The Oncology Podcast
The Oncology Podcast including The Oncology Journal Club Podcast by Professor Craig Underhill, Dr Kate Clarke and Professor Christopher Jackson; and Supportive Care Matters by Dr. Bogda Koczwara.
Oncology News and Expert Analysis from a unique Australian viewpoint.
Proudly brought to you by The Oncology Network.
The Oncology Network are producers of digital resources that support busy oncology health professionals. For more information visit our website www.oncologynetwork.com.au.
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The Oncology Podcast
The Oncology Journal Club Podcast Episode 9: PROMS, Oral Cannabis and ASCO Rectal Cancer Guidelines
Curious about the latest breakthroughs in oncology treatment? Prepare to have your perspective shifted and hopefully a few laughs too, as we dissect the most compelling research and clinical insights with our expert hosts, Professor Craig Underhill, Dr. Kate Clarke, and Professor Christopher 'CJ' Jackson.
Today’s episode covers an eclectic mix of papers. Craig tackles patient-reported outcomes. Kate looks at oral cannabis for nausea and vomiting. And CJ reviews the ASCO Guidelines for the management of locally advanced rectal cancer.
Plus each Host presents their favourite Quick Bite papers.
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
Welcome to the Oncology Journal Club podcast, a fun and educational oncology learning resource for medical professionals. 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 tackles patient-reported outcomes, kate looks at oral cannabis for nausea and vomiting, and CJ reviews the ASCO guidelines for the management of locally advanced rectal cancer. Plus, each host presents their favorite Quick Byte papers. For additional insights, links to the papers and bios of our hosts and more information, visit the show notes on oncologynetworkcomau. The Oncology Journal Club podcast is produced with pride by the podcast team at the Oncology Network. Thanks for listening.
Speaker 2:G'day. Welcome everybody to Episode 9 of the Trans-Tasman version of the Oncology Journal Club podcast. That segues nicely into the fact that Chris Jackson is standing for UICC Council. Was that a good segue, chris? You want to tell us about that, chris? Please vote for Chris.
Speaker 3:People in Australia probably know, the UICC has been led by Cedric Aranda previously and also currently led by Geoff Dunn, actually current president. He's on his way out, finishing his term. There's never been a Kiwi on UICC, and so if all you Aussies would vote for me, it'd be awesome. Okay, vote one.
Speaker 2:Chris, chris, do they have translators for the Aussies on USCC? They might need them, I tell you, I think. How are you Kate?
Speaker 4:Yeah, good, good, looking forward to summer in a big way. It is cold and disgusting in Wellington today.
Speaker 2:Don't be careful what you wish for, because we've had record-breaking heat in western, central and northern Australia, so unprecedented winter temperatures in the ski fields. Many of the ski fields have had to close early, so don't look forward to it too much.
Speaker 4:Well, the little eastern island has to have something going for it. So you know, that's maybe our one little advantage.
Speaker 2:Yeah fair enough.
Speaker 3:You know, when Australia bakes, new Zealand pours, because all the hot air in the anticyclone then goes down over Antarctica and then whips up back our way.
Speaker 2:We're always happy to send you over our hot air.
Speaker 3:You see, there's your convicts and also the weather. Thank you very much.
Speaker 2:So, Chris, do you want to kick off? What have you got for us in terms of your prime paper?
Speaker 3:Today I was going to cover the ESCO Locally Advanced Rectal Cancer Guideline, which has just come out in JCO, defining locally advanced rectal cancer as T3-4 node positive. And this is the smorgasbord of options. Previously, guidelines were simply the mutterings of the in-crowds, compiled in dark rooms in strange ways and published on the basis of anything they liked to do and wanted to justify the publication. And now at least we have some randomized trials to guide our therapy and this is being disseminated and distilled by luminaries.
Speaker 2:Is there anything controversial in it?
Speaker 3:Look, I don't think so. I mean, I think really the really good studies we've had in retinal cancer over the last couple of years have really helped. You know, I think Pradige, Rapido and Oprah have been really practice changing for a lot of people. Prospect sits in there as well. Let's just go through those quickly. There's a couple of supportive studies as well.
