The Oncology Podcast

S3E10 The Oncology Journal Club: I am large, I contain multitudes!

• The Oncology Network • Season 3 • Episode 10

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Welcome to The Oncology Journal Club Podcast Series 3
Hosted by Professor Craig Underhill, Dr Kate Clarke & Professor Christopher Jackson | Proudly produced by The Oncology Network

Welcome back to The Oncology Journal Club podcast, your essential dose of the latest oncology research, expert analysis and our trademark blend of healthy scepticism and bad jokes.

Hosted by Professor Craig Underhill, Dr Kate Clarke and Professor Christopher Jackson.

This week’s episode really does contain multitudes, with an incredibly eclectic mix of papers.

  • Craig looks at the effectiveness of cancer control measures and optimising drug dosages.
  • Kate talks us through interactions between solid neoplasms and the microbiome and shares a curious paper on extra virgin olive oil.
  • CJ tackles a sobering paper on substandard anticancer medications and what lessons can be learnt from KEYNOTE-585 and Matterhorn in gastric cancer.

We’ve a great selection of Quick Bites and a heartfelt discussion about taboo thoughts and the challenges carers of people with brain cancer face.

To learn more about The Oncology Network, subscribe to our free weekly Newsletter and listen to other fantastic podcasts, visit our website: www.oncologynetwork.com.au. You'll also find the Show Notes on the website with links to papers, a transcript and bios of our hosts.


SPEAKER_02:

Welcome back to the Oncology Journal Cub Podcast, your essential dose of the latest oncology research, expert analysis, and our trademark blend of healthy skepticism and bad jokes. Brought to you by the Oncology Network. I'm your producer Rachel Bevan, and I'm once again joined by our Journal Cop Dream team, Professor Craig Underhill, Dr. Kate Clark, and Professor Christopher Jackson. This week's episode really does contain multitudes with an incredibly eclectic mix of papers. Craig looks at the effectiveness of cancer control measures and at optimising drug dosages. Kate talks us through interactions between solid neoplasms and the microbiome, and shares a curious paper on extra virgin olive oil. CJ tackles a sobering paper on substandard anti-cancer medications in sub-Saharan Africa, and also looks at what lessons can be learned from keynote 585 and matter horn in gastric cancer. We have a great selection of quick bites and a heartfelt discussion about taboo thoughts and the challenges carers of people with brain cancer face. We hope you enjoy listening to this thought-provoking episode. If you'd like more information about the Oncology Network and the Oncology Journal Club podcast, head over to OncologyNetwork.com.au. And just a quick heads up: our 2025 Christmas special episode will be out soon. So you can expect more fun antics from the OJC team then. Thanks for tuning in. Let's get started.

SPEAKER_00:

G'day, g'day, g'day. Welcome to the Oncology Journal Club podcast. G'day, Dr. Clark.

SPEAKER_03:

Hey, g'day, Craig. How's your uh man flu treating ya?

SPEAKER_00:

Yeah, I'm over the man flu. Thank you. It is a thing. And um Professor Jackson agrees with me. There's scientifically proven evidence.

SPEAKER_05:

I just don't think people well, when I say people, I mean women, uh take man flu seriously, Craig. I mean you and me understand the seriousness of this condition. But for other people to diminish its severity, they clearly just don't understand illness. Yeah.

SPEAKER_03:

I don't you think that that new drug, TTFUMAB, has really changed manflu for life.

SPEAKER_00:

What does TTFUMABU It's is TFUMAB? What was it?

SPEAKER_04:

That's what I thought you were saying too, Craig. TTFUMEB. TTFUMAB is that the one that you serve with a cup of concrete, Kate.

SPEAKER_03:

Yes, very much.

SPEAKER_04:

Well, it's good to know our co-host is so empathic to our um You know, I've got to say the the bug that I had was really serious. I mean I was almost an ICU with it, I mean, for 48 hours.

SPEAKER_05:

Uh and the fact that I recovered so quickly is just a testament to my wonderful constitution and the strength of my character. I'm sure it was the same for you, Craig.

SPEAKER_00:

Yeah, absolutely. So we've been very heartened recently by the number of people downloading the episodes and for the nice feedback we're getting. So please keep it up. Let us know if you have uh suggestions for papers to cover or topics. Uh we're trying to reach a fairly general audience, and today's episode I think is a good example of a fairly eclectic mixture of topics. So let's get straight into it. I'm gonna go first today. So I have a paper from the Australian New Zealand Journal of Public Health from June from Lynch et al. It's cancer control measures have prevented 230,000 deaths in Australia since the mid-1980s. So I'm sorry for the 10 listeners in New Zealand that uh uh this is focused on Australian cancer control, uh, but I'm sure um you could extrapolate similar results in New Zealand population as well. So this is from a team led by the Cancer Council in Victoria. They wanted to estimate the lives saved because of cancer control measures implemented in Australia since age standardized mortality rates have been available, which is in the 80s. And so they looked um at the estimated the the expected number of cancer deaths, the number of avoided cancer deaths and standardized mortality rates um over time. So the overall age standardized mortality rate peaked for females in 985 and then declined. For males, it peaked uh also uh in the mid-80s and has then declined. So overall um they estimated that there's been 66,000 female lives saved, 164,000 uh male lives saved, and that might reflect the earlier drop-off in smoking rates in males. So overall, that's an 11% reduction in overall cancer mortality in that time. So this is going uh out to 2018, and of course, since then we've seen lots of new treatments coming into play, immunotherapy and targeted therapies and in various cancers. We've also seen national uh bowel cancer screening program in Australia, which is thought to have led to further reductions in mortality. So um the overall um take-home message from this paper was that the all the cancer control measures put together in that time has led to a significant uh reduction in in deaths. Just of note is that we've seen improvements really right across uh all cancers, apart from one, and that's uh liver cancer. And so that we haven't seen reductions in the age standardized mortality rates uh in liver cancer. So that the suggestion from the authors would be that this could be a focus uh for targeted research going forward to to really try and bring into play reductions in liver cancer, which is becoming more prevalent not uh through both viral mediated but also through uh metabolic liver disease and other risk factors such as alcohol intake. So, anyway, so I I find it's always interesting to sort of take a bit of a you know step back and and look at progress made and where we're going. We tend to present a lot of papers about new treatments in individual cancers, but this was a nice kind of snapshot about where certainly we are in in Australia. It refers to some data also in Canada, which uh is anal is similar. And as I said, I think it probably makes some similar assumptions in New Zealand as well.

