The OJC Episode 4: New Zealand vs Australia, Optimising Breast Cancer Treatment, ChatGPT Insights, ASCO Guidelines, Hand-Foot Syndrome and More!

How do cancer outcomes in New Zealand compare to Australia? How can we optimise post-neoadjuvant treatment in patients with early breast cancer who achieve pathologic complete response? Does bevacizumab improve efficacy when administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous non small cell lung cancer? And how do AI chatbots perform when asked for cancer treatment recommendations?

Welcome to The Oncology Journal Club Podcast – your go-to source for in-depth discussions on the latest oncology research tailored for medical professionals.

Join our esteemed Hosts, Professor Craig Underhill, Dr. Kate Clarke and Professor Christopher Jackson for the low down on the latest oncology papers. 

They also discuss ASCO guidelines, inequities, financial conflicts and environmental issues.  

But that's not all – we also add a touch of whimsy to the episode, rounding off with a fun song inspired by Craig's latest half marathon, crafted in the style of Taylor Swift (courtesy of CJ's favourite new lyric-writing machine, Chat GPT!).

Tune in to The Oncology Journal Club Podcast for an informative and entertaining journey through the world of oncology research and practice.

For papers, bios and other links visit the Show Notes on our website.

For the latest oncology news visit www.oncologynews.com.au.

We invite healthcare professionals to join The Oncology Network for free - you'll also receive our free weekly publication The Oncology Newsletter.

The Oncology Podcast - An Australian Oncology Perspective

Transcript

Rachael Babin: 0:02

How do cancer outcomes in New Zealand compare to Australia? How can we optimise post neoadjuvant treatment in patients with early breast cancer who achieve pathologic complete response? Does bevacuzumab improve efficacy when administered with platinum combination therapy and atezolizumab in patients with advanced non-squamous, non-small cell lung cancer? And how do AI chatbots perform when asked for cancer treatment recommendations? Welcome to the Oncology Journal Club podcast, your go-to source for in-depth discussions on the latest oncology research, tailored for medical professionals. I'm your producer, Rachael Babin, from the Oncology Podcast. I'm joined by our esteemed hosts, Professor Craig Underhill, Dr Kate Clark and Professor Christopher Jackson. For additional insights, links and comprehensive bios of all of our hosts, visit the show notes on oncologynetwork. com. au, produced with pride by the podcast team at the Oncology Network. We invite you to join us as we delve into the intricacies of oncology research and its clinical applications.

Craig Underhill: 1:24

Kia ora. G'day kia ora. Welcome back everybody to the Oncology Journal Club podcast. Great to be here with Kate Clarke and Professor Chris Jackson from New Zealand. We have some exciting papers to discuss. Today each do a long paper and then some quick papers that we can then delve into some detail on via the links on the webpage. Thanks for all the feedback to date to everybody, who's been some great feedback. We love hearing from you all and please let us know about anything you think could be improved. Or if you have any suggestions for papers, please send them in and you might even score a chair at this mixing desk and be interviewed about a paper if you wish. So, without any further ado, we'll get straight into it, and I think Professor Chris Jackson has the first paper, which is a little bit sad, a little bit of a reality check for all of us. So, Chris, over to you.

Christopher CJ Jackson: 2:25

Kia ora, craig. Great to be back on the show this week. Nice to see you again. Also, craig, you are on the road at the moment, is that right?

Craig Underhill: 2:32

Yeah, on holidays, Chris, I'm actually in my leisure wear. I don't know if listeners need to conjure up the image into their brain, but I'm currently in a nice, let's say, relaxed, attire.

Christopher CJ Jackson: 2:46

Well, a good oncologist can create a verbal picture with their words, like a radiologist or a pathologist perhaps. So let's see how we go. The show host is dressed in mid-grey with an elasticated hoodie. The white Apple AirPods drapes from his ears. He has a dishevelled look, as if he's been concerned and sweating over his papers over many hours. He looks intelligently into the screen as he considers the data. Professor Craig, what will he come up with next?

Craig Underhill: 3:17

What it's going to do is it's going to prod you to get going on your discussion.

Christopher CJ Jackson: 3:22

We're Rachael a a lot of editing now. This week's contribution is from the mighty New Zealand Medical Journal and instead of doing an original article, this week I'm going to cover an editorial which came out and has garnered a lot of attention here in New Zealand and that's looking at the cancer stats Cancer outcomes in New Zealand and other countries. How are we doing? There's been a lot of talk over recent time about New Zealand's cancer outcomes because historically we've done a little bit worse in Australia and there's a lot of chatter about why that might be. I think this editorial brings out the stark contrast and it used a figure of something like 1,200 people would live if New Zealand had Australia's cancer survival rate, which is always going to get people's attention, and behind those numbers is quite a complicated story. So this editorial in the New Zealand Medical Journal by Professor Mark Elwood, professor of Cancer Epidemiology, a world-renowned and respected epidemiologist, dived in and has compared the outcomes over time for three cohort periods and has compared the excess mortality and the five-year survival over these three time periods. And has compared the excess mortality and the five-year survival over these three time periods and has looked at them by cancer and seen where the difference is when we're talking about cancer epidemiology we have to think about incidence, mortality and survival, which of course are all related. But you can't just get one figure to get what's going on. There's not one easy way of summarising the whole lot.