Speaker 2:It's a very confusing area, I think, for a lot of people.
Speaker 3:So I'd love to hear your take on this. Well, I think we need to think about rectal cancer still in terms of the good, the bad and the ugly. It's a really helpful way of thinking about it. And the neoadjuvant rectal cancers with TNT are very much the uglies. So this is T3 or T4 or T2 node positive. So these are the ones that have always needed local therapy.
Speaker 3:The ASCO guideline looked at 12 relevant RCTs and they stratified them and tried to tease out some key points. First of all, one of the key things I think which is helpful that the guideline disseminated was how important the degree of T3 extension is in terms of the local recurrence risk. So if your T3 extension is the amount the tumour extends beyond the muscularis is less than five millimetres, your local recurrence rate is under 5% and your overall survival is 80%. So it's important to think about that MRI depth of invasion. Second of all, if your depth of invasion is 5mm or more, your risk of local recurrence is 20% and your overall survival is 40%. So really, that extent of T3 involvement is absolutely and utterly critical. It's so rare these days to see mesorectal fascia actually involved in the time of operation because of the effectiveness of downstaging therapy. We're all so worried about the margins. It's important, though, to think about the depth of invasion, the risk of local recurrence, the risk of distant relapse and therefore what the optimum strategy is.
Speaker 3:Should intensify chemo? Should you intensify radiation? The studies of stella and rapido were short course radiotherapy followed by chemotherapy, and both showed long-term distant metastasis, free survival and improvement of overall survival, um. But in the polish 2 study the overall survival gain had gone on longer-term follow-up and on Rapido, on longer follow-up, so 25 and 5, followed by chemotherapy. The local relapse rate was actually quite high. So the short course followed by intensive chemo seems to be falling out of favour in terms of the guidelines. That leaves us with long-course chemoradiotherapy, with chemotherapy. And then the main question is which way around do you do it? And the guideline says one study shows that doing long course chemo, radiotherapy first, is better, followed by chemo, which is what they did not prove. True, that's very true. But you can do it the other way around if you like, because that's what they did in Pradish.
Speaker 2:Can you define what long course means if long course is now the standard, Because a lot of people won't know.
Speaker 3:And so the two main studies well, three actually are of long course chemoradiotherapy and chemotherapy, and long course is usually five weeks of radiation followed with, you know, concurrent with 5-E fuel capsidabine. There was the Oprah study, which was the which way round chicken or the egg. And there's also a German randomised phase 2, which is also which way round chicken or the egg. And the age-old answer to the question of which came first, chicken or the egg, was certainly answered in that and that is it's better to do long-course chemoradiotherapy first if you want to have improved long local control or TME sparing, and if you want to have improved long local control or TME sparing. And the question, of course as well, is can we sack the radiation oncologists? Is there any way we can get rid of them? Medical oncology have been trying for ages and DMMR patients. I'll talk about those in a moment. Yes, we can, and there's only some patients who you can get rid of the long-course chemoerotherapy for, but they are the lower-risk patients, so usually T2N+ or T3N0. So that's where that's looking. This guideline doesn't look at the early rectal cancers, so T2N+, so it doesn't look at that particularly. That's more looking at the T3, t4s. Then when we want to look at the DMMR or MSI high patients.
Speaker 3:I think everyone pretty much knows the Dostalimab study which was headlined at ESCO a couple of years ago with the headline that you can now get rid of brutal radiotherapy, and the investigators have tears of joy streaming down their face when they found the results in 12 patients of a clinical complete response which is now out to 40-odd patients, I think, with no patients relapsing with that. I think it's an interesting question because of course not everyone's got access to PD-1 inhibitors like Dostalaminib and they are very expensive. So what are the outcomes with standard chemoradiotherapy in DMMR patients? We've actually got really limited information on that. The only one I could really find was an MSKCC retrospective on 16 patients which showed actually the local recurrence rates were higher and in a chemotherapy study, six of 21 who were treated with Folfox you had DMMR progressed, which is not our standard experience with chemo.