SPEAKER_05:

Behind all that data, there's uh some real complexity, eh, Craig, like so endometrial cancer, for example, is certainly going up. And then you've got the pre-menopausal versus post-menopausal breast cancer discrepancy as well. And then whilst you've got the age-specific reductions in colon cancer, which are going down for older people, the curve in the younger people's ticking up slightly as well. So while the individual risk of cancer is lower than it ever has been, primarily due to cessation and smoking, for example, and uh known risk factors, directly others, where um modifiable risk factors, particularly uh obesity, remain a really important feature. And our efforts in cancer control, still far from done. What is that 30% of all cancers are related to uh what they call preventable um risk factors, which are minimal to social policy intervention, um and particularly things like uh air quality and um the like are going to be big factors in EGFR, um mutant lung cancer in years to come.

SPEAKER_00:

Yeah, so when you say an uptick, Chris, are you talking about the incidence now? So this what this focused on was uh the age standards mortality rates, which you mentioned uterine cancer, for example, that hasn't really been there's an uptick in incidence because of the aging population, but not an uptick in the mortality rate, so as our treatments uh are are better.

SPEAKER_05:

Yeah, well there's there's obviously uh incidence there is survival and there is mortality, and where you have your incidence going up and your survival rate's the same, then your mortality will go up because you've got more cases, right? But if your incidence goes up and your survival goes up, then your mortality can go down. But those ones where you've got a higher incidence, such as endometrial, for example, I mean that's a genuine increase definitely in uh Malian New Zealanders and the Pacifica, for example, in our population, and that's going to lead to a genuine increase in death rates, so mortality will go up from there. Yep.

SPEAKER_03:

Yes. So that's what I was going to say is that this it's all very well looking at all however many Australians there are, but I suspect if you broke this up by ethnicity, a decile of wealth, that there will be communities that are not benefici benefiting as well from many of the interventions that are helping those that are well served in the health system.

SPEAKER_00:

That is a really fascinating that you said that, because when the authors posted this on LinkedIn, that was my question to them. Could they do the same work, but actually to look at some of those uh priority populations? So let's look at whether we've seen the same fall in regional populations and then extrapolate out well how many lives haven't been saved in those populations because we haven't been able to bridge the differences in outcomes between you know the uh privileged populations and some of the priority populations. So that would be a really fascinating piece of work. Hopefully, the authors may take that on board and look at some of that. So there was this is overall Australian population, they haven't teased out those very issues that you've that you've raised.

SPEAKER_05:

Yeah, and fascinating data on skin cancer as well. So in um in populations around waterways, the incidence is going up, so people are detecting it more often, but the cure rates have remained identical. Similarly for prostate cancer, the incidence is going up, but actually that's to do with PSA testing, eh? And then um the mortality itself has remained uh broadly similar, so there is a disconnect there. And the points that you've raised, Craig, around identifying priority populations. You know, we're really blessed in New Zealand to have some uh very gifted epidemiologists who that's a very core part of their work. And um, our good friend and colleague, Professor Jason Gurney, does exactly that with um priority populations. And I've added my name to a couple of his papers by post-it note uh on occasion, so it'd be great to have Jace on um the show at some stage to talk about how that works in um at-risk populations. We should do that, eh, at some point soon.

SPEAKER_00:

Sounds good. So this was dated to 2018, Chris, so we haven't really seen the impact of the new melanoma treatments in this data. You'd expect there would have been uh quite a substantial amount of the lockdown phenomenon too, right?

SPEAKER_05:

Where your diagnostic went down uh to see what happened with uh mortality rates.

SPEAKER_00:

Yep. All right. So let's move on. Kate, what have you got for us to talk about today?

SPEAKER_03:

So I want to talk about a I think I think it's called in a review article, but it's probably not really one in JCO, and it reminds me of Walt Whitman. I am large, I contain multitudes, because it's about the interaction between solid neoplasms and our microbiome. Just to run through this quickly, because I was told I was not allowed to wax on lyrical for too long. Three current approaches to influencing one's microbiome and its interaction with your cancer, prebiotics, which is probably where the money is. So high fiber diet. The best outcomes in patients on immune checkpoint blockade is in those people who have a dietary fiber intake of greater than 20 grams a day and no probiotics. And it is a dose response curve, so improved outcome at every five grams per day of fiber. And in case you're wondering, a breakfast of oats and berries has 10 grams of fibers, you've got half of your fiber in a day. Uh, one cup of baked beans, 14 grams. So that's pretty awesome. The probiotics have been looked at mostly to try and counteract the fear we all have of antibiotics, pre-immunotherapy disrupting the gut microbiome and lowering over response rates. We've all seen that. But you don't want to not treat people's uh infections, so it gets very complicated. Or fecal microbiota transplantation. So the sharing of fecal slurry. So there are two phase twos in patients with eye uh uh immunotherapy-resistant melanoma who were treated with fecal transplant from someone with a deep response to immunotherapy. Uh, and those people that had been resistant then went on to have a 30% response rate at rechallenge. So absolutely fantastic.