Christopher CJ Jackson: 4:44

Cancer incidence is largely driven by two things. One is your cancer risk factors, so smoking, alcohol, obesity, et cetera, et cetera. And then also your diagnosis. So for example, prostate cancer incidence is high if you have high rates of PSA testing. For example, melanoma rates are high if you take off a lot of skin lesions. Melanoma rates in New Zealand went down during COVID because they took off fewer skin lesions. But then there are other cancers which are always going to turn up, like pancreas cancer. You can't over-diagnose that Cancer. Mortality is a product of both your incidence, so how many cancer you get and actually how many you cure. So your mortality is affected by those two things. And then relative survival. Five-year relative survival is a reflection of your success of treating the cancer. The five-year relative survival was influenced by stage of diagnosis. So if you diagnose earlier cancers, so more stage one cancers, through over-diagnosis, say early melanomas, then your five-year survival could look artificially better than it actually is. So when you're trying to understand how a country is doing, you have to consider incidence, mortality and relative survival, because no one of those three actually tells you the whole picture. What this editorial summarises is a mix of all of those three things.

Christopher CJ Jackson: 5:55

Over that time period it found that a lot of the excess deaths in New Zealand were due to excess deaths in females, which has persisted over time between the two countries. The excess deaths between men in Australia and men in New Zealand isn't all that different. Within New Zealand there's differences too, because our indigenous population, new Zealand Maori, do a lot worse in terms of both cancer incidence and cancer mortality. Cancer mortality the paper breaks it down. It looks at the excess deaths in lung, breast and colorectal in particular, and also uterine cancer. There are a few cancers where Australia has a higher incidence and it said that this is actually not a factor in the survival rates. But I would take a slightly different view. I think if you've got a higher incidence it can reflect over-diagnosis or the pickup of incidental cancers or otherwise not have caused that person's death. Over time we've had a bunch of change of risk factors as well between the two countries. So smoking rates in New Zealand females are actually higher than in many other countries. That could drive an excess of incident lung cancers in particular. There's excess colon cancer deaths in New Zealand compared to Australia over that time. But actually Australia was five to eight years ahead on the implementation of the screening programme. So you would expect Australia to have lower colon cancer related deaths than New Zealand. But we are also picking up cancers at a later stage in New Zealand. That much as irrefutable. But we are also picking up cancers at a later stage in New Zealand. That much as are refutable.

Christopher CJ Jackson: 7:30

It also coincides with another paper that's come out recently from the International Cancer Benchmarking Project and been rerun by a cancer agency here in New Zealand which looks at the rate of emergency presentations of cancer, and New Zealand unfortunately has one of the highest rates of emergency presentation of cancer of comparable countries. More than 30% of all cancers are picked up via emergency presentation. Now emergency presentation is defined as someone comes to an ED and the cancer is diagnosed within 30 days of that first emergency presentation. So it can be an inpatient admission or a result of that emergency presentation. That's higher for bowel cancer in New Zealand, that's higher for lung cancer in New Zealand as well, and that high rate of emergency presentation reflects probably a dysfunctional early diagnostic pathway that could be better. We have a higher rate of emergency presentation in New Zealand than in comparable countries. Now, you're never going to get a zero emergency presentation rate because we all know that people turn up with bowel obstruction for the first diagnosis of bowel cancer. But it's higher in New Zealand than other countries and it probably reflects a relatively less well-developed diagnosis and referral pathway than, say, in Australia.

Christopher CJ Jackson: 8:34

New Zealand has, interestingly, 35% fewer CT scanners per head of population than Australia does, but a similar number of MRI scanners. We've certainly got poorer access to nuclear medicine than you do in Australia and we've certainly got poorer access to luminal investigations such as endoscopy and colonoscopy than you do in Australia, and part of that is the funding mechanism, I suspect, between the two countries. When it comes to cure rates, we're doing okay on some things. For example, brain cancer, pancreas cancer, ovarian cancer. There's no difference in outcomes between the two countries Melanoma, stomach and esophageal cancer. Unfortunately, there's persistent disparity between the countries. But for men the outcomes for lung, esophageal cancer, brain cancer and pancreatic cancer are actually slightly better than Australia. So it's a complicated picture. Between all of those there will be some therapeutic differences. So Australia has better access to cancer drugs, but mostly that's in the palliative space rather than the curative setting. So the drugs aren't the entire answer either. And also, most of those palliative drugs might improve your one-year relative survival, but shouldn't improve your five-year relative survival.

Christopher CJ Jackson: 9:38

So what do I take away from this editorial? I take away from this editorial that we do have a higher rate of excess deaths than Australian when it comes to cancer. Some of that is driven by differences in incidence, which, in particular, is female lung cancer. Some of it is due to differences in screening practices, such as diagnosis of early breast cancer and melanoma. Some of it will be due to probably better access to therapeutic services, particularly early, due to probably better access to therapeutic services, particularly early investigation, with scanning and access to early investigations. Having said all of that, australia is one of the best countries in the world routinely when it comes to cancer survival and lower rates of cancer mortality than many other comparable countries, and I think we have to have an open mind as to why that is. And and I'll be interested in any listeners' comments or thoughts, reflections on things that Australia does particularly well and thoughts from Craig on what Youth in Causey is doing which is world leading.

Craig Underhill: 10:34

It's interesting to postulate why some of those differences are. I picked up a question in the paper that there was a lower incidence of cancer in New Zealand, which might just reflect that you're not picking up cancers as well at an early stage. But clearly there's some differences in access to drugs, as you say in the palliative setting. But given that we see now with immunotherapy such long-term survivals in significant subgroups of patients, I'm sure going forward in the next set of this is 2006, 2010,. But I would have thought in later sets of data we'll see potentially bigger differences.