Speaker 3:So again, an early rectal DMMR if you can use a PD-1 inhibitor. If you can't, please don't use chemo because it doesn't seem to work very well and your patients progress. And use chemoradiotherapy if you need to, because we don't have any good data to omit it at this stage. So a guideline which summarised things nicely. It seems to favour the Oprah approach of long course chemo radiotherapy, followed by chemotherapy in their preferred guideline, with a little wee asterisk to candle it, the French way, if you like. And the French way seems to be what we like to do in New.
Speaker 2:Zealand which is what God help us.
Speaker 3:That is Fulthurinox chemotherapy followed by chemoradiotherapy, so triplet chemotherapy followed by chemo RT. That one actually did show improvement in overall survival, the others didn't, and I think ultimately we're looking at improvements in overall survival here. That's what we want to achieve. We want to cure people, so we've got these ugly tumours, t3, n plus or T4. Improving overall survival seems to be the goal there. Dr Clark, what are you doing in your neck of the woods.
Speaker 4:We nutted this out a couple of years ago and decided that Prodige would be what we would do. I think, when each department nuts this out, though, the issue is what can you do so within your department? Can you go straight from MDT to radiotherapy, or is that where your resource concerns are? So for us, it's easier for us to get chemo started first, and so that was where our biases sat. We did have quite a lot of arguments about the fact that trials all include different people, so that is really tricky to do. Cross-trial, naughty cross-trial comparisons that we all do, because there are three, four different strategies here that have not been compared here to here.
Speaker 2:So Kay and Chris. So in places where we don't have the constraint of starting radiotherapy quickly. So I get the practicality of going with the chemo, but there's some good radiobiological reasons why you don't want to do that. So you want to hit chemo radiotherapy first. So, chris you mentioned there are a couple of studies that looked at that chicken versus egg, chemo versus chemo-radio therapy, all the other way around. So in a purely scientific form, it is better to do the chemo-radio therapy first if you can or did. It show no difference.
Speaker 4:No, there's no difference in OS or DFS. There's a difference in your ability to do, watch and wait, and that might be artifactual from your MRIs. So I think if you are doing an Oprah-type style, then chemo, radiotherapy, chemo is the right thing to be doing, but again, resource may limit your ability to watch and wait, which I know sounds daft because surgery is expensive, but so are MRIs. So I think the and Chris is right, the only rectal TNT trial to show an OS benefit over the other strategies is Prodige, you know, over their control strategy. It was small, it's only a 3% difference, but it is, you know, it's there.
Speaker 2:Yeah, a couple of other questions, chris. So the staging is based on MRI.
Speaker 3:Absolutely. It's based on MRI staging.
Speaker 2:I think that's the handle of care now pretty much everywhere, so we don't need to worry about rectal ultrasounds anymore. No, no more, no good. Do you have MRI machines in New Zealand? Yes, good, I think we've got one.
Speaker 4:We may not have staff use them, but we've got machines.
Speaker 2:Yeah, so let's just step. Well, that is a rate-limiting step for a lot of people, right. There's now even in high income countries like Australia. There's resource constraints around time to get an MRI appointment and get it reported.
Speaker 3:And I also think that New Zealand does not have PBS reimbursement restrictions on MRI and that was one of the things New Zealand had access to In excess of Australia. We could actually do more MRs for rectal cancer than you guys can. So that's you know. The availability there and the skill of the MR radiologist is important. When we were doing the watch and wait studies at the Marsden when I was a fellow, there was a big difference between a Gina Brown read MRI and an anyone else read MRI, and so it very much is a technical skill, exactly.
Speaker 2:So, look, we've spent a bit of time on this, but I just want to spend a minute or two. Can we just step through, chris, the conclusions, and don't mention the acronyms of the study, but spell it out, because some people don't know what prodige and opera means, et cetera. So, for each stage, what were the conclusions or the options that we have?