SPEAKER_05:

Fast any but gross.

SPEAKER_03:

Yeah. I don't know about your MDM, but our gastroenterologists sometimes come with a brown paper bag, which they give between them. We all know what's in that now. Brown paper bag is a fecal transplant. I we're really only using it in our centre at the moment for uh patients with intractable uh clostridium or some inflammatory diseases. We haven't been tempted to use it in immunotherapy resistant melanoma. But you know, if we're not gonna get epilomab funded, it might be what we have to go for.

SPEAKER_05:

Can't you see the market here though? People ending up selling their poo, the super responders, and then ending up with a poo bank that people can, you know, there must be something in that. Or maybe people are just look gonna be looking for the bacterial products which are going to be the ones which are associated with that of the microbiological signature, which you can then actually engraft. So it is fascinating, eh?

SPEAKER_00:

Yeah, he is. I mean it's TMI Mamab, and we should move on. But I think there's you can either do a whole yeah, we could do that's great. We could do a whole episode on the microbiome. I think it's really fascinating area.

SPEAKER_05:

How many grams of fiber are there in bagels, Kate? Because I'm quite keen to know that.

SPEAKER_03:

Oh, sweetie. You'll need an everything bagel, I think. Rather than your your bland white man bagel.

SPEAKER_00:

DJ, what do you bring to the table today? Hopefully not in a brown paper bag.

SPEAKER_05:

I don't have a white paper bag, but I've got some papers to rustle. Um I've had some feedback from a lot of callers that they really like to hear all my papers rustling in the background, so they've asked me to do more of it. So I promise today, Craig, I'll rustle my papers regularly.

SPEAKER_00:

Ah, it's great.

SPEAKER_05:

I thought we outrustled by you though. Um so the long paper I wanted to talk about today was Substandard Anti-Cancer Medications in Sub-Saharan Africa, a systematic pharmaceutical investigation, which was published recently in Lance at Global Health. Now, why this matters? Well, cancer treatment demand in low and middle-income countries is exploding. But actually, there's surprisingly little surveillance of drug quality. Now, that's something that we take for granted in high-income countries, that's what you get in a vial is what it says on the box. But apparently that is not true worldwide. Wow. And there are there are people in uh pharmacies uh abroad that will vial split and mix it up with water in order to charge patients full price in order to make profit, uh or people who are unscrupulous and will just sell water and there was a beversisamab scandal where be whereby all people were getting instead of bevasisamab was water. You can argue over whether that was of detriment to them or not. But certainly when people are paying for stuff, they should be getting it. So what this group did uh was they took 251 samples of seven key drugs uh from low and middle-income countries. So these drugs were cisplatin, oxaloplatin, methotrexate, doctorubicin, cyclophosphamide, iphosamide, and leukovorin. So pretty core oncology drugs, right? That they're testing for whether or not what they say on the box is what you get uh in the vial. They sourced these um samples from 12 hospitals plus 25, what they call private or grey market pharmacies across Ethiopia, Kenya, Malawi, and Cameroon. And they um essayed uh versus um they essayed using uh liquid chromatography uh using US pharmacopoeia standards, which I'd never know what that was, but apparently there are standards for measuring quality of cancer medicines. They also did a visual inspection of packaging. And what I learned from this um article was that what does that mean? Well, when you look at a vial, is it the right colour? Uh has it got crystals or precipitants in it? And sometimes the boxes are just photocopies uh or downloads from the internet of a random vial. And some of the medicines or TKIs were just paracetamol, which is outrageous that people were getting um paracetamol instead of their targeted therapy. Anyway, a full 19% of all products failed the chemical SA test. And the active pharmaceutical ingredient ranged from 28 to 120% of the label claim. So the quality of what people were getting was massively variable. Uh, expired stock was 24% of all samples. So of all of the samples they got from pharmacies, a quarter was expired. Uh, interestingly, expiry status didn't actually make it more or less likely to fail. Uh, and there was no difference found in hospitals versus the private sector. Uh, unfortunately, the visual inspection was quite useless. So just looking at the quality of the box didn't actually help you, or looking at the quality of the medicine, or saying, ah, that Dr. Rubison's not the right colour. That didn't actually help particularly. So there's no correlation between visual inspection and medicine quality. And some manufacturers had failure rates of more than 70%. So 70% of cancer medicines from some manufacturers failed the basic assessment of what they said they did in the box. There are substandard or falsified anti-cancer drugs, and these are present in major hospitals and private pharmacies alike. And given that we've got globalized supply chains, this is likely an issue across other lower middle-income countries globally. And this compromises treatment outcomes, research interpretation, and survival data. So whilst we have medicine regulation in terms of at the time of manufacture, we do not have robust post-market surveillance and regulatory tools in most countries. So once a drug is approved, that's generally it for surveillance. Um and that probably needs to change. We need to have uh low-cost screening tools. We have to improve supply change management and supplier vetting, and we have to record lot numbers and brands and clinical practice and link these to outcomes and do some post-market surveillance. And this is uh a very important issue for low and middle-income countries in terms of cancer uh medicines quality, given that this is where the burden of cancer is going to hit uh over the course of the next 20 years, and it's incumbent upon us to ensure that this is true. I was a little worried initially that this is going to be a scaremongering paper that was one of those ones that was used by a big pharma to say, no, no, don't get your uh TKIs from generic pharmacies uh in India, etc., because it's just bad drug. You need to buy the full-price medicine from us uh and pay 10,000 bucks a month as opposed to the cheaper 600 bucks a month you can get from other countries. But this seems to be much more serious than that, and it's including these core drugs like cisplatin, uh Dr. Rubicin, etc. So this paper really shook me up in terms of what I thought the quality was uh of people getting medicines around the world.

