The Oncology Podcast

The Oncology Journal Club Episode 10: Sarcomas, Precision Oncology, FIT + Meaningful Consumer Involvement

• The Oncology Network • Season 2 • Episode 10

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Unlock the secrets of the ever-evolving oncology landscape as Professor Craig Underhill, Dr Kate Clarke and Professor Christopher Jackson take us through another brilliant OJC update.

Craig reviews new sarcoma research and also looks at a mortality comparison study of six high-income Anglophone countries. Kate delves into the exciting advancements in precision oncology, particularly the impacts of on children, adolescents, and young adults. CJ looks at a groundbreaking cohort study from Christchurch, New Zealand, revealing how Faecal Immunochemical Tests (FIT) could revolutionise colonoscopy referrals and optimise healthcare resources.

Craig announces his career change, stepping away from clinical practice  to a research-centric career, after many years of dedicated practice and impassioned advocacy for regional and rural patients. His passion for changing the healthcare scene in regional Australia, particularly during the COVID-19 pandemic, shines through as he reflects on the emotional yet rewarding transition.

With a focus on enhancing patient care, this episode of The Oncology Journal Club provides a comprehensive look at how precision medicine and innovative research are shaping the future of oncology.

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

Rachael Babin:

Welcome to the Oncology Journal Club podcast. I'm your producer, Rachel Babin from the Oncology podcast. I'm joined by our esteemed hosts Professor Craig Underhill, Dr Kate Clark and Professor Christopher Jackson. Today's episode covers an eclectic mix of papers. Craig reviews new sarcoma research and also looks at a mortality comparison study of six. Thanks for having me, Thank you, Thanks for listening.

Craig Underhil:

G'day Kia Ora. Kia Ora. Welcome everybody to episode 10 of the Trans-Tasman Oncology Journal Club podcast. Where did 10 episodes go? Thanks everyone for continuing the feedback. We're getting lots of messages, which is lovely, and lots of downloads, so spread the word. We're, as usual, aiming for an eclectic mix of papers so people can keep abreast of oncology in general and some things outside their specialty streams. Craig, welcome Kia ora. Craig.

Kate Clarke:

How are you?

Craig Underhil:

Yeah, good, If we hear a boarding announcement, I must disclaimer. I'm in the Qantas lounge on the way to ESMO as we record this. Apologies in advance. Chris or CJ, how are you going?

Christopher Jackson:

Got it, craig. Look, I just wanted to say that my mum's responsible for half the downloads of the OJC. She uses multiple devices to do so and she tells me she doesn't understand much of what we're talking about, but she's sure I'm doing very well in none of this. And also, I just want to take a minute, craig, just to acknowledge a very significant event. This last week, professor Craig Underhill has decided to take a research-oriented direction and take the very bold and difficult step to step away from clinical practice. So, craig, I'm sure there'll be a lot of patients who will be reflecting on your contribution to their lives and, of course, your advocacy for the border communities, particularly over COVID as well. You, the border communities, particularly over COVID as well. You have been an absolute servant to regional Australia, pioneered a lot of work and a lot of research. Good luck on the research phase of your career. I imagine that stepping back from the clinic has been something that you've done with a degree of sadness, as well as moving on to a new phase.

Craig Underhil:

Oh, absolutely Lots of sadness, chris. I've got a wobbly lip thinking about it. It was a really difficult decision but it was time to hand over to others. I was motivated as a teenager to become a doctor and then to become a medical oncologist during physician training and I loved it, loved seeing the patients. I really kind of miss that aspect. But you know, part of it is to work at a systems level, doing the health services research and working on some advisory boards and still on some important committees, and so I think my focus is going to be that systems level change rather than just squeezing one more patient into the clinic.

Craig Underhil:

Um, but yeah, it's a hard decision but you know, turning the page onwards and upwards and um been thank you to everybody who's reached out and sent messages. It's been quite overwhelming and I have grasped opportunities that were put before me as one of the first medical oncologists in regional Australia and it's been a pleasure to be able to try and move things forward. And it's not just me, it's a whole team of people. Of course we keep going and lots to do. I tell people that I feel like I've sort of cut down to full-time employment and I'm hoping to really put some energy into the research over the next few years.

Christopher Jackson:

Yeah, well, I think you're off on the right step by heading off to ESMO just now, craig and don't worry, we won't kick you off the OJD just yet and hopefully your way of staying up to date with clinical papers. So yeah, if you find Kiwi Craig on the podcast audience, you'll know that we're phone number nine.

Craig Underhil:

Okay, thank you. And just to say too, the other 50% of the download is probably my mother in Albury. Kate, how are you going? I'm sorry to hear you had recent bereavement and Kate, like all of us, really has a lived experience with cancer, having had a family member die recently of advanced cancer. You know this is we're not just doctors, are we? We're also all really users of the system because it's so prevalent.