Craig Underhill: 11:10

I like to bring it down to the sort of human level. So you're talking about a 4% difference between New Zealand and Australia. Five in survival, 10,000 annual deaths in New Zealand 2008. So that's 4%. 10,000 is 400 people. So it's 400 extra deaths, 400 extra families and sets of families and friends. It's quite stark when you translate it into those kind of numbers. And it's a similar kind of difference we see between regional Australia, metropolitan Australia and the state of Victoria that there's about 10,000 cancer cases diagnosed Regionally to a 4% difference. It's about 400 people. When you put it in those terms it's quite substantial. It's way more than the road toll and billions of dollars is invested in fences along highways and promos on telly and all the rest of it.

Kate Clarke: 12:04

That's exactly where I was going to go, Craig, which is that we value deaths by accident and value is probably the wrong word, but we put a monetary value on deaths by accident. It's much higher than deaths by illness, and the justification for billion-dollar highways is often one or two deaths, but we can't spend $100 per person on having easy GP access. We're going to have a health target shortly in New Zealand which is from decision to treat to treatment, but that's not where there are gaps. Our gap is before that. So you're cheating by having a target that we know we can meet and not fixing the real problem, which is symptoms to diagnosis and then diagnosis to get in front of somebody who can actually help you. So yeah, look, I despair. I don't really understand why it's okay to build billion-dollar highways and it's not okay to spend millions on health care, but part of me wonders whether there genuinely are people in positions of decision-making who think they are immune to illness but maybe not immune to road accidents.

Craig Underhill: 13:10

Yeah, I guess it shows that we need this information and we need to translate that into digestible information that we can use to advocate for more resources across the cancer control system to try and address it.

Christopher CJ Jackson: 13:25

Yeah, the cancer control continuum when you're looking at cancer control system to try and address it. Yeah, the cancer control continuum when you're looking at cancer control from a systems perspective. Clearly a lot of gains from prevention, which again it was sad to see the New Zealand government dismantling the world-leading smoke-free laws, for example, and that will ricochet for generations in terms of the number of people who will die as a result of that. It's madness. But also our inability to regulate the food environment and the persistence of easy advertising to kids, for example, and the normalisation of alcohol around schools, for example, as well as advertising in liquor store outlets around schools. So there are certainly things you can do from a political and structural perspective when it looks at that, you can't do risk factors without unnecessarily limiting adult freedoms, because I accept there's a trade-off between any state and freedom of choice et cetera. But we can't ignore the capitalist pressures of marketing which actually are carcinogenic, by promotion consumption of products which are poor for your health.

Kate Clarke: 14:16

And just while I'm on my transport bugbear, we are not continuing to encourage active transport. Even walking to the bus is frowned on. We put everybody in cars, everybody in a car, everybody in a car. Even if you talk about pollution, the pollution inside a car is significantly worse than the pollution for those people who are riding past the car, and we don't know what those micro particulates are doing to people. But we're quite comfortable putting people in that environment time and time again for hours of their day, and that's not normal and it's not what we were designed to, how we were designed to live.

Christopher CJ Jackson: 14:46

I really agree with that, kate. I think you look at New Zealand's third on the International Obesity Index scale as well, and so I think we have to double down on active transport as well. I agree with that, and also there's some great work done by Charlie Swanton and his group, which looked at the incidence of lung cancer in relation to air pollution in the UK, and that, I think, is demonstrating the link between air pollution and lung cancer and probably explains a large number of those 15% of cases of lung which are not related to smoking, for example. So I think we'll see more of that in the future too. So air quality, air pollution, are certainly going to be factors in carcinogenesis too.

Craig Underhill: 15:23

Right, Chris refers to the editorial in his discussion. We'll also put a link to the original paper that the editorial was talking about. People want to dive into more detail, Kate, what have you got for us this episode?

Kate Clarke: 15:36

So my long paper won't be as long as Chris, but I just wanted to draw people's attention. I despair, I think, perhaps, at the inequities between disease types, even in the way that we think about things. So for those, for the uninitiated, those patients that gain a pathological complete response after systemic therapy in breast cancer, before resection of their breast, and whatever axillary staging you're doing, do beautifully well, it doesn't matter how you get there, whether it's three days of chemotherapy or six months of chemo with pembro. If you are lucky enough quote unquote to get to a pathological response, your event-free survival across almost all trials is 95, 96%. Many of our new trials mandate therapy after the surgery as well, regardless of PCR.

Kate Clarke: 16:20

Some of those therapies obviously are toxic. Many of them are financially toxic and if that's in the trial and there's no where a pathological complete response, a patient who attains a pathological complete response has a de-escalated regimen, then we are stuck retrospectively doing de-intensification, non-inferiority trials which will never prove that a LESA standard is safe. So this is just an editorial talk about how we could do that and where we've got to, and I think it's very interesting. But the inequity is that in 95% event-free survival and any other disease type that I treated, I would be delighted, and I would not be despairing about the fact that there are some, and so it's a 95% invasive disease-free survival, which in breast cancer, means that new breast cancers new oh look, it was the crap out of me, you know. It may be not even an endpoint that's relevant for an adjuvant curative trial. So that's my little rant. We really need to start planning trials rather than doing trials and then going whoops. We've just mandated nine months of therapy that may or may not be necessary to 65% of our women.