SPEAKER_03:

It's heartbreaking because not only was there a lot of underdosing, but that overdosing, depending on what the drug was, could have been significantly toxic. And was there any uh mention in the article about whether oncologists had a feel for which drugs were a problem?

SPEAKER_05:

Not that I recognize, but you know, I think one of the problems with clinical practice is, you know, you sometimes see clusters of patients with side effects, right? And you start to think, oh, well, was that a dodgy batch? And you sort of chuckle to yourself about it. But actually, generic substitutions often only have to be within a band of what, 15% variability, anyway. So you can actually have quite marked variations in a generic switching. So it is, I think it is a thing that we have to watch out for. And I really like the recommendation around the post. Registration surveillance stuff that we should really be looking at as a new regulatory measure. So I was pleased to see that the UICC made some very strong statements around this and have partnered with some pharmacy organizations also to make some recommendations whether they'll get picked up or not remains to be seen.

SPEAKER_00:

Thanks, Chris. Has a similar study been done in in uh higher income countries such as Australia or do have we had the same kind of audit process to see what the rates are?

SPEAKER_05:

Not that I'm aware of Craig, and I actually couldn't and I'm certainly no expert in what the post-marketing uh regulation is in New Zealand, but I'm actually not aware of any post-marketing or random ordering that you get. When I worked as medical director of the Cancer Society of New Zealand, we would get stung every couple of years by consumer who would check out our sunscreen and work out whether or not it meant it's SPF labelling. But you know, SPF 15 versus SPF 30 is like 99.8 versus 99.9% good. Um, so that was always uh, you know, a bit subjective in the methods for testing sunscreen are dodgy anyway. But I'm not sure we actually have those same standards for um medical products. We just rely on the integrity of the supply chain of the manufacturer.

SPEAKER_03:

Yeah, and look, even um I'm just Googling very quickly, and it would be really interesting if there's an expert listening, because the FDA have a very similar process to us, which is that calms, you know, that doctors put in, oh, my patient had a bad outcome. But are they actually taking a hundred milligrams of cisplatin and checking it's a hundred milligrams of cisplatin? That's what I'd like to know.

SPEAKER_05:

Yeah, I don't think they are, but it'd be great. So if you're an expert out there listening to our podcast, uh let us know because otherwise it's just us randos randing on about things we don't know too much about. Okay. Thank you.

SPEAKER_00:

So my first quick bite is, I guess, segues from that a little bit. It's called The Totality of the Evidence Optimizing Dosage Selection Strategies Oncology, published in JCO in July. It's basically discussion paper discussing the issue about uh drug development and how with the newer targeted therapies we it may be now we need a new paradigm. Instead of using conventional maximum tolerated dose to develop the dose, we should actually have a more sophisticated way of looking at appropriate dosing of these drugs because there's been recent examples in in some of the conjugated antibodies where post-uh marketing there had to be recommendations to drop the dosing down due to toxicity. So just something uh to note for people who are involved in clinical trials and drug development, interesting uh paper published in the JCO. Kate, I came across one uh and you do more breast cancer than than us, a propitent use during chemotherapy and association with survival in women with early breast cancer in the journal of the National Cancer Institute in July. So showing that this is a retrospective analysis, but suggesting that women who had received this is done in Norway using some linked nationwide registry data, 13,811 women diagnosed with early breast cancer between 2008 and 2020 who had had chemotherapy and antics, and showing that those who received a pripad had a superior survival with about a 30% reduction uh in the risk of death, and this was strongest in women who with triple negative breast cancer. So I don't know if you've read this paper, Kate, but I guess this is the assumed hypothesis would be that by using these effective anti-medics, women have been able to stay on the optimal dose of the chemotherapy regime, not had to have a dose reduction of their chemo.

SPEAKER_03:

Yeah, I think in the absence of interventional data, I think you have to say it's the anthracycline and the platinum dose intensity is possible with a prepotent, but a 0.7 hazard ratio, you know, you you think that's that's huge. And triple need of breast cancer is a really evil beast. So I suspect someone will the the tricky part is you couldn't randomize now women to not having be a prepotent uh in an anthrocyclin and a platinum. Um so we may never understand this. But if there's a clever scientist who can think of a kind way of of of figuring that out, I'd love to know. But I I'm not giving my women with anthracyclins and platinums without, you know, particularly young women cannot get through it without a prepidant. Craig, Chris, and I are all old enough to remember when all we had was steroids and metaclopromide and oncology was not a fun place to be sometimes.

SPEAKER_00:

Well, I remember my first job as a second-year resident was working at St. Vincent's Hospital in Melbourne and I was clerking in patients, and you know, a huge proportion of people receiving chemotherapy on that day stayed overnight and were getting effectively sedated overnight to get through. So, and then I remember when I first came to Aubrey, I was allowed to give uh on Dancetron to three patients. I had to pick which three to give these like uh was you know a supply program that I could have three people to choose. So really things have really changed. But I would have thought Apribidin's now built in or other drugs in the same class are now standard of care according to ASCO and MAS guidelines for um these treat chemotherapy regimens anyway. Is that correct?

SPEAKER_03:

Yes, very much so.

SPEAKER_00:

Yeah. So yes, we'll never get a trial, but it would seem reassuring that you know we do have to ensure that adequate antiometics are incorporated into the chemotherapy regimes.