Kate Clarke:

Yeah, look, and I think also I have a very culturally appropriate hangover after the Irish Catholic wakes. But you know, so, thinking of Uncle Paul and his whanau, you know we had a brilliant time, amazing man, but he had one of those wildfire cancers that maybe the tumor agnostic stuff will answer for us in the future.

Craig Underhil:

Yeah, I think we're learning that. You know, prostate cancer is probably a heterogeneous disease, like breast cancer or lung cancer or anything else, and there's a spectrum and the younger patients tend to have the more aggressive and the older tend to have the more slow-growing hormone-responsive. But he was 76 and died very aggressively so maybe he had a mutation, who knows? Anyway, I'm sorry to hear all that, kate. I'm working on my hangover, so I'm having my first glass of champagne as we speak and hopefully I'm not slurring too much by that. End of the podcast.

Christopher Jackson:

The Journal Club sponsored this week by the Qantas Lounge in California. All right, craig. What have we got today?

Craig Underhil:

Let's get on with the journals. Kate, do you want to go first?

Kate Clarke:

Yeah, look, my journals this week are all, or journal articles this week are all on a theme those of you who are astute, every episode listeners will remember that Dr Jackson challenged me with are tumour agnostic therapies really tumour agnostic? So I wanted to present three papers which I think are starting to answer those questions. They have a theme also that they are all either first authored or last authored by Vivek Subia and his various collaborators, who will be speaking at the joint ASCO ESMO session, at ESMO 2025, on precision oncology and the future thereof. So, craig, get across it.

Kate Clarke:

So my first paper is fascinating. It's called Precision Oncology Across the Ages Impact on Children, adolescents and Young Adults, and it was published in Cancer Cell, the two authors, vivek Subia, from Sarah Cannon and Razelle Kuzrock from San Diego. That's that hangover slipping San Diego. It focuses on N-TRAC-track, braf and RET fusions and the fact that, although the responses are tumor agnostic, the cancers they show up in are age specific, which I find fascinating. So, for example, babies perish the thought get infantile fibrosarcoma with an N-track, whereas older adults might get secretory breast carcinoma or an anaplastic thyroid carcinoma. So just really interesting for us to be just thinking perhaps what implications that has for future research. So that was my first paper. There are more coming. I think it stresses the need for including much older adults than we do and much younger children than we do in a lot of our routine research, because there's a lot of stuff to be learned out of the experience of those people.

Craig Underhil:

Fantastic. So in this paper everyone presumably had a next generation sequencing done on their tumor.

Kate Clarke:

Yeah, they were looking at the patients from the NCI match trials mostly, so they were all. I think we're a long way away from that in Joe Blog community practice being able to do whole genomes on everyone, and I realized that there are places in the world, and even places in New Zealand, where that's becoming feasible, but that's a long way for us. So we very much are of the thinking about the cancer in that person. What target doing an individual test if we can afford it. So this, this gives me a little bit more information yeah, great.

Craig Underhil:

it's a recurrent things in it that we we need to be thinking not just about tumor types but getting a bit more precise in the diagnostic testing. So there's a program can't remember the name it's run out of of New South Wales and it's basically all of the children diagnosed with cancer in Australia are able to have genetic testing done and then matched to trials. So it's like that Omicode Prospect program in adults. So that's a great initiative. So really bringing precision oncology to the child with cancers and they're about to run out of money, decision oncology to the child with cancers, and they're about to run out of money. So they're looking for more funding to continue that program, which I'm hoping they'll demonstrate cost-effectiveness because you imagine the quality adjusted life years of saving kids' lives is enormous. So, yeah, interesting field. So thanks for pointing that paper out, cj.

Christopher Jackson:

Where's the iSpy study up to with breast cancer? So that's the other big platform study in breast cancer, isn't?

Kate Clarke:

it. Yeah, ispy1, ispy2, and maybe I don't think they're quite up to iSpy3, multiple different platforms. They're twiddling and twiddling and twiddling constantly with how they do it. So for those of you who haven't read about this before, this is a mostly neoadjuvant study where they look at a group of patients with similar features and try out the most logical therapy as neoadjuvant therapy and then graduate those therapies that go over, that exceed the threshold for pathological complete response that they have chosen as appropriate for that disease type. I think it is a massive project. It's a decade old already and I think it's got a lot more ahead of it. I'm imagining at San Antonio there will be lots. There was a whole session at ASCO on iSpy Interesting.

Christopher Jackson:

Lots more to come. I mean precision. Oncology is hundreds of years old. Actually, it was 1896 when Sir Henry Beatson first published his paper on oophrectomies in patients with metastatic breast cancer and induced spontaneous remissions in many of them, or surgical remissions in many of them, from having done so. And that was 1896, and it wasn't until what was it? The 1960s or 70s when tamoxifen in the ER receptor was discovered. So certainly, we often make an observation clinically and then find the target much down the line. We're trying to re-engineer that, of course, to find the target first and then do a rational therapy, but that's got very mixed successes. I still maintain, kate, that a BRAF mutation in colon cancer is really important.