Craig Underhill: 17:21

Great paper Kate and I think in the context of that discussion about improving cancer survival in New Zealand and in Australia, I think clinical trials are an important issue, aren't they? Because I think that's one way that we drive new knowledge, but also an individual patient. We see people who do better than expected often on the clinical trials. I like the discussion in the paper. They use the word optimization of treatment rather than de-escalation, which has this negative connotation. It doesn't mean that you're reducing the treatment, but it's really about optimising the treatment and not exposing the people to treatment they don't need.

Kate Clarke: 18:00

Yeah, I think, particularly when you're talking about immunotherapy, where you do get late surprise toxicities, some of which are devastating, but some of them, even though they may only be annoying, might be a tablet for the rest of your life, and some of these women are in their 30s and 40s.

Craig Underhill: 18:15

All right, I'm going to talk about lung cancer and also black humor warning. In the context of our recent discussion about outcomes in New Zealand and the tearing down of the anti-smoking laws, I thought it might be important for the Kiwis listening to Chris and Kate to learn a bit more about lung cancer. So this was a randomised clinical trial comparing atezolizumab sorry, and platinum plus pemetrexid, with or without bevacizumab, patients with metastatic, non-squamous lung, small cell lung cancer a randomized clinical trial in JAMA Oncology in March. The atezo-platinum, pemetrexib, bevacizumab regimens for drug regimen has been the standard of care for some time and the question was shown in a randomized trial to be effective. But it's been often discussed do we really need the bevacizumab?

Craig Underhill: 19:16

This was a paper done in Japan, so first potential criticism of this paper has been done in a predominantly Asian population in Japan. This was a study done at 37 hospitals across Japan, and so patients with advanced non-squamous, non-small cell lung cancer without driver alterations of the gene were randomized to receive pemetrexed, carboplatin, atezo and Bev or the same combination without the Bevacizumab. So after four induction cycles of the four drugs they then went on to maintenance atezo and pemetrexed without the Bevacizumab and went on to two years. So the primary endpoint was a progression-free survival as assessed by a blinded, independent central review in the intention to treat population. There was 400 patients. So the study was fairly well-powered and actually showed in essence the blinded, independently assessed progression-free survival was 9.6 months in the combination versus 7.7 in the arm without the bevacizumab, which was not a statistically significant difference.

Craig Underhill: 20:30

They did do a specific subgroup analysis in patients with oncogene-positive patients and these were predominantly patients with EGFR mutations and interestingly that did show a bigger difference 9.7 months versus 5.8 months. So this was pre-planned subgroup analysis but it's really hypothesis-generating and the authors postulated that purposeism and mechanism of action may be delivering drug bev to the local environment, which has been the sort of postulated mechanism of action bevacizumab for some time. So the toxic effects related to bev were increased in the patients who received that and basically the conclusion from this study was that the four-drug combination did not show superiority over the three-drug combination for non-squamous, non-sorcerous lung cancer. But they noted that there was this hint of potential improved survival in the patients with driver oncogenes who were predominantly getting the drugs second line after having their targeted therapies first line. So an interesting paper.

Craig Underhill: 21:43

It probably hasn't answered the question definitively but I think that it's safe to say that if there's any concern about possible relative contraindication to giving these struggling patients with lung cancer that we could withhold the Bevacizumab regimen. I think on the PBS in Australia it mandates the four but there is a PBS indication for patients who are intolerant. So I think this move is now allowable under the current treatment restrictions in Australia. So I think people should be. My take-home message would be that people can be a bit circumspect on the need to use bevacizumab and if there's any doubt about whether it's just going to add toxicity, which can be significant, then probably that's the right way to go.

Christopher CJ Jackson: 22:35

Do you see much haemorrhage or cavitation in lung cancer with use of bevacacimib? Craig?

Craig Underhill: 22:40

Well, we see haemoptysis actually relatively infrequently, I think. Certainly in my practice we don't seem to see it that often. But the bevacizumab we've had patients remember the first trial. It might have been lung cancer, but one of the first patients we enrolled on a randomized phase three study had a stroke and they were on the Bevacizumab so that was a concern. So it can be not just about bleeding, Chris, but you know, there's sort of life-threatening vascular complications in a population of people that are at risk of that right.

Christopher CJ Jackson: 23:14

Yeah, certainly I remember one of my early days as a research registrar as well, looking at the oral VGF agents and similar experience Craig, causing someone to stroke out and I think it's fair to say Bevacizumab is one of the most overhyped and underdelivered drugs in the history of oncology and I actually don't remember a trial with Bevacizumab I've been impressed with, particularly because the gains are always very, very marginal, aren't they? With the use of the agent. I think I'd have to say it's one of the most weakly active drugs around and that its impact on outcomes overall is very small. I'm not going to say it's inactive, it's just very, very modestly active in most tumors.

Craig Underhill: 23:46

Great, let's move along now. We've all got a series of quick bites, short bites, call them what you like.

Christopher CJ Jackson: 23:53

Well, my first quick bite is something because we run this podcast at five till six. When we record it I get quite peckish. So I've brought my own Quick Bites today and I'm having smoked provolone cheese with some hunting and palmer salt and crack pepper biscuits. I've got to say it's quite delicious to be taken away on these. So that's my Quick Bite. I'm also interested in Quick Bytes and the way in which oncologists and pathologists and radiologists always describe cancer in terms of food. Why is it that we're so obsessed with food? We had someone today describing their rectal cancer as like a broccoli in the lumen of the bowel, and that created quite the mental picture, didn't it? So here's my quick bite, mmm cheesy deliciousness.

Craig Underhill: 24:38

You invited him up to the show.