SPEAKER_05:

Yeah, I mean these days with um a prepitose with a lanzepine metaclopamide and uh on dancetron or an Aussie, obviously plancitron, you we don't have admissions for northern invomining with chemotherapy now, it just doesn't happen. Yeah.

SPEAKER_00:

Yeah, that's right. I mean occasionally had a patient who, despite everything, was needed to come in overnight, um, but now very rare.

SPEAKER_03:

Just as an aside, there was an article published in today's New England Journal of Medicine, I think, where a neuronkin inhibitor was used for hot flushes with women and uh and apparently works, but they were taking a daily uh neurokinin inhibitor. So I will I've I've watched this space, I will look that article up properly.

SPEAKER_00:

Yeah, okay, maybe we can bring to that class next time, Kate. And then my last one was a paper I found really quite confronting, I guess, triggering. Unveiling the unspoken, exploring taboo thoughts and difficult experiences among carers of people with brain cancer, published in Psychooncology in July. I found this quite triggering. Uh unfortunately, my father passed away of metastatic uh bowel cancer at the age of 67 with brain metastases and actually died uh in status epilepticus. So it brought back quite a lot of memories of that terrible time for our family. But it's an interesting paper, it was a qualitative interview studying people with primary brain tumours, but I think same principles in people with uh with brain metastases as well. And it spoke about four themes identified um in these interviews with carers about staying safe. So aggression um and violence is an is an issue sometimes in these patients, conflicting and complex emotions. I love him for who he was. It's a quote wishing for the end with grief and relief. So this sort of guilt experience, and then the uh bad experiences of patient death and end-of-life treatment decisions, and care is talking about five coping strategies being committed to care, life alongside the carer role, acceptance of circumstances, self-silencing and information seeking safety planning. But the paper gives some guidance about for clinicians and how to manage this issue. And firstly, it's about asking about how carers are coping and whether there is issues of, for example, of domestic violence, and then putting this suggested coping strategies that are talked about in the paper. So fairly niche paper, but I think with some learnings for everybody looking after people um with cancer in most tumours where there can be um pray metastases.

SPEAKER_03:

Thanks for sharing, Craig. And my heart goes out to you and your family, even though it it's years ago, it doesn't go away, does it? I don't know. I also I think caring for carers, you know, cancer isn't something that happens to one person, it happens to a whole community of people attached to that person. And the more that we as oncologists understand that and do our very best to hear uh the lived experience of patients and their carers, the the better oncologists we can be. So I I applaud you for bringing that to our attention.

SPEAKER_00:

Thank you. Yeah, I just I don't know how I came across it, but it just really resonated with me. And I think, as I said, it's quite a practical paper with some great suggestions about how people you need to be aware of these issues and and actually ask about them and then some coping strategies.

SPEAKER_05:

I think that's what's really nice about that, Craig, too, isn't it? Is the uh the practical suggestions for how to make a difference there, those coping strategies and also the power of acknowledgement of people in those circumstances, even just to have your suffering seen can be uh very relieving. We don't like to talk about the fact that actually, unfortunately, people with brain secondaries or primary brain cancer, it fundamentally robs people of their personality sometimes, and it does so that the individual dies before they're dead before they go, you know, their personality goes and it it's cruel in the way in which it can take the child's personalities.

SPEAKER_00:

Yeah, and then there's a whole you know, you're wishing them to be dead, and there's a hard guilt about that. You know, my dad's case we used to say, Oh, you know, Jim checked out a long time ago because he just wasn't the same person. But yeah, all right, let's talk about something a bit happier, but more cheerful. Okay, I think you wanted to tell us about some new treatments.

SPEAKER_03:

Yeah, so I'm gonna start with a hematology one, and embarrassingly, I'm not even sure I can say this. So the this is a long-term outcome from Cartitude One, cute. Um siltacaptogen autolucell, which is uh a B cell maturation antigen-directed, genetically modified autologous chimeric antigen receptor T cell therapy. Edith's is gonna love me saying that.

SPEAKER_00:

Yeah, congratulations on the pronunciation of all these big words.

SPEAKER_03:

So this is uh was being given it's this trial. Patients were infused in 2018 and 2019, and so published only recently. 32 of those patients, uh 32 of 97 patients, are still alive and progression free, are significantly more than five years after their infusions, potentially curative. Seems to be that the more well you are when you start, the better you you get on. Curiously, the minimum residual disease negativity, so this is where you can't find anything on blood tests to demonstrate that the patient still has multiple myeloma. In this trial, cartide one was only 59%, whereas it's 73% in later trials. So the hope is actually data's just going to keep getting better. And in terms of the long-term uh toxicity, the extra toxicity, quote unquote, it's 2% solid malignancy and four serious infections. So it feels like something that will be brought earlier and earlier, remembering that this population routinely have a life expectancy of less than 12 months. So that's miraculous. Uh, we as a met solid, all of us GI oncologists are heartbroken about early onset uh colorectal cancer. Early onset muffled myeloma is also a real thing. So these are not all frail elderly people getting involved. So that's that's pretty exciting.

SPEAKER_00:

Uh this whole field's another exciting kind of, you know, we talk about chemo, radiotherapy, hormone therapy, targeted therapy, immunotherapies, all these cellular therapies, I think, is a whole new wave that we're all going to have to be informed about and um refer patients for trials.