Kate Clarke:

Hold that thought, hold that thought. There's another paper going to explain that in a minute Shoot. Well, when we come back to my other papers, there is some really good thought being put into that very concept. The only thing is, the current solution, which I'm dropping hints about now, is just more expensive therapy on top of the other expensive therapy. But we'll get there, we'll get there. Yeah, I was talking about this. We have a spa pool. It's cold in Wellington and my son and I talk in the spa pool because he can't play on his devices. And we were talking about organic chemistry and the fact that, with computing and organic chemistry combined, we can now not only figure out what targets actually look like you that can then rationally design drugs to affect those targets, leaping over you know, what previously have taken decades in the lab can now be done in a computer in a couple of days, which obviously opens, opens up massive doors. So we've got these great tools. Now we have to understand how they actually should be working.

Craig Underhil:

Exactly and ensure that all populations are able to access that kind of technology.

Christopher Jackson:

Yeah Well, the first paper I wanted to talk about was completely and utterly the opposite of intensifying everything. So this is a paper from the New Zealand Medical Journal this week on the use of fecal immunohistochemical testing to prioritise symptomatic cases referred for colorectal investigation, aiming to streamline the diagnostic processes and improve colorectal cancer detection. Now we all know that a lot of people get referred for colonoscopy for people who have gut symptoms and that that can, in resource-constrained environments, lead to long waiting lists and only a small proportion of those patients who are referred with suspected colon cancer actually have bowel cancer. How can we make that pathway more efficient? Do you just do fleximal sigmoidoscopy, which was one pathway, or others have suggested adding a FIT test to those who have colon symptoms as a rule out? Basically, if you're FIT negative, perhaps you don't need to go on and have a colonoscopy. This was being piloted in the UK in the NHS and it seemed to reduce the number of colonoscopies that were required.

Christopher Jackson:

This study was a cohort study based in Christchurch, waitaha, christchurch, and it was looking at the use of FIT in people who had been referred for direct axis colonoscopy to see if you could improve the sensitivity and specificity of the diagnostic criteria. Now, for those who live in Australia, it's often quite easy to get a colonoscopy if you've got insurance. I understand In New Zealand you have to meet a certain number of criteria before you get access to colonoscopy in the public system and that gets prioritised within two weeks, within six weeks or routine. The criteria for that are coarse and the symptom clusters are crude and they're not highly specific and aren't highly predictive. In this cohort study, 739 patients were initially referred to the pathway, so triage by a clinician determined as appropriate for foot-based testing, and 97% of patients who were referred provided samples Of the cases investigated. 15 of 739 patients, which is 2.2%, were diagnosed with colon cancer and 8% had advanced polyps. They set the FIT threshold at three different levels less than 10 micrograms, 10 to 149 micrograms per gram or greater than 150. And the overall FIT positivity rate for hemoglobin of greater than 10 mics was 17.1. Sensitivity was 80%, specificity 84.3% and what that means in practice is that if you added FIT testing to referrals for colonoscopy that were not deemed quote unquote super high risk, then 62% of patients may not have needed a colonoscopy because it could have been ruled out by the FIT, which would have a lot of resource implications.

Christopher Jackson:

There's a couple of things that stand out in that study to me. First of all, only 2.2% of patients who are referred via the symptom-based pathway, meeting the symptom-based criteria, ended up having colorectal cancer. Just think about that. We've got a guideline which says if you've got these symptoms you should be referred for a colonoscopy, and only 2.2% of people actually had colorectal cancer. That's pretty low. Put that in context If you've got a positive fit on the National Bowel Cancer Screening Program with no symptoms, your positive predictive value of having colon cancer is around 7 or 8%. So it's actually a very poor test. Symptoms are a very poor discriminator of bowel neoplasia.

Christopher Jackson:

There were three cancer cases missed by the FIT test but actually they were cancers in adenomas so they probably weren't even bleeding and I would doubt very much that the patient's symptoms were actually caused by those small adenomatous cancers anyway.

Christopher Jackson:

But if you had the FIT rule out, eventually they would have grown into cancers. There was limited data on patients not included in the pathway and it was a single centre regional study, non-randomised. Of course it's a cohort and these things are always better if you do them randomised. And there was limited analysis on non-cholorectal findings because some were referred for CTC, which then had incidental findings. There's quite under-representation of Māori and Pasifika patients and if you're only getting 15 cases of colon cancer out of 739, you're going to have clearly under-represented indigenous patients as well. The fifth threshold, variability, could be altered up or down depending on where you want your sensitivity and specificity to sit, and I think this is an important area for rationalising the investigations of patients with colonic symptoms by the addition of FIT, with further refinement still needed on this and more research needed, but a very positive thing to be doing to reduce the number of colonoscopies, which we need to do to make them more available for others.