Kate Clarke: 24:40

I think it was the other way around. I think he was here pre-existing, but the sad thing is the listeners at home don't get the image of him head down, furrowing away towards the camera, which is quite intimidating.

Craig Underhill: 24:52

Chris, when's your professorial status up for review?

Christopher CJ Jackson: 24:57

I'm almost about to celebrate my one year since my inaugural professorial lecture, which is available on YouTube. Download now.

Rachael Babin: 25:04

Before we delve deeper into today's episode, we want to thank you for your continued support. If you're a healthcare professional who shares our passion for these insightful discussions, we invite you to join our community at oncologynetwork. com. au. Registration is free and includes a complimentary subscription to our weekly publication, the Oncology Newsletter, and regular podcast updates. But that's not all. Your voice matters to us. We value your input and welcome your feedback and paper recommendations. Together we can shape the conversation and drive the direction of future episodes. Visit oncologynetwork. com. au today and join us in our mission to advance the field of oncology through collaboration, knowledge sharing and innovation. And now, CJ, has finished his snack and we can get stuck into his quick bites.

Christopher CJ Jackson: 25:58

Jay has finished his snack and we can get stuck into his quick but just published last month in the JCO and this is one of my favourite studies from all of last year and it's so good to see it in print. And the D-Torch study is a randomised, controlled, double-blind investigator initiated study of diclofenac hand gel in patients treated with capcitabine. Now -study study has an Australian connection because the protocol was actually worked up at the Accord workshop under the watchful eye of Martin Stockler and co, and the Accord team get a shout out and the thank yous at the end of the paper too, which is a really nice connection there. Anyway, it's a single centre study undertaken in India of topical diclofenac 1%.

Christopher CJ Jackson: 26:42

1 gram to each hand twice a day, but the feet, just the hands, and a gram was one finger daub worth on each side of the hand rubbed in twice a day. 30 gram tubes, that's pretty much going to be about 12 to 16 tubes over the course of a 12-week course. They gave 12 weeks worth of the gel. The primary input was grade 2 or 3 hand-foot syndrome, which everyone will know. Grade 2 and 3 hand-foot syndrome is plenty meaningful and distressing to patients. The beauty of the study was it showed that 12 weeks use of diclofenac gel one gram twice a day both hands reduced the incidence of grade 2, 3 hand foot syndrome significantly. Grade 2 hand foot syndrome went from 9.8 to 1.5% and grade 3 went from 5.3 to 2.3%, and that's highly statistically significant. The number needed to treat is around about 10, which is pretty good.

Christopher CJ Jackson: 27:33

Importantly, we saw well they saw the investigators saw fewer dose reductions in people who were treated with prophylactic diclofenac, with 41 patients having dose reduction in the placebo arm and 21 patients in the diclofenac arm. Importantly, there was no excess toxicity of other types as a result. So if you have reduced dose reductions because you've got these same foot syndrome, the chances you're having more pills. You're more at risk of having GI toxicity, for example. But they didn't see that there was no additional excess toxicity in other organs, which I think was very, very reassuring. So I thought that was a really lovely study. It's practice changing immediately in our neck of the woods and we are recommending people use the diclofenac hand gel. So that is available at the chemist's warehouse for about $20 a tube, which unfortunately is not subsidised, but all of us here in New Zealand are quite keen to write to Pharmac and see if they'll fund that alongside the treatment, because it should hopefully lead to long-term better outcomes of cancer by better dose intensity.

Craig Underhill: 28:32

Great, Good paper.

Kate Clarke: 28:34

We've started doing the same thing, Chris, so eh, we're a proponent here for women on capecitabine, particularly for breast cancer, of the one and a half gram BD, seven days on, seven days off regimen, which is very tolerable. I don't think we've got our CAPE doses right yet. I don't think we've got our doses. I don't think we've got our schedule right. I think maximum tolerated dose for two weeks if you can get through and then recover and then start again. If you're back to grade one, it's not right. I use a diclofenac gel or I ask my patients to use a diclofenac gel as well. But I applaud any investigators who continue to try and finesse what is a really good drug if you can get it into people. But finesse our understanding of what the right regimen is, because I don't think we know yet.

Craig Underhill: 29:18

Yeah, good point, Kate. You got a couple of quick papers for us.

Kate Clarke: 29:22

Yeah, look, just a couple of papers, mostly for the Kiwis. I don't know who treats liver cancer in Australia.

Craig Underhill: 29:27

Well, some of the upper GI medical oncologists GI medical oncologists there's probably, you know, and maybe one of those, because it's relatively rare that it's seen in a number of different units at low volumes.

Kate Clarke: 29:40

Yeah, I don't know. Sure, it's that rare, my friend. So we've just had a trial open in our tin pot little city for a matter of weeks and filled our four slots.

Craig Underhill: 29:49

Oh, wow.

Kate Clarke: 29:50

Screen date seen in four slots. So you know it's not rare. I just don't think med-ocs are seeing it. I think we haven't got our pathway sorted.

Craig Underhill: 29:57

Yeah, that might be the case, Kate. That's a good point.

Kate Clarke: 29:59

And I know a lot of gastroenterologists are treating it. But these are drugs with sometimes earth-shattering toxicity, and so I think this is something we're going to have to be moving into that space and if we ever get funding, that would be great. But so there are two papers that are ASCO guidelines, which I think and acknowledge the fact that you're treating two diseases, because it's very unusual for somebody to get a hepatocin, other carcinoma who doesn't also have an unwell liver, and so you've got two competing diseases. It's also an unusual place in that it's probably one of the only cancers, perhaps except for diffuse gastric cancer, where the person keeps developing new cancers because the driver for the cancer is sitting there still chugging away. So it's fascinating.