Speaker 3:Yeah. So, like a lot of guidelines it's got, can pick your favourite out of the options. I think in clinical practice you have to be very clear about what you're trying to achieve with the patient and be very clear with the patient with what the evidence shows. If your goal is to maximise overall survival and you're not as concerned about organ preservation, then the best evidence is for triplet chemotherapy with Folfironox, followed by chemoradiotherapy, followed by surgery. That's for all of those stages. Yes, well, yeah, for T3, n1, and for T4. And then the other option for that well, this is only locally advanced, craig. So this is all locally advanced really, so it doesn't quite stratify it down to T3, n1, t4, et cetera.
Speaker 3:This is all t3 or t4, yeah, so it's all of them. And then if you want to do organ preservation where you've got a low rectal tumor, then you should do chemo radiotherapy first, followed by consolidation chemotherapy. That gives you the best chance of achieving a clinical complete response and go to watch and wait. But there isn't data to show that that improves overall survival compared to the converse. So again, I think it's likely that it's just as good, but it's not proven. So ensuring that you're clear about what the evidence shows and what your goals of care are and people vary in terms of their priorities on how important sphincter preservation is to them versus the certainty of improving overall survival.
Speaker 2:So in summary, for all stages of locally advanced disease the best evidence for survival is you can do chemo first, followed by chemo radiotherapy, which fits in with those kind of constraints sometimes about time to radiotherapy. But if organ preservation is the goal, so for low tumours or that's important to patients, then you should kick off with the chemo radiotherapy first, followed by consolidation.
Speaker 3:Absolutely. And if you've got a patient who finds preservation of sexual function is critical or wishes to avoid radiation for some other reason, then you can do the approach that was used in the PROSPECT study, which is induction chemotherapy with either Folfox or Capox, and if they have an adequate response you can omit the radiation. So that is, for the slightly lower risk tumours, radiotherapy can be omitted, particularly if a patient goal is to preserve sexual function.
Speaker 2:A great discussion, good paper. So people should click on the link and read a bit more. I think it's probably a bit of a landmark, state-of-the-art summary right of where we're at. Yeah, I think so. Rectal cancer and you and I are both in a chat group about GI tumors and lots of time the rectal cases get put up because it is fairly confusing even for the so-called expert. So let's change tack. Now I've got something that's sort of relevant across tumors.
Speaker 2:Really this is paper from JAMA Oncology patient reported outcome measures in cancer care and updated systematic review and meta-analysis. So who would have thought that doing PROMs or particularly this is focusing on PROMs actually may have a survival advantage, and so I guess this story is a little bit analogous to the early referral to palliative care, which has been shown to have a survival advantage, and it may be because we're looking after people's symptoms better and they're able to stay on treatment for longer and therefore do a bit better. So this is a meta-analysis of patient reported outcome measures, or PROMs, from randomized clinical trials with PROM as an intervention. They looked at 45% randomized trials with close to 14,000 participants between 1996 and 2002. And overall it looks like the addition of a PROM reduced the overall risk of mortality, improved quality of life at 12 weeks, but no improvement at 24 weeks, and it wasn't associated with reduction in emergency department visits or hospital admissions. There was a clear trend but didn't quite meet statistical significance. But the take-home message from this paper is that using PROMS actually has an overall survival advantage 0.84. So if this was a drug intervention we would probably have drug companies lining up to tell us all about it.
Speaker 2:An interesting paper. I don't know whether you guys use PROMs routinely in care, but there is a move in Australia as part of the new Cancer Australia, Auspice and National Cancer Plan, Australian Cancer Plan. They're doing some work with Movember with their philanthropic money to introduce PROMs next year into routine care. So Movember's done some work with prostate cancer patients using PROMs and they're now going to pilot it in or introduce it in, I think, up to 10 tumour streams, with some making available some online resources, training kits, PROM tools that health services can utilise. So we'll be hearing a lot more about PROMs, certainly in Australia, in the time ahead. But this provides some of the evidence base why we'd bother to do that not only to people have a better quality of life, but they also may do better. Overall, it's an interesting paper.