Craig Underhil:

Very interesting, Chris. So is that the same as the fecal aqua blood tests that we use in the national I don't know what you use.

Christopher Jackson:

We do use a FIT test in New Zealand, a FIT for purpose, so a fecal immunohistochemical rather than GWAIC. Gwaic, of course, gets animal heme as well as human heme and using a fecal immunohistochemical test for human heme is more specific than the guaiac based ones. You know we're getting a lot more other tests. You know stool DNA, that type of thing being looked at, as well as other potential symptom clarification tests. But the FIT has been tested in this way and has found that you can reduce the number of colonoscopies by 60 odd percent, creates more space for screening and creates more space for surveillance, which we're struggling to keep up with the demand.

Craig Underhil:

Yeah, and three cases missed out of 739, but they were early cancers. You said two were added at the moment. So at a population level this would seem to be a step forward, because I think our colonoscopy services, even in the private sector, are a bit overwhelmed.

Christopher Jackson:

Yeah, I think it's really important to look at de-escalation of investigation, right, you know, we have a real problem with that pipeline and that funnel of getting in, and it's also as oncologists we often think oh yeah, patient had change in bowel habit with a tendency to lose from more frequent stool, healthy colonoscopy and they had bowel cancer. We often don't think about the huge number of people who have those symptoms, who don't have bowel cancer, because we are the wicket keepers right of the cancer cricket team and we're always the one who are, you know, standing behind the wickets and catching the ones that go through and all the others that don't get turned into cancers with equally suggestive symptoms are ones that we just never see.

Craig Underhil:

So we've got to be careful of our confirmation bias, I think, just assuming that all the symptoms that we're familiar with are always cancers, fantastic. So I've got a bit of a change of tack. So there is still chemotherapy studies being published. So the reasons for choosing this I'll elucidate. But this was a study of doxorubicin, trabectin with trabectin I can even say it maintenance in leiomyosarcoma. The first author was Dr Portier, on behalf of the French Sarcoma Group. This was in patients with advanced leiomyosarcoma, a total of 150 patients, and they were randomized to receive six cycles of doxorubicin plus trabectin, followed by trebectin maintenance. So trebectin is available as a second-line treatment. The primary endpoint was progression-free survival, overall survival. Secondary endpoint Half the patients had uterine lyomyosarcomas, the others soft tissue, and this median overall survival was longer in the combination, followed by maintenance group, 33 months versus 24 months. In the doxorubicin alone group, the grade 3, 4 adverse events were double. So what would you expect the grade 3, 4 be for six cycles of doxorubicin? Anyone, 40% approximately. Yeah, there was 50 in this paper and so it was 90-something percent in the combination group. There's no quality of life difference but significant survival difference. So that was published in the Journal of Positive Results New England Journal with an accompanying editorial.

Craig Underhil:

But one of the reasons for mentioning this was the French sarcoma group have done some landmark work. They have a national sarcoma program and so we mentioned the work in Brazil where they centralised a review and found that a significant number of patients were either had their diagnosis changed either to benign or to a different subtype of sarcoma. So the French pioneered a national platform where they refer slides electronically for centralised review, make recommendations for treatment which can occur in local region. All the patients are registered on a portal and that generates a lot of data. This group's been highly active at publishing data, generating research questions, so they were able to do this trial of 150 patients nationally and showed a positive result. The company editorial suggested that this may be a new standard for those patients. One of the sad realities is that the drug's about to go off patent so they're not expecting any more studies to be done. In fact, this may, outside of investigator-led studies, which this was, and in fact may be difficult to get a listing because it's about to go off patent but presumably would become generic.

Craig Underhil:

So a few interesting spins on that paper. So one of the reasons for talking about it was. There's been a pilot study done in Victoria of centralising review for patients with penile and testicular cancers there's about 200 a year in Victoria and so there's a program piloted and sustained with Barwon Health in Geelong leading on that and patients can be referred for an opinion from a centralized program. So it's a bit of a we be some data collected and published and research hopefully done by the collective group in what ultimately are fairly rare cancers 90% grade 3, 4 toxicity, craig, I mean, is that more than just hematologic and alopecia, are there things that will impact there on patients' quality of life?

Craig Underhil:

It was mostly hematological crest, but there's abnormal LFTs as well.

Christopher Jackson:

So more the paper toxicities and really ones that were patient reported, Because quality of life in an unblinded study can be biased towards an interventional arm right Because people can heal better because they're getting more intensive therapy. So that's the potential for bias in that. So it is good to see that it's mostly those paper toxicities of hepatic and blood count derangement.