Kate Clarke: 30:38

And then the other paper is the four-year outcomes from STRIDE, which is beautifully designed in terms of those of us who are budget conscious One dose of an anti-CTLA-4 and then low dose anti-PD-1. No further doses of anti-CTLA-4. And the four-year OS is 25%, which is, you know, stonking. If you respond at all, your four-year survival is more like 50%, which is really useful information for those patients. So I like these two papers for those of us who are in the niche but increasingly busy medical oncology practice and look after liver cancer patients. They are also some of the most interesting people, because all sorts of people end up with hepatocellular carcinoma. So my clinics are full of some really, really interesting great storytellers, which is always fun.

Craig Underhill: 31:26

Yeah, and our Aboriginal and Torres Strait Islander population 2K. Hcc is overrepresented as one of the more common cancers. So we've been doing some work in that space to try and improve access to clinical trials in our large MRFF-funded grant and one of the things is to try and match cancers and the types of trials you have. So we're now trying to actively have trials open for HCC so that if we do see an Aboriginal patient with hepatocellular carcinoma hepatocellular carcinoma we do have a potential clinical trial available to give them access to latest regimens which, on the funding system, tend to lag behind real-world biophysicists. So in the guidelines paper, kate. So what is the standard first-line treatment now? Is it immunotherapy or is it immunotherapy and a targeted therapy?

Kate Clarke: 32:21

No, so the two standard regimens, because there's not been head-to-head comparison are either and I struggle so hard to say these so stride regimen, which was from the Himalaya paper, or the atezobevacizumab and BRAVE paper, and I'm fascinated by. In lung cancer, the thought is the bevacizumab and BRAVE paper and I'm fascinated by. In lung cancer, the thought is the bevacizumab isn't particularly helpful except in X, y and Z, and then we retrospectively find a justification. The thought in liver cancer is you've got an exhausted immune system and the bevacizumab acts to wake that up. Again. Fascinating that we even look at the drugs differently depending on who we're putting them into, rather than having a thing Anyway. Yeah, so those are the standard first regimens for whom there isn't a contraindication, and then your TKIs are either second line or that's what you reach to. So those patients who have a contraindication, kate the EMBRAVE study.

Christopher CJ Jackson: 33:12

I know it's subgroup analysis stuff, but the origin of the liver disease seemed to be important in terms of your outcomes in that one right. So the Hep B patients, for example, responded much better than the non-viral origin patients. Is that correct?

Kate Clarke: 33:26

It is correct, and it would be my clinical experience too, of about 10 patients. So you know, naughty anecdote Exhaustive, yeah, exhaustive.

Kate Clarke: 33:34

Yeah, I think one of the complicating factors, though, is that there is in New Zealand and in most of the world there is often an ethnic difference right down the line of those two things, and the way that many of the trials define ethnicity patients' ethnicity means that the data that they can get out of that is very so. We are Asian on occasion. We are rest of world on occasion. In terms of where we are, our patients are white, black or other, which means that you're not actually getting.

Kate Clarke: 34:06

I suspect that, yeah, some of it is about viral hepatitis and subsequent cirrhosis. Some of it is about the person themselves. So I suspect there's more going In pharmacogenomics. I suspect there's more going on there than we are going to tease out from that. In New Zealand, the vast majority of people I see with cirrhosis, with HCC, are viral related. Sadly, we've had a vaccine in this country since the 80s and still seeing it in young people, but you do see people with alcoholic histories or more concerning for joe blogs in the street. Um, whatever we're calling non-alcoholic fatty liver disease is their probable progenitor problem.

Christopher CJ Jackson: 34:39

Yeah, I think there's been eradication programs I've been in prisons, for example which have been quite successful down this part of the world. So we're expecting our part of the world for the viral hepatitis to be a sunset disease, hopefully, and we're seeing a lot more of the metabolic type at hepatogons, which I think are certainly growing with the demographic shift as well. Interesting though, in the Himalaya study there in the forest plots, it didn't really seem to be a viral versus non-viral origin. Hep Bs and Cs did quite differently according to the regime there as well. So I think there's still a lot more to be teased out in terms of origin of liver disease and the efficacy of these agents and the approach we're supposed to take.

Kate Clarke: 35:22

Yeah, I just would, and I realise it's a lot of work being done in the hepatitis B space and hepatitis C space but really we can't go to sleep on those. We routinely screen and I'm sure everybody does and and I'm sure everybody does, and looking after the patients, that I do. There is a lot of silent hepatitis out there, hepatitis B out there particularly, that we have not been picking up in any other way. And somebody will come to me in their 50s with transaminitis and hepatitis B that I find are incidentally to their breast cancer.

Craig Underhill: 35:48

Okay, thank you. So we're big fans of hypothesising guidelines on the OJC. So, Kate, that was an interesting guideline on HCC. And I put up two concurrent publications from ASCO Guidelines for Stage 4 Non-Small Cell Lung Cancer, both with driver alterations and in separate paper Without. The first author was Ishmael Jayashimi and senior author Jayoji Patel. So it's a group of experts set up by Al Esko, includes some people known to the podcast, including Leighl and and Balash Helmos. G'day, Natasha and Balash. And I think there's really good guidelines the one without driver alterations dated previous one by addition of 10 new randomized clinical trials. So that goes through all of the detail. But there's some really great tables in the paper which are basically flow charts of how you might manage patients. So I urge any of you who are looking after people with lung cancer to have a look at those tables and they grade the treatment regimens according to strong or weak. So there's multiple regimens available. For example, in a patient with non-squamous lung cancer with a PDL expression that's high, there's a total of nine listed there, but three given a strong recommendation. So a good paper. And then in the realm of patients with driver mutations, again it goes through the detail of the randomised control trials published to date. It also summarizes it in some excellent flow diagrams, so I'd urge anyone interested in lung cancer to have a look at that.

