interesting, and coupled with the use of PD1 antibodies in MSI patients. It seems to me that that is a good example of de-escalation. On the other hand, unfortunately, there is a lot of increased neo-adjuvant treatment in Stage 4 patient, either oligometastatic or even not with the hope of making them operable which they become but then the tumour, is not really eradicated by surgery, and therefore the value of that is really very flimsy. And you should look into the 2 trials that have shown this. I think that this is a very good period for the De-escalation, because there are several new technologies. First of all, liquid biopsy that will allow us to really select the patient that are in need of treatment. 30 years ago, I was one of the people that started a trial for demonstrating that you needed chemotherapy and in stage  2-3 high risk colon cancer. We needed to treat all in order to save the sum and increase the survival rate between 10 to 15%, according to what you say. Then followed 20 years of incredibly stupid trial, pardon  my French, we had to end up with more than 20000 patient treated 3 versus 6, and still not a firm answer on that, obviously because it was not on the biology of the tumour, but just on the length of  treatment. Now liquid biopsy has shown us that we can do otherwise, and in the current right that I've just closed and I'm going to open another one in 6 months from now we figured out that practically , 75% of the patient that are now treated with mostly 6 months of a regiment that leaves 15 to 20% permanent neuro toxicity damage really don't need to have any treatment because after the surgery. They have no micro metastatic disease. There is no way. There is no CT-dna in the blood of these patient 30 days after surgery, which means that since the CT-DNA has a half-life of  2h in the blood, if it's present, there are metastatic sites that we cannot see, whereas if it is not including you know a certain number of false negative that you have to accept, still we are overtreating 75% of the of the patients, and this is something that it's very difficult to make a physician understand. I think, that one of the major reasons, It's also because the guideline we have kind of created a monster with evidence based in a way. You know I was instrumental in my country 20 years ago to introduce the concept of evidence made with doing large randomized clinical trial. But now the combination of evidence medicines guidelines and the fragmentation that the industry imposes in the timeline between the diagnosis and the deaths of the patient if the patient is not responding, has created a monster. For instance, again, in colon cancer, you cannot test a new drug unless you are in fourth line. However, the first, second, and third line, which are established, after the first line it's not clear, because nobody has really done the trials that need to be done to establish what is the real benefit that it's given by the second and third line with very toxic regimen, to the overall survival of the patient. Now again here I think that we need markers to convince people that we can predict for instance, the effectiveness of chemotherapy in front line. As you said, there are no good proxy of survival usually, but in the case of colon cancer it has been proven by a variety by Mark and his group in Belgium, that response, it's a good proxy of survival in late disease, however response is only obtained during frontline. Second and third line responses are close to 0. That notwithstanding, because of the fact of using another non-good proxy, which is PFS we continue to allow industry to say that this drug is splendid because it adds a 1.5 months of PFS to the patient, and I think that this is something that we need to discuss more. The bad influence of these 3 things put together. Guidelines should be more restrictive than they're saying, you know, there is one trial which 1.5 months PFS And therefore it will be unethical not to give this drug to the patient.

Kevin Knopf: Everything you say is true, you know, in colon cancer I was reading recently that there's really no need to add oxaliplatin unless you have 4 or more positive nodes, there's no incremental benefit. But across the US everybody will give it for any node positivity and stage 2 disease and I think the Ct-dna may help deescalate care, although I see it also escalating care. We have minimal residual disease testing in myeloma with no evidence that treating to maximal minimal residual disease will make the patients live longer so it's a double edged sword. I think many of you have read the article evidence-based medicine has been hijacked, a letter to David Sackett, and I think that describes some of what's going on. I will briefly mention one of the companies I'm working with. Cadex genomics. We have an assay based on fragment sizes that are expressed by cancer  ubiquitously, and the way it works is by day 20 you can check this assay, and if it's going up, that means the chemotherapy is not working or the immunotherapy is not working, so we hope to use this to de-escalate by saying you know, you're starting an immunotherapy. You normally have to wait 9 weeks to see if it's working or not. By day 20, you could say it's not working and drop it from the regimen. If the assay doesn't go up it doesn't mean it's working for sure then you follow the usual imaging and things like that, but I'm very interested in this Cadex assay and I think if it goes forward it, I have a lot of opportunity, particularly in the Third World, where patients are paying for chemotherapy out of pocket to deescalate care. So that's why that's a conflict of interest.