Speaker 3:Yeah, look, I think that's absolutely great. You're absolutely right there, Craig, that if this was a drug it would be funded tomorrow, and I think that's an important take-home message is that there are lots of things we could do to improve patients outcomes that aren't just chemo right or new drugs. We need to push just as hard for those as we do for our novel therapies. You know I've always found it interesting that you know you do your tox reviews at the end of your cycle, right towards the end, and patients memories are starting to fade. It's just like women going back to have another child. They forget what it was like the first time around, which is why they have another, and patients are just the same. They forget what the chemo was like for the entire cycle.
Speaker 3:That's why they turn up for another one, and maybe the PROMS and PREMS is giving us a better idea of what the appropriate dose intensity is for people, which is doing really what is most important, and that is focusing on patient outcomes that matter. Craig, I'm really impressed with the Cancer Australia and the patient charity work on incorporating PROMs into clinical practice. I think that's a really important advance and one that governments are perhaps less good at doing. How are they physically doing that? Is that checklist? Is it IT-based? How are they doing that there?
Speaker 2:Well, I think there's going to be some options there. I think the whole program is still being designed and rolled out. So I understand that Movember has brought multiple millions of dollars. Cancer Australia has brought some millions of dollars. I presume that there'll be paper-based tools that you can print off or there'll be electronic tools that can be utilised. So the concept being, you know, a patient can sit in the waiting room, fill in a form that can be handed to the health specialist, could be a doctor, could be a nurse, and reviewed before and during an appointment. And so you know, we all, when we're seeing patients with chemo, we go through and we ask them a whole lot of questions, but, as you say, they might forget or you might not ask them all the specific questions. So this way, the issues that they've experienced can be flagged and addressed during the consultation so that their experience, hopefully with the next round, is better. And, as I said, perhaps the explanation for this is people are able to stay on treatment a bit longer.
Speaker 4:Yeah, we have to use number eight wire tech over here because nobody's giving us millions of dollars to study this, sadly. One of the most useful things that I suggest to patients is to diary every day, write down how you're feeling. Is it a good day, a bad day? Are you tired? Did you do everything you wanted to do today? And it's actually quicker to go through somebody's diary than it is to make small talk for 15 minutes. So I would encourage people to not wait and to give patients back the mana, the power to monitor their own symptoms and a very simple notebook. Written diary is an incredibly powerful tool. People's memories do fade, and I love Chris's analogy about the, the second baby, because, uh, yes, I fear that may be very true about second and third cycles of chemotherapy. Oh shit, this is what this feels like, so I'll talk with it, kate.
Speaker 2:we do it in a trial, don't we? We give people diaries and maybe that helps explain again why people on trials do better, because they have a diary and they see that the um clinical trial coordinator or trial nurse and those symptoms get addressed. And the most commonly used instrument was the EOTC-QLQC30, which is readily available. People can print that off online and give it to patients to fill out in the waiting room if they want. So, as you say, fantastic, there's going to actually be a national program to try and implement it. I presume evaluate it as well, but there's probably not a good reason for people to wait if they want to be proactive.
Speaker 2:I'm hitting the print button, now Fantastic Practice changer, chris. So, kate, what have you got for us?
Speaker 4:So I've really got three little things today.
Speaker 4:The first one is from Peter Grimason and team from Lifehouse, with my friend Martin Stockler as the last author, using oral cannabis as a chemotherapy-induced nausea and vomiting secondary prevention.
Speaker 4:A couple of interesting things, though. Most patients were on both a neurokinin 1 antagonist and a 5-hydroxy tryptamine antagonist, so that's a prepitant and the like and odesitron and the like. Very few were on olanzapine by virtue of when this was randomized, and the doses of THC, cbd are tiny if you compare them with what people might be using in gummies, example for other indications, only 2.5 milligrams of each, and it does increase the chance of complete nausea control from 8% to 24%. It is statistically significant, but the team really struggled to complete their recruitment and the difficulty was people didn't want to take cannabis. So I find that fascinating myself and maybe if they did that again now they randomised between 2016 and 2022, maybe if they did it again, maybe now, maybe in a different jurisdiction, they may get different answers. I would say a good third to a half of my patients are routinely accessing cannabis, maybe not in the pharmaceutically produced sphere, however, oh, I think it's a fair estimate.