Craig Underhil:

Yeah, it's just a sober reminder that you know the toxicity that we cause through chemotherapy. But you know and these people stayed on maintenance treatment, you know, so again had low-grade toxicities over a period of time. So it's that trade-off. So the quality of life data would have been really interesting because you're trading off extra toxicity with extra survival, but that wasn't featured in this paper. All right, I'm having a bit of salt and pepper calamari as my quick bite and I'm hoping that someone can see with my champagne glasses and might need a refill, but Kate.

Kate Clarke:

So I've got two things I want to do together because I can't figure out which one goes first. So both papers are last author or first author of the exubia. Again, one paper is Westphalen from Munich and Martins Branko from Lugano, and it is the paper to explain all papers. It's the ESMO Tumor Agnostic Classifier and Screener, a tool for assessing tumor agnostic potential of molecularly guided therapies and for steering drug development. Now this is where I think this is interesting.

Kate Clarke:

So much of the arguments that we have in oncology is when we are not using the same language. So I think this is really helpful. So rather than using the concept tumor agnostic, they prefer molecularly guided treatment options and then break that up. So in order to be called tumor agnostic, you have to have a response in at least one out of five patients, in two-thirds of the investigated tumor types. I think that's quite a low bar, but that's what they're calling tumor agnostic.

Kate Clarke:

Tumor modulated is when the therapeutic effect on a targeted driver molecular aberration is modulated by the tumor-specific biology. So, for example, parp inhibitors in tumors harboring BRCA mutations is what they use for that, or HRD. So it's not really the target, it's the process I suppose you're looking at. And then tumor-restricted is when the therapeutic effect on a targeted driver molecular aberration is only present in a specific tumor biology. So, for example, pik3ca-mutated breast cancer. We don't have the use of PIK3CA inhibition in any biology, so, for example, pik3ca mutated breast cancer. We don't have the use of PIK3CA in admission in any other. So I think it's useful to have unshared language as we're talking about these things. I probably, like Chris, am a little bit disappointed that I don't really think that's truly tumor agnostic if the response rates are that very low.

Kate Clarke:

Then the other paper is Also Razelle Kozrok and Vivek Subia, joined by Guda Rill and Burris. That's called the Evolving Landscape of Tissue Agnostic Therapies in Precision Oncology. It's a review article in Cancer as in the Cancer Journal for Clinicians slightly different paper on how to do the research. But the bit that I particularly liked was that not only does it have a lovely diagram demonstrating the frequency of many of these tumor agnostic targets which I am demonstrating for on an oral podcast for the two that are watching and it uses a female, which is fantastic. If you've ever tried to Google dermatomes for a patient, you always end up with a male body. It's very annoying.

Kate Clarke:

But it also says resistance mechanisms are also molecularly driven, and so they will need identification of molecular targets and molecular therapies to overcome them. So the example they use is the one that Chris was alluding to. So why don't dual breath inhib inhibitions, or BRAF inhibitions, work in colorectal cancer as they do in melanoma? The theory is that the colorectal is clever and it uses the EGFR pathway to overcome the fact. You've turned off your BRAF and that's the TuxMab works. Now we also all know that although that works, it works for a short period of time. So where we're going to get to in this team's dreams is that we will have an understanding of the complete molecular landscape of each tumor, understand how they all interact, and then we'll have some way of turning it off in a way that kills the cancer, but hopefully not the patient. Interesting reading, and I think an up-to-date review is always useful to get your head around.

Craig Underhil:

Yeah, absolutely. And Kate, does that mean that we should be doing re-biopsies of people and retesting to look for new mutations? I mean, that's getting the lessons from breast cancer right. Even with ERPR and HER2, you see changes between the primary biopsy and relapse of the patient.

Kate Clarke:

Well, you see changes between the primary biopsy and relapse. Well, you see changes in real time in ctDNA in patients with metastatic colorectal cancer who are undergoing anti-EGFR therapy. You see changes in the dominant population. So we know this happens. How are we going to do that in the real world? I remember 10 years ago talking with one of my colleagues about having a little machine on the desk. Put your finger in there and let's see what's going on. I think we're a long way off.

Christopher Jackson:

So look, I think that's really interesting and I agree with you, kate, that's quite a low bar.

Christopher Jackson:

Response rate of 20% in two-thirds of tumour types is not really suggesting it is the driver in a significant proportion of those cases really.

Christopher Jackson:

And I wonder if we use that same criteria for chemotherapy instead of response rate of 20% in two-thirds of the tumor types, and therefore that chemotherapy was agnostic for cancer types, I think many of us would balk at that suggestion and would want to see it tested in that specific condition before we would then add that to it because of its potential toxicity. But I also think there's the other issue and that's of opportunity cost, because every time you use a targeted therapy you are foregoing the opportunity to use a different type of therapy which may or may not be more effective. So we still do have to hold it to the standard of a randomized trial. I think I'm delighted they're making progress in this direction and I know there'll be a lot of medically focused oncologists out there who will strongly disagree with that view. I guess I've just seen too many patients on targeted therapy where it just hasn't worked. And the enthusiasm and I'm bridled with enthusiasm for molecularly targeted therapy I think needs to be somewhat tempered, and the enthusiasm needs to be matched by the evidence.