SPEAKER_03:

Very cool. And then another short bite that a patient drew my attention to, so thank you very much uh to that patient. An Indonesian group looked at using olive oil, drinking it to prevent PPE, Palma Planta erythema, common side effect of capesytamine. And so what they did was everybody had to drink 30 mils of extra virgin olive oil per day. They compared that with a group that uh they called placebo, which was extra light olive oil. So I thought that was very interesting. So apparently, extra light olive oil does not have any of the good stuff in it. The instance of grade two or greater PPE in those patients that took the real extra virgin olive oil every day, 30 mils, six tablespoons, was 13%, versus 67% of those on the placebo, which is the extra-light olive oil. And so the theory is that extra virgin olive oil can tr contains something called oleocanthal, which is very similar to a non-steroidal and inhabits Cox 1 and COPS 2. So there you go.

SPEAKER_00:

Amazing. I don't think we've ever had a paper from Indonesia. So this was from Actamed Indonesia, Tiramakasi, to uh the authors from Indonesia. That's about the only word of Bhasa I can speak. Um that was thank you. So X the old extra virgin olive oil, it's not just good for your salad. Taking origin rather than topically cake.

SPEAKER_03:

Yeah, they were drinking 30 mils of it. Yeah. I did actually, I I had planned to try and drink 30 mils as a shot and see if I could do it, but I um I'm sorry, I just didn't get around to it.

SPEAKER_05:

You should see the way I cook. I mean, I probably miss about 30 mils a day of olive oil.

SPEAKER_03:

I worked with a man at UCLH in London uh who was from Trinidad and Tobago, beautiful clinical oncologist, who used to his secret recipe for his jambalaya was about half a bottle of olive oil. So I think for some communities it wouldn't be a problem.

SPEAKER_05:

I think it'll be hard to get past pharmac as well, given the price of olive oil these days. Very interesting. And I'm presuming these people um weren't having Voltarian hand gel at the same time because the Dicophonac hand gel from the trial in India has been something that we've adopted wholesale uh as well in our practice from some of the um pharmacies of generic is quite cheap uh or cheap enough. So we've been using that as a primary prevention, uh, Kate. Have you guys adopted that up your way?

SPEAKER_03:

Uh yes, yes and no. So yes and up lightly. This is a yes when I remember. So this is one of those things where I think it would be very useful to have uh it on patient information so the patient reminds me. But yes, we do, and it you're right, you do have to shop around, not mentioning the brands of the pharmacies, but there are some pharmacies significantly cheaper than others.

SPEAKER_05:

Yeah, and it's one of those ones that because it's not on prescription, you can't quite build it into your automatic prescription protocols, so it's a little bit harder, and yeah, you're right, you have to remember it.

unknown:

Yeah.

SPEAKER_05:

So olive oil and uh Voltaran hand gel, it's a great combination there.

SPEAKER_00:

Yeah, we talked about the Voltaran hand gel on the podcast before. I think we have Chris, but we might just also reference that paper in our notes for today. And Kate, do you have one more?

SPEAKER_03:

Yeah, just very quickly. So uh SOPEC, which we've spoken about before, so flot versus cross, still lots of arguing and EMDTs all over the country, I'm sure. Countries, I'm sure. Um, compliance has been discussed heaps. Uh cross components saying that it wasn't fair, that the patients on Cross didn't get enough. So Florian Lordics has published uh 95% of flot patients got all the four preopdoses, meaning that 5% didn't. I love German clarity about things. Cross, only 4% had less than four pre-op chemidoses. 99.4% received at least 41.4 grays. So what he's trying to say is actually the compliance to both regimens was very high. R0 resection was similar. Nodal uh clearance was very similar. A PCR rate was significantly higher in the flot than cross, so 17%, which is quite high. This is 10%. But the outcome is still clear that flot is better than cross, and we can't say it's because patients didn't get enough therapy.

SPEAKER_00:

Is there still debates about it? I thought pretty much could have been settled.

SPEAKER_03:

Look, I think there's still some radiation oncologists who've got that. You know, if you've reached the original cross-trial did did look like it had knocked things out of the park, but that's the naughtiness about cross-trial comparison. So you have to do the proper randomization.

SPEAKER_00:

Just stop inviting them to your MDD. That's what you need to have it adjust and would say.

SPEAKER_03:

But yeah, so some of my best friends are radiation oncologists.

SPEAKER_05:

Let's call it out. Radiation oncology and upper GI have got a series of points of denial, you know. We use newer techniques now, those old techniques and that trial don't apply to my patients. It was all about dose intensity. In my hands, they would always get that. And we're now using better imaging techniques to ensure that the fields are tighter so they get less toxicity. And that's always a full range of excuses. But I mean, I really do like the uh ESAPEC study because it did sort of settle a wee bit. I also don't think there's any doubt that uh flot is a harder to tolerate regime than cross. I mean, cross is a doddle in terms of getting people through the five weeks of preoperative therapy. And if you've got a patient who's T3N naught or T2 slash T3N naught, um there's probably not that much advantage to a more intensive regime. And when people crash on flot, they crash really badly as well. So if you've got someone who's got frailty or comorbidity, it is still a debate. Also, when I talk to my colleagues who are in uh low and middle income countries about flot versus cross, actually they love the chemotherapy because you can deliver that regionally much more easily than radiation, where you have to go to a centre and so it's more deliverable in terms of their communities. So uh we have to be careful about recommending treatments that do dislocate people from their community.

SPEAKER_00:

Absolutely. Chris, have you got some quick bites?

SPEAKER_05:

Are you asking Chris for quick bites or Russell?

SPEAKER_00:

Uh Chris, please.