Craig Underhill: 37:40

And then my other two papers were a little bit more provocative, let's say the first one is a letter to the editor in German Oncology, the use of artificial intelligence chatbots for cancer treatment information. We don't have time to go through this in detail, but it basically matched the chat GPT chatbots recommendations versus the insensing and guidelines. Interestingly, 12% of the outputs were hallucinated. So the chatbot came up with a treatment recommendation that wasn't even contained in the guidelines and in one third of recommendations they were non-concordant with the current guidelines. So it was a bit of a caution check for some people, including oncologists, who've leapt onto chat GPT.

Craig Underhill: 38:34

Chat GPT has these language learning models have been shown in other papers to pass the US medical licensing exam, encode clinical knowledge and provide diagnosis better than lay people. But what they don't do in this paper is clearly an individual patient come up with correct recommendations in a third of the cases. So that was a very interesting paper. It was done at a point in time with the current model of CHAT GPT and obviously that's evolving and things will improve, but for now, interesting information.

Christopher CJ Jackson: 39:15

Craig, what was the last question that you asked, Chat GPT?

Craig Underhill: 39:17

I don't use ChatGPT, chris, because I've been getting some letters from people clearly generated by ChatGPT and they are garbage.

Christopher CJ Jackson: 39:26

So instead of being Well, it's like birthday cards from your wife, that sort of thing no some letters from colleagues.

Craig Underhill: 39:31

Instead of saying no, dear Craig, it would be like dearly beloved, I wish to see that you are well at this time time-space continuum and couldn't you please let me know? It's like florally language. It's clearly stuff that people don't say, and so I think I have quite a radar for chat, gpt generated stuff, and to me it's getting there, but it's not quite there yet.

Christopher CJ Jackson: 39:59

Maybe next time we'll stop in a Chat GPT developed OJC paper and we'll see if anyone can pick up the difference between the real paper and the chat GPT developed paper.

Craig Underhill: 40:09

So are you a fan, Chris?

Christopher CJ Jackson: 40:11

I think one of the things that AGOTG circles have come across with Dr Jackson in years gone by is my love of medical comedy rock songs and I certainly have a penchant for those. And I've certainly got ChatGPT to try and write me a few comedy rock songs in recent times and they do quite a good job of writing lyrics according to a genre of a particular artist. Yeah, that's cool. I'll see if I can get ChatGPT to write you a song by the end of particular artist. Yeah, that's right, I'll see if I can get Shappi Tito to write you a song by the end of this podcast.

Craig Underhill: 40:37

Yeah, that's good, that could be our outro. And the last one's a bit of a serious paper Financial Conflicts of Interest Payment at the Expense of Patients, editorial done by Nina Sandstreet and Vishal Gowali. Big shout out to Vishal, who's, of course, one of the leaders in the common sense oncology space. But this was based on a paper out of the Netherlands conducted between 2019 and 2021. And they found that 48% of oncologists received payments from drug companies, various bits of work and, interestingly, that was concentrated in the key opinion leaders, so 47% of the total sum went to just 20 oncologists, or 1% of the clinical population. It was similar to the previous finding in the US, where 37% of total general payments in the EU went to 1% of oncologists, and so being conflicted is not a problem per se unless it's not disclosed, and it may become a problem if these people who are receiving the high levels of payments are also sitting on advisory boards for government or writing guidelines. So what this editorial suggests is that disclosure is one step and not sufficient, and they recommended that physicians sitting on national guideline committees, such as the NCCN in the US or the CIBO in Netherlands, should not receive any general payments from pharmaceutical companies during the time they are active committee members. Secondly, professional society should also mandate that members serving in their leadership do not receive any general payments. That's ASCO's current policy, and they argue that this policy should also include not just the president and leadership members, but also the annual meeting, presidents, educational track leads and discussions at major meetings.

Craig Underhill: 42:40

I think that would be a good move. Principal investigators and investigators of clinical trials should not be permitted to hold stock for the drug or product while it is under study. And fourthly, editorialists should not have financial conflicts of interest with the same company whose drug or product is under discussion. This was previously the policy at new england journal until 2002, and some other leading journals, such as b and j, have, since 2014, restricted editorials and educational authors to those without financial conflicts of interest, and they recommend that this policy should be implemented and monitored.

Craig Underhill: 43:22

So it's interesting when I give a talk occasionally asked to give a talk and it's a company sponsored event, I will put up a slide with disclosures, and it's often most of the funding, not an episode of the time. It's funding that's going to the department, but I still declare that we're doing trials with these companies and so my department has received the funding. But occasionally I'll be on an advisory board, not very often. Occasionally we'll tour paid, accept payment for educational weekends somewhere, somewhere. But I think it's really important to disclose it and I think these recommendations going further, that should also come off any public appointments where that financial conflict could have an influence. So interesting paper, eight looking pensive.