Craig Underhil:

Yeah, good comment of trials like N equals 1 trials, where we can match targets and our drugs and get answers to the research questions quicker, rather than doing randomized trials against poor standards of care. So I think part of this new paradigm of targeted therapies and precision medicine needs to be thinking about tele-trials as a tool to bring trials to rare populations, but we also need to be thinking about other innovative models of trials that can get the answers.

Christopher Jackson:

I also don't think that you need to restrict yourself to clinical studies, craig. I think we underuse registries in that sense. There's an awful lot of people out there getting an awful lot of molecularly targeted therapy which is driven by their genomic profile in the clinic these days anyway, which would be off-piste. And the thing about the literature and studies is that I think the problem with them is that fundamentally, I'm making my point very slowly here. Rachel.

Christopher Jackson:

Please again edit this up a little bit to make it sound a lot smarter than it really is. I think the issue with that is that you tend to have a bias towards positive reports, and that is, if you do get a spectacular response to a target, you're more likely to write it up as a case report in a journal and then that gets listed. If you're doing proper phase four off the back of a registry and you're putting all of your patients in, you're also going to get a sense of what the denominator is, and that is how many patients succeed out of how many patients in whom it was trialled, and being able to give that information to patients, what's the likelihood of this often unfunded therapy being helpful for you in your condition, could save people from financial toxicity, and most people don't have pockets of cash sitting around to spend on these highly expensive drugs, which may or may not work for them.

Kate Clarke:

And I think the other thing that needs to be stressed is that the trial populations are so artificial. I was speaking to a patient the other day and I said I think maybe one person in this clinic of 30 patients would actually be eligible for any reasonable Phase 3 trial by virtue of comorbidity, by virtue of pretreatment, by virtue of you know, unmeasurable disease. So actually it's very hard to translate that into real people. And these very rare trials, short of being the MD Anderson, you're never going to have enough patients to warrant opening the trial. So yeah, so I'm with Chris. I would love a like we did with COVID. We had, you know, we had an international cancer patients with COVID registry. We should be able to do the same in drug therapy.

Craig Underhil:

Yeah, so that's where registries come in registry trials. But let's push on. Chris, do you want to tell us about your-.

Christopher Jackson:

Yeah, I just wanted to do a very quick shout out to the New Zealand EVQ Only Better which is called ACT. Now, this has nothing to do with my paper, but just to back on to what Kate said about the registry trials, the New Zealand equivalent of EVQ is called ACT. Now what we're doing is we're listing this dictionary of possible regimes and then matching it to electronic prescribing so we can look at duration of therapy, which can be a surrogate for PFESfacial response data, for example, and tie that to hospitalisation. So it's effectively going to be an ongoing national cohort study, which I think is really powerful, and, unlike EVQ, we can collect the outcomes back from those groups that use those regimes. So it's a really good innovation in New Zealand, again catching up with Australia, but hopefully maybe even overtaking it in a place or two we're going to have a look at that on Google, maybe even overtaking it in a place or two.

Craig Underhil:

I'm going to have a look at that on Google.

Christopher Jackson:

Is it ACT now? Act now, ACT now. Anti-cancer therapy nationally organized work.

Craig Underhil:

Okay, Chris, quick bite.

Christopher Jackson:

Okay, quick bites, all right. Well, I'm going to do this in my best of British accent, just so Craig can understand me for the remainder of the podcast, and I'll see how much it drives him mad. Okay, queen's English, all right. Okay, all right, craig, I'm going to go back into my Kiwi's vernacular. This is an important study for all those GI oncologists out there.

Christopher Jackson:

Modified de Grimaud 5-FU, of course, is actually two days of bolus 5-FU with a 24-hour 5-FU pump, and then it took a long time for that to go to bolus One, and then it took a long time for that to go to bolus one-off bolus and a 46-hour infusion of 5-FEU. Right, that's what we would all consider now de Grimaud, but obviously not what de Grimaud originally described. A lot of controversy is around whether or not you even need the bolus. You get mucositis, you get eukopenia and you can get a little bit of alopecia from that bolus as well. Can you go without it? What does it add? Many of us drop it quite early. What's the impact in terms of PFS?