Speaker 3:Really, kate and half of my old classmates produced sphere. However oh, I think it's a fair estimate, really, kate and half of my old classmates. It's a common topic in clinic, isn't it? I mean, I think there's always something in vogue which is doing the circles and the patient circles, be that vitamin C or be that THC, cannabis oil, whatever it is, there's always something which is there. I'm really pleased to see this being studied in a structured way. I think my clinical experience is that olanzapine is a very, very good anti-emetic and at 2.5 milligrams, chemotherapy-induced nausea and vomiting just isn't a thing in our inpatient wards, whereas it was at the start of my career when we didn't have even 5-HT3 antagonists, so pleased to see it studied. I'm interested, kate how much is in a spliff or a spot compared to a gummy?
Speaker 4:So the gummies that you can buy commercially are 15 to 25 milligrams a tablet, so 10 times the dose that this team were using, and maybe that is just like with olanzapine people start off on much higher doses than we actually need. Maybe same is true of recreational cannabis. Maybe we could cut the doses back, save yourself some money and get the same effect. But it is actually very tricky to get hold of this very low dose of thc cbd, and that was something I did a little bit of research on. In new zealand we have a quasi legalization, a decriminalization, and access is possible, but the therapeutic pharmaceutical preparations are very expensive indeed, which is why people go off piste and access their own.
Speaker 2:I would imagine your government didn't overturn those quasi-legalisation laws in the first day of Parliament.
Speaker 4:They've got enough to be getting on with Craig. Enough other things around doing. You just see, chris, and I just deflate. Sorry, I'm sorry.
Speaker 3:Sorry. I'm sorry, kate. Was there any difference in rescue or control in people who'd used THC or CBD in the past? Was that a certification factor at all?
Speaker 4:No, Martin's going to email me now and go. It was too, but not that I recall when I read the paper. I'm scanning as quickly as I can.
Speaker 3:Yeah, but again, bloody great Aussie investigators leading this really important study, which is something that patients are interested in. They ask us every day, and good on them for conducting a randomised clinical trial in a supportive care area to ask a meaningful question. So you know, big ups to the team.
Speaker 2:Yeah, I agree, because it's been an absence of data, right? People ask you should I be using it and you just didn't know. So it's great, the study's been done, great.
Speaker 4:So the other interesting paper that I have again on the number eight wire is a very pragmatic paper from the TATA. So Mihak Trika and team did the CLOUD-HIGH study? Have either of you had a look at this? So it was in microsatellite and stable metastatic colorectal cancer patients and it's non-randomized. Those that could afford standard doses of nivolumab got standard doses of nivolumab. Those that couldn't got a range of very low doses from 10 to 20 milligrams every three weeks sorry, every two weeks as an attempt within what they could afford. All of the endpoints that they measured in this non-randomized small trial response, progression-free survival, overall survival are identical. So I think this is very thought provoking. Obviously, the price is set already for the high doses and now that we have access maybe I'm less concerned, except I just I find that absolutely fascinating and the trialists are very open about why they had to be so pragmatic.
Speaker 2:Yeah, I agree, kate, really fascinating. I don't imagine that drug companies will be lining up to do studies of low dose versus high dose. I think we've covered this topic before, although it might've been about different intervals of dosing based on translational evidence and PK. We did it in about February or March this year I remember talking about it and I was again. So this adds to that body of evidence that in fact we may not need to use the same dose and it will be cheaper if we can sort that out.
Speaker 3:The dose question's a really interesting one, isn't it, craig? Because when we did the original PEMBRO studies in melanoma and you were looking at 10 mg per kg or every two weeks should be three weeks it did seem that the higher dose tracked slightly better, but with a bit more tox as well. So the dosing question, I think, is far from sorted and of course it's a different mechanism of action to chemotherapy, so dose response isn't necessarily clear that it would work. And again, that other beautiful study from India, again in head and neck cancers, looking at NEVO20, I think that was a post for ESCO, then published in JCO. But again great pragmatic work of great relevance to low and middle income countries. Probably great relevance to high income countries too, if we'd actually just get on with it.