SPEAKER_05:

All right. This week in my clinic I've uh had a patient who has got a metastatic peraganglioma. Now I've had a couple of these patients, and in our part of the world, we have a couple of patients who've got an SDH mutation, usually the SDHB mutation in in our region. And uh the question was how do we uh manage this metastatic disease that had become unresectable? And there was a bit of chat about peptide receptive radionucleotide therapy. Now, PRRT, of course, Australia was a country who really did adopt PRT early on and often led the world in terms of the implementation of that with a large number of PRT centres per head of population. And so certainly when I was learning the craft of neurodocrine treatments, uh, we learned a lot from our Australian counterparts who had a lot of expertise in that. Uh, and the New Zealand Neurodocrine Centre has only been open for uh a couple of years now, but we've only got the one compared to Australia, for example. This was a study of 177 lutetium dotatate uh in patients with metastatic paraganglioma or phaochromosotoma, half of whom had SDH mutations, the other half who were sporadic. And what the study did was it looked at the response uh of people who uh had um lute therapy. And what it found was six month PFS in all comers was 86%, but lower in the SDH mutations at 72% versus sporadic, which were 100%. Uh Overall survival was 51.7 months in total, 31.2 months in SDH versus not reaching the sporadics. The SDH mutations were doing much, much worse than the sporadic and perigangliomas. The toxicity was mostly hematologic intended lymphopenia and anemia and is usually not all that significant in terms of managing it patient-wise. And interestingly, with the phoochromosotomas being often adrenaline or adrenaline secreting tumors, 17%, so one in six, are getting grade three or more ketochalamine release syndrome requiring ICU level care. The interpretation of the study was that luate was active and generally tolerable in metastatic periganglioma with durable disease control, but SDH tumors fare worse, likely due to aggressive pseudo-hypoxic biology and radioresistance. Why is that? Well, um, these cancers often display a pseudo-hypoxic phenotype with elevated uh HIF2 alpha and a hypoxic tumor microenvironment which drives radioresistance and faster progression. Uh so the patients with it with the SDH mutation do worse uh on lutate, even though they still do benefit. And it's important to be aware of that. Just briefly, I also just looked up also other available treatments of metastatic paraganglioma, as well as uh luate. There is evidence for sinit nib, uh BFS of nine months, a carbozetinib, EFS 16 months, and bilzutufan, which is a HIF2-alpha uh inhibitor, which is FDA approved in 2025, uh, with a 25% uh response rate. So there are some treatments available for this patient group, and important to bear in mind that mutation predicts uh a worse outcome for patients. Amazing. Another quick quickie uh here, Craig, which is the uh key results from the keynote 585 study. This was um a randomized phase three study of patients with resectable gastric and GEJ adenocarcinomas. This is the same population as the Matterhorn study, which was D flot, so flot versus develomer flot in the um gastric and GEJ patients. This was the keynote study, it's the pharma sponsor study, looking at cisplatin fluoroprimidine plus minus uh Pembro. Towards the end, they did change that to allow flot plus plus minus Pembroke, but largely it was a cisplatin fluorocyl backbone involving a lot of uh Asian countries. The key findings were that PASCR was markedly improved with the addition of the immune checkpoint inhibitor of 13 to 40% versus placebo of 2% to 3%, uh, and median event-free survival was 44 months versus 25.7 months uh with chemotherapy alone. A subgroup trend towards greater benefit in MSI high and Pedial1 CPS greater than 10. The MSI high patients do worse with chemotherapy generally, and the addition of uh a checkpoint inhibitor is probably no surprise that they do well. But why was this interesting? Well, this is a negative study, uh, whereas Matterhorn was a positive study. So why was this study of cisplatin fluorie uresol with Pembro negative, whereas Matterhorn was positive? And does that tell you that Matterhorn was an outlier, so we should ignore it? Uh or is it this a bad study and therefore we should ignore it and accept Matterhorn in terms of uh adding in um immune checkpoint inhibitors to your chemotherapy? Well, one of the interesting things about this was the backbone, of course. So just cisplatin 5FU is not a standard in the West. The uh triplet chemo flop is certainly the standard, and that does worse. Uh, but also the way they did the study was they uh tested the primary endpoint of event-free survival at multiple times. And when you test the um primary outcome at multiple times, you have to increase the alpha in terms of making the assumptions to reach statistical significance. But because they were so conservative and tested it so often, they ended up having a negative study. And perhaps if they'd only done it once, um they would have had a positive study because the alpha would have been more reliable at that point, you would have had two confirmatory studies. So the take homes were that Pembroke improved PES CR and trended towards better survival, but the trial was over in negative. Um, Matterhorn, meanwhile, sets a new global standard of flop with DevelopMap, and it shows the backbone matter, the statistics matter, and the biology shows that actually adding an immunotherapy probably does work.

SPEAKER_00:

So approved for use in your country?

SPEAKER_05:

Absolutely not, nor should it be. But I think it's a good lesson in trial design and how multiple testing of your primary endpoint does matter, uh, and that if you get negative for EFS because you test at multiple time points, uh, then that can affect your later interpretation if you spread your alpha over EFS and uh and OS and it stopped your testing for that. And it shows the chemotherapy backbone does matter as well. Uh so I found that an informative study for trial design, uh, and I also found ultimately when I looked at the details and showed that the EFS was actually better, PCR was better, but we are getting a signal from another study that adding immune therapy to your backbone does actually make a difference and it reinforces the rationale uh for development with flot, um, which is what the Metalhorn study tested.