Christopher Jackson:

This really nice multicenter cohort study that was published in the journal of the NCCN was to determine if the emission of 5-FU bolus affected overall survival, pfs and toxicity profiles, a retrospective cohort study across multiple institutions. Patient with advanced GI cancers who are undergoing treatment with the multidrug regime included 5-FU that were divided into two groups those received 5-FU bolus and those who didn't and data collected demographics, cancer type, treatment regime, dosage and key outcomes such as survival and adverse events. Primary endpoints were OS and PFS, secondary endpoints were toxicities. The key findings drum roll please. I will do this in an English accent, greg. There were no significant differences in overall survival between the patients who received the 5-FEU bolus and those who did not. This suggests that omitting the bolus does not negatively impact survival rates in patients with advanced gastrointestinal cancers. Similarly, progression-free survival was comparable between the two groups, indicating that disease control remained effective without the bolus.

Christopher Jackson:

So answer number one you can drop the 5-EFU bolus and it doesn't make people's cancers get worse. In terms of toxicity profile, patients who emitted the bolus had lower rates of adverse events, particularly hematologic toxicity utopenia, fibromycopenia less frequently in the emission group. Non-heme toxicity, such as GI symptoms with diarrhea and nausea, were also lower in the group that didn't receive the bolus, contributing to an overall better tolerance to the treatment regime. Now, in clinical practice, I've been halving the bolus in many of my patients at a very early stage for quite some time and this is going to give me a lot of confidence in terms of dropping out that bolus 5-FU in pretty much most patients. I know this has been around our chat group before Craig, when the study was presented for the first time, and I'd be interested to know if many people, including our listeners, can text us in yes, that's you, mum and let us know if you're dropping the 5-EFU bolus in your deGromont-style regimes and how you found that.

Craig Underhil:

Well, fantastic. It's a very heretical view, and the dogma has always been that you needed to do that, bolus, and I think it was a pharmacodynamic effect, wasn't it, chris? That was thought to be important, so that's great. We've not had the really good data, and so I'm sure that soon, on EBQ and ICNEL, this paper will be referred to. So well done for bringing that up.

Christopher Jackson:

If I was going to say anything about that study in advance, I would have thought to myself that, oh yeah, the selection bias issues are that people in whom you omit the bolus may have been frailer or had slightly more adverse characteristics. So if I'd seen a lower OS or PFS it wouldn't necessarily have discounted the possibility that omitting the bolus 5-FU was actually a bad thing. It may have just been selection right because it's a cohort, but seeing them be the same, that would tend to suggest that you've accounted for those subtle selection biases and they're still doing just as well. So actually that because of the way the effect goes, I think is again quite reassuring. That because of the way the effect goes, I think is again quite reassuring.

Kate Clarke:

Was there any mention in the paper about dose or delivery of a flinic acid?

Christopher Jackson:

No, really great question, just only the leucovorum when you're giving a 48 hour infusion.

Kate Clarke:

Probably not, and our current protocols have it given over two hours, which is a lot of share time for something that may not be doing, jack.

Christopher Jackson:

Wow, we give a 15-minute bolus push. So again, different practices around the place.

Kate Clarke:

I'm having an argument with my team at the moment about that.

Craig Underhil:

Yeah, okay, so I've got a couple of interesting ones. This is one that's not oncological, but I think it's something that people might refer to. In fact, both of these papers I'm doing might be useful for people who are thinking about applying for grants, because this one, entitled Life Expectancy and Geographic Variation in Mortality an Observational Comparison Study of Six High-Income Anglophone Countries, published in BMJ Open, wanted to compare life expectancy levels and within-country geographic variation life expectancy across six countries. So they were the US, uk, canada, australia, ireland and New Zealand, so six countries that speak variations of the queen's english, and they were analyzed by gender and then analysis of sub-national geographic inequality, mortality with each country, and so australia won as having the best life expectancy, correlated with the lowest incidence of within-country geographic disparity, which is interesting, and unfortunately, new Zealand didn't do as well on the league of those six countries. So the learnings in that for me, though, is that how important those within country inequalities and disparities are, and so if we want to make inroads into life expectancy, we need to address those issues, the inequalities, the social, social, social determinants of health outcomes, and so Australia by luck, because I think we're going backwards with an increasing disparity between rich and poor is still leading the league table in those six Anglophone countries. But if we want to do more to improve life expectancy and, I'm sure, cancer outcomes, there is now this evidence that it's important to address those inequalities if you want to make a difference. And so the same in New Zealand. Hashtag change in government. If New Zealand wants to move up the table, they're really going to need to work in those areas or populations that suffer from this inequality. So there you go.

Craig Underhil:

And then the second paper is entitled Meaningful Consumer Involvement in Cancer Care a Systematic Review on Co-Design Methods and Processes. So a shout-out to the senior author, anna Ugaldi, and first author Nicole Kiss. And we've got a couple of regular listeners to the podcast who are authors Sabe Sabeson, telehealth guru in Townsville, and Dana Shwiatek, who formerly worked within the Department of Health in Melbourne but now works at the Livin' John Cancer Centre in Melbourne. Dana's a regular listener, tells me the story about one time she was driving and had to pull over on the side of the road because she was laughing so much listening to the podcast that it wasn't safe to continue driving. So g'day, dana.