Silvia Marsoni: We are trying to do delta liquid biopsy basal versus the liquid biopsy at the first CT-scan in immunotherapy treated patient to see if we can, by gorging the curve of the quantitative diminishment of the Ct-DNA predict whether there will be a long term or short term response and the preliminary data is very interesting. There are some data already out in head and neck cancer suggesting that if the liquid biopsy doesn't drop, the Ct-dna doesn't drop, then there is no point in treating the patient with 6 months, of expensive and not so non-toxic, immunotherapy, especially at the doses of which we are using.

Kevin Knopf: We hope this is used wisely this new technology. I don't think the Grail, you know, for screening, for cancer has good performance characteristics, and people are very excited about that in the States.

Leeza Osipenko: Just a few questions in the chat. Can you expand more on IVPE trial, collaborations between developing countries and where's the trial run, who are the sponsors?

Kevin Knopf: Yeah, I think that there are some groups that the IVPE and other groups that that are talking and perhaps designing some of these trials. You know a great one would be to see about dose ranges for PD1 therapy and translating what happened over here.

The sponsors would have to be government agencies, or maybe in America insurance companies, because they're the ones that are interested in the outcome so I haven't myself seen a lot of trials like this. I think maybe that'll be the topic of the future talk here that I'll come and listen to. Others may know more about trials that are being designed that way, and I'm trying to get into that field myself.

Leeza Osipenko: Another question from chat. If you can share your thoughts on the EBCP flagship 6 , the new cancer diagnostic and treatment for all initiative which was launched at the end of 2019  and will help improve access to innovative cancers diagnosis and treatments, and it promises to use the next generation sequencing technology for quick and efficient genetic profiles of tumour cells allowing cancer centres to share cancer profiles and applying the similar diagnostics and therapeutic approaches to patients with comparable cancer profiles. So the initiatives will ultimately help optimize cancer diagnosis and treatment and reduce unequal access to personalized medicine and cancer care. So are you aware of this initiative, any comments?

Lydie Meheus: The EBCP is the European beating cancer plan for your information. And this is really what the European decision makers are putting there. And we are very worried about this because we think there is a lack of data and they're just going to push through, and we don't know how to kind of fight against that. Happy to hear suggestions for that.

Kevin Knopf: Yeah, you need a group of rational scientifically thinking people to look at that honestly. What happens in the US is every patient gets next generation sequencing, and they find a target and they try a drug. And when you actually read the evidence about how well that drug works, a lot of the time, no. Sometimes the targets are really important, and you can get really great results but in America it's done almost ubiquitously. Patients are asking for it. The drugs that are used are very expensive, usually  15 to 20,000$, a month. And the results are not always staggering and there's a lot of momentum to do next generation sequencing on every patient, and you know there's a lot of questions. Is the genomic profile of the cancer at the time you do the sequencing the same as it is after they've had 2 or 3 lines of chemotherapy.  You know it's different even in one part of a tumour versus another, and there's a lot of you know, buzzwords, precision medicine, and AI and decision inference analysis that's behind that. And so I think that train has left the station. I'm not sure how to apply rationality to that. To me the economics are the way to apply rationality because somebody has to pay for these experiments, and I'm hoping that there will be a way to do that, particularly in Europe, where you will have single-party payer systems. I don't know how the people in the budgetary deal with when they see these rising costs. Do they say, what outcomes are we getting for this? That’s I think where to go, but another way to deal with it maybe, might be just to really analyse the data and write papers and try and get it out there to people, even in the newspapers that this is you know, chasing a pipe dream rather than actually helping patients. Next generation sequence is both good and bad but there's a lot of hype behind it, and in America every cancer centre has a precision medical Institute with a large building and there's definitely a lot of hope, as we say oncologists are optimistic. They're very optimistic about the utility of next generation sequencing for their patients. I'd love to learn more about that.

Lydie Meheus: And just for your information, EORC, the European organization for research on cancer, they are pushing hard for the de-escalation, for checkpoint inhibitors and they have set up trial on that topic so maybe that's an organization that's very much interested in this.

Kevin Knopf: They could easily do the weight-based dose thing, and then they could start looking at a lower does per kilogram and save a lot of toxicity and a lot of expense.