SPEAKER_03:

I'm I'm a simpler human, and one of the things that's that when you texted us very late this afternoon that that you were gonna have a look at that trial was I had went back and had a look at flot AR4 and at Metahorn, and the PCR rates are all very different, right? And I think this feels a little bit like the early Satuxab trials in that some of them were positive, some of them were negative, and you can argue you're very cleverness, but I wonder whether actually we're we there's something we're missing. There's a biomarker that we are missing, and we will look back at this and go, oh, why didn't we enrich that population for those people? Or why didn't we, you know, and so I I feel like we're on the verge of understanding something, but we just don't, we can't see it yet through the the wood because the alpha and the matterhorn's only 10%, which means we're and that's only EFS, we don't have OS yet. And the same's true in breast cancer. The EFS is about 10%, OS is only 5%. So we're picking out a small subset of people and exposing all of them to a to a crack blood drug. So I'm I feel like we're on the verge of something, but we're not there yet.

SPEAKER_05:

Yeah, I think that's you know a lot of fair points there, uh not least of which the fact that I sent you through the paper later, that's a particularly fair point. Um but also when you look at the history of gastric cancer, three to five year survival with surgery alone, 23%, add ECF adds 13%, gets you up to 36%. Then you do flot, it adds up another 10%, so you're up to 46 to 49%. Uh and flot performs pretty reliably through the study as well. I mean, that that's what's good. So the the landmark analyses for flot are reliable, the landmark analyses for Cisplat 5 FU uh are reliable, and and you're adding 10% EFS, which is the same as adding the the third drug in flot uh or a little bit less than just adding the chemo backbone in the ECF versus surgery alone studies. So I think the extended benefit is similar. Now, like you, Kate, in the neo-adjuvant um and adjuvant studies, uh EFS are go, well, that's nice that you've got EFS, but show as you survival because actually that is the gold standard in the uh perioperative enagiven setting. So I always try and ground myself in what are our standards and what are our benchmarks, and then of course you go back to your ESMO scores and you start saying what is the benefit in landmark uh analyses and to be your hazard ratio and your EFS at your landmarks. And actually that comes out pretty well. The flots, uh the flot with Develomab comes out pretty well. I think it's a B in ESMO, which is decent in the curative setting, and it accepts that early EFS is okay in some settings. And also bearing in mind that in uh gastric cancer, um, the addition of immune therapy in adenocarcinoma isn't curative. So it's PFS enhancing and OS enhancing rather than actually salvaging and curing people. So I think getting EFS in in a solid tumour like gastric is actually a meaningful intermediate endpoint. Of course, we want overall survival, um, but it's uh it's a pretty decent intermediate uh endpoint for now. Uh I hate PCR because I think that largely is how hard do your pathologists look, how many sections do they do, uh, how much time do they have and how good are they? Uh and of course you saw in ECPEC that PFS and um PCR were not related at all, uh, and that your PCR rates were higher in the arms that got radiation, but that didn't necessarily translate.

SPEAKER_03:

No, they weren't they were higher in the slot arm.

SPEAKER_05:

Sorry, I'm not ECPEC confused. Uh Aegis, A-E-I-G-I-S, uh, which was cross versus uh ECF. Of course, your PCR rate was higher uh with carbotexile radiotherapy than it was um with uh ECF chemotherapy, but that didn't translate into a survival game. The curves were superimposed. Yeah.

SPEAKER_03:

Anyway, we can argue about this for ages, but I do I do think we're missing something. And I and and I hate the fact that we are, if you think about a numbers needed to treat, we're still at 10 at 100 grand a year, and that's not good enough.

SPEAKER_05:

Well, the cost the cost component of that's high, Kate. The numbers needed to treat for perioperatives 10 as well. Six to ten. I said it's treat for her septin, twenty.

SPEAKER_00:

We are running out of time, but I'm just gonna quickly mention the FDA released on the 18th of August a new guidance on endpoints in clinical trials and emphasising the need to have overall survival as a primary endpoint. Talked about the circumstances in which it could be a secondary endpoint, talked about when we needed adequate crossover design in studies. So this is sort of an issue that's come up multiple times on the podcast, but there we are, a new FDA guidance, and I would urge the clinical trialists listening to have a look at it and also trainees to get some understanding about endpoints in randomized clinical trials in oncology.

SPEAKER_05:

We should perhaps um also schedule a bit of a chat about crossover at some point because that's a critically important issue. You sometimes have crossover which must be done, uh, and other times where crossover must not be done. Uh so that'd be good to dive into that. Really looking forward to reading that paper on FDA guidance and so glad the FDA is listening to the wisdom of the common sense oncology movement, which is calling for good endpoints, outcomes that matter to patients.

SPEAKER_00:

Yeah, that's right. Well and that that issue about when to include crossover and when not to, is discussed a little bit in this guidance as well, CJ. All right, thank you. It's been a real cook's tour in various topics in oncology. I hope people found that at least one of those papers of interest. As always, a pleasure to discuss it all with you both, Professor Jackson and Dr. Kate Clark. Thank you very much. Hope you stay well. I'll try to, and thank you, um, our producer Rachel, who's been herding us along while we've been recording this. Thank you, Rachel.

SPEAKER_03:

Always a pleasure. Thank you, Olivia. Thank you. I'm off to have my uh cup of baked uh jeans, baked beans, and my 30 mils of bottle of oil.

SPEAKER_05:

I was just wondering if you were gonna say that you're gonna have some baked jeans there, Kate.

SPEAKER_03:

That's what I did say. I think I got stuck in the in in a thought thing. Yeah, that happens. Menopauses, not fun.

SPEAKER_05:

All right. Is that buckle book and a um a gooning joke in there, Craig, but I couldn't quite work out how to run that in?

SPEAKER_00:

No, leave that alone, things. Bye. We have the Christmas special.

SPEAKER_01:

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 oncologynetwork.com.au. 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 Babbin signing off for the Oncology Journal Club Podcast.