Kate Clarke: 44:09

I don't at all disagree that conflict of interest needs to be declared and I don't at all disagree that people in positions of power have the potential to be influenced and need to be open and aware of those concerns. I just worry, in a little community like ours, that you would very quickly not have a lot of people available to do those public jobs if anybody who had ever spent some time having a cup of coffee with a drug rep would have to recuse themselves. And I think I'm not accepting luxury weekend holidays in Hawaii, but I'm just not quite sure how to put my finger on it. That's my pensiveness. I think it's complex. I think, in a place this small, where those type of roles are all unpaid, that you'll have fewer and fewer people wanting to do them.

Craig Underhill: 44:57

Yeah, I think it's important that at least we're mindful of those potential conflicts, and if I was in a major public position in New Zealand giving running guidelines, I probably wouldn't have a cup of tea with the drug company.

Kate Clarke: 45:12

Yeah, I think the other thing that I giggle is that when you sign up to be a PI or a sub-I, you have to say you have less than $50,000 US stock. And I always giggle because you know that's a lot of stock in one company. You have to be seriously wealthy. So I wonder whether some of our thresholds for declaration are very, very soft.

Kate Clarke: 45:32

Yes, and maybe need some tightening up and actually maybe very soft. Yes, it maybe needs some tightening up and actually maybe buying stock. You know it's possibly cheap while you're running the study but that might not be when you're making all the money anyway. So again, I think maybe these guidelines need some thought. I'm not saying they don't need thought, I'm just thinking that maybe they need support. Uh, and we push for many of the publicly guideline did kind of assistance is unpaid and the quid pro quo was always that that would somehow come out of space in your clinical work. But it doesn't, and so the same people are doing a lot of work after hours.

Craig Underhill: 46:04

Yeah.

Kate Clarke: 46:04

So congratulations to those people.

Craig Underhill: 46:06

If anybody's listening in, I think there's some good suggestions in this paper, Chris. Final word.

Christopher CJ Jackson: 46:11

I don't think I've got anything particularly wise to add. I think that financial conflicts of interest do have a potentially corrosive effect, particularly in people who have positions of influence over regulatory decisions and funding decisions. So I think that is an area where you can't have any financial CIOs at all. But I also think people who've got public advocacy roles, who have got strong financial conflicts of interest, need to have those able to be disclosed, because they can influence a public discourse in a very negative way. So I think the disclosure forward-free disclosure, putting sunlight on it, as is done in both Australia and New Zealand, declaring all financial clear whites in the public research database is very important for that. Okay, and ChatGPT has come up with the goods for us.

Christopher CJ Jackson: 46:56

Now, what our OJC listeners won't be aware is that Professor Craig is currently about to run a marathon, a half marathon. So I've asked ChatGPT to come up with a song about an erstwhile running oncologist in the style of Taylor Swift. So you're going to have to imagine me singing like Tay-Tay. In a world that's often grey and cold. There's a story that's seldom told of a man who wears two kinds of shoes one for healing and one for the truths. He's a hero in the wars of white, fighting battles through the day and night, where the heart is vast, at the southern sea. Craig's the name that whispers believe in me From the shores of Sydney's sunlit bays to the Melbourne streets in the pouring rain. He carries the Well done, are you converted? I'm actually feeling a bit emotional listening to that. It's fantastic. Every finish line is a new life start. He's the healing force, the marathon heart. Well done are you converted.

Craig Underhill: 47:57

I'm actually feeling a bit emotional listening to that. It's fantastic, thank you. At a point it's a half marathon, huge difference. But even so, you know, I'm happy to tell you I'm the wrong side of 60 and when I did the half marathon in melbourne october I came in the top 100 for the over 60-year-old. So it wasn't bad the age of 60 to still be able to run 21K. I was very happy just to finish, and this was my daughter challenged me to do it and she got injured and didn't do it. So that's why we're doing the second one. So hopefully she'll make it to the start line on Saturday and we'll do this half marathon together. And Taylor Swift does not feature on my playlist that I've been listening to, chris, but she does now.

Christopher CJ Jackson: 48:43

So, listeners, if we have a different host next time. You know to run his Instagram so well.

Craig Underhill: 48:49

Thanks.

Christopher CJ Jackson: 48:50

Will you be using a diclofenac foot gel, Craig, to reduce inflammation of of your sore toes? I was just thinking about that.

Craig Underhill: 48:57

It's a big sore currently, so maybe that's what I need to do.

Christopher CJ Jackson: 49:00

All right listeners. Tweet in your predicted time for half marathon marathon and the person who gets closest to the actual time will get one of Jackson's crackers sent out to you personally.

Craig Underhill: 49:12

I want you to record that now and send me a sound file before Saturday, please, Chris. All right, it's been good chat to everyone, hopefully informative. Again, please if you have suggestions, if you like it or don't like it, or whatever, just send us some suggestions and any suggested papers will be welcomed. We want to make it relevant to as many people as possible. We know we have a very multidisciplinary audience and people see this as a way of trying to keep up with what's going on out there, so hopefully we're achieving those aims. Thank you to Rachael, who's patiently sitting on the sound desk fixing our errors as we speak. Thanks Rach for all organisation. Thanks Kate. Thanks, Chris Kia ora,

Kate Clarke: 49:57

ora. We do shout out some birthdays, so let us know. I'll just do a quick shout out. This is to Dr Catherine Hahn of Auckland. Thank you for letting me know that you're listening and I hope you listened today.

Craig Underhill: 50:05

Nice, okay, see you next time, everybody.

Rachael Babin: 50:08

Thank you for tuning in to the Oncology Journal Club podcast, proudly brought to you by the Oncology podcast, part of the Oncology Network.