Speaker 2:Exactly, yeah, absolutely, kate.
Speaker 4:So my third one is a shout out to the trainees. I don't know whether Craig and Chris felt the same way, but one of the hardest things about being a medical oncology trainee is that somebody will go to you have you read Keynote 522? And you're like I'm still waiting through the last 30 years of data. Give me a minute. So I love a good review article, and the review article I want to draw your attention to is may, lucy, mayer and team and this is a team. So uh, professor peter, solange peters, professor passy yarn, professor fred hirsch, their summary on the uh up-to-date non-small cell lung cancer, and it is in Lancet, published August the 6th, so hot off the press. I would direct any trainee to it as a good starting point when they are doing their lung cancer reading.
Speaker 2:Yeah, we do like endless review and you know it's been a fascinating and rapidly evolving history in non-small cell lung cancer and that we used to think about small cell and non-small cell and now we know that in fact, non-small cell and now we know that in fact non-small cell lung cancer is actually about 30 or 40 different diseases that all happen to start in the lung, triggered by different genetic mutations, and the testing for those mutations is now in the forefront and this paper Understand discusses that and looks over the horizon at some other new things coming. So I think it's great, a nice review, and we like a good review on the podcast to refer people to. So I've just got another couple of quick ones to finish off. One is from the JCO Utilization and Outcomes of Multi-Gene Panel Testing in Patients with Pancreatic Ductal Adenocarcinoma. So they actually pointed out that the ASCO guidelines changed a few years ago and they recommended the routine testing of all patients with pancreatic ductal adenocarcinoma or PDACs, and this was a study done at a single institution, good old Mayo Clinic.
Speaker 2:They looked at the discussion, uptake and outcomes of the multi-panel germline testing before and after the guidelines were released in May 2019. They identified 533 patients. 60% of those were pre-guideline, 40% after, and they found that the uptake of testing was not improved after release of the guidelines, which is interesting. But when they did test the patients, about 17% had a pathogenic variant, so that's a really interesting result. It was more likely that younger patients were tested or people had seen a medical oncologist versus other cancer specialists, and those surviving more than 12 months were more likely to be tested, I presume because they were looking for second or third line treatments. So in your same paper, you know the different published rates of positivity, somewhere between 10, this paper, 17%. Is it something that you guys routinely do, testing all your pancreas patients looking like the lung cancer patients referred to, looking for mutations?
Speaker 3:Really no, craig. I mean I think it's still very expensive to do that About $4,000, foundation One's our best option to access that for multi-gene panels. I'm not so convinced about the BRCA data for maintenance. I thought that was a pretty poorly executed trial, looking at either randomization discontinuation or maintenance PARP inhibitor, showing that maintenance PARP improved your PFS and improved your OS. So I don't really think there's much evidence for it in a therapeutic context in pancreas cancer and almost all of them have got KRAS G12 mutations anyway, don't they? So you don't find a lot. I think you've got a high-risk population or family history of breast or prostate cancer as well, worth doing the testing there. But that's looking for germline more than somatic, I think.
Speaker 2:We're really lucky over here actually that we're over the other side of the ditch, that we're able to. In all patients with advanced cancers we can now get next generation sequencing done on the tumours so we can look at actionable mutations in multiple tumours and plug people into clinical trials if they're available.
Speaker 4:I just wanted to split the two up. So I think it's really important we don't forget about young pancreatic cancers and germline mutations. They are a canary in the mine for their whānau and it's really important that they are tested, and it is quite tricky to get them accepted. The EVIQ guidelines last time I looked are a bit vague and you are more likely to get tested if you have two aunts that have breast cancer than you have pancreatic cancer in your 30s. So that's my first little shout out. My second shout out is yeah, look, I agree with Chris. Until we have pan KRAS antagonists, you're going to get the information that you're expecting out of the vast majority of pancreatic cancers. But there is some work being done in the wild type KRAS and I see enough of these that I might see one of those every couple of years, I think. Watch the space. It's nowhere near lung