Craig Underhil:

This is an excellent paper. Again, we're all expected now to address meaningful consumer involvement in cancer care and embedding the consumer voice in processes, including implementing new programs or in grant applications, and so I found this a really useful paper. So it sets out, it's a systematic review, and so it synthesises and evaluates these principles of co-design in the oncology literature and provides a series of recommendations on methodology to use, frameworks to use, how to effectively recruit and engage co-design participants and the evaluation of the co-design process, with the end point of being that we should, that should, help drive appropriate, meaningful and equitable co-design leading to better cancer research and care. So this is really highlighting this as a bit of a reference, I think, for people going forward if they're thinking about how to more effectively engage consumers in their health service or applying for research grants.

Christopher Jackson:

I really like the distribution within countries paper, craig. That's work we've looked at with the International Cancer Benchmarking Project too. I think it's critically important to make sure that you get fair and just access to cancer care, no matter who you are or where you live. And that distributive issue is quite critical to moving ourselves forward, and it runs a little bit against the centralisation hypothesis that you have to build big towers and big temples to cancer in a couple of major centres. I think the issue is distributive and we need to focus on that a lot. Yep.

Craig Underhil:

And very quickly, two PBS updates. So two new drugs listed in Australia. One is cabizantinib. It changed the PBS wording to allow use in non-clear cell renal cancer. So there's never been a PBS drug in the non-clear cell carcinomas. So there now is. It's based on a small population of patients in clinical trials. We've listed those references for people to look at. Is there anything available outside of studies or access programs in NZ for non-clear cell renal cancer patients?

Christopher Jackson:

Just busily phoning a friend who treats GU Craig.

Craig Underhil:

Okay, Well, I expect the answer to that is probably no, and I think this is really important and we might actually look at these, discuss these in our next episode. But trastuzumab Duruxtacan, one of our favourite molecules, has now been listed on the PBS-CATE or the HER2 HER2 Low Advanced Breast Cancer on the basis of the Destiny 04 study. So we've listed the link to that New England Journal paper from 2002 if people want to review the data, and I've listed an interesting paper that came out of a group of pathologists in Italy, funded by the Italian government and philanthropy, but they've done some guidelines on the testing of HER2 based on the ASCO and ESMO guidelines in this population. So just a couple of interesting references for people.

Christopher Jackson:

That's fantastic. Well, there's an outro here I'm just going to. We've been using a lot of ChatGPT recently to help me manage large workloads and I've been finding it really a helpful resource. So I asked ChatGPT to maybe summarize Craig's career and pay tribute to him as he makes this big change. So we've got ChatGPT having given Craig another poem oh, we certainly do From red dust roads where the silence hum, big change. So we've got ChatGPT having given Craig another poem. From red dust roads where the silence hums and the eucalypt whispers of home he comes.

Christopher Jackson:

Craig, a healer, once bedside spoilt rural Australia. His hands knew the pulse of a thousand lives in towns where the hospital barely survived. He gave hope to the regions. Deaf ears he quelled with wisdom and patience in hearts he held. Yet science called with a quiet plea. A world of research he yearned to see, to understand cancer, to dig deep and explore and bring answers to those who had less before. His colleagues gathered a circle of trust with voices of admiration, of pride and of dust For Craig, who always gave them the tools to fight. In the darkest of days he brought back the light, rural and regional. He made them strong, a pioneer of hope where few belong. Craig the seeker, with science in hand, has reshaped the future of his beloved land, of his beloved land.

Craig Underhil:

Well, I'm speechless, but thank you so much, chris. Really, I think we should say goodbye. Safe travels, craig. Keep up the DVC. Have a great week everybody.

Kate Clarke:

Say hi to Barcelona for me. Oh, me too Love it, love it.

Craig Underhil:

Thanks, Rachel. I will Craig you can do the next OJC podcast in your Qantas PJs. Yes, the other one's worn out, that'll be.

Christopher Jackson:

The next episode will be called the OPJC.

Craig Underhil:

Well, thank you for that lovely speech, chris, and have a great week everybody.

Rachael Babin:

Bye, thank you. Thank you for tuning in to the Oncology Journal Club podcast, proudly brought to you by the Oncology Podcast. Part of the Oncology Network For healthcare professionals. Seeking regular news, updates and insightful discussions, we invite you to join our community at oncologynetworkcomau. Your free registration includes a complimentary subscription to our weekly publication, the Oncology Newsletter, a valuable resource to stay updated on the latest advancements in the field. We value your input and welcome your feedback and paper recommendations via our social media channels, email and website. Your insights help shape the conversation and drive the direction of future episodes. This is Rachel Babin signing off for the Oncology Journal Club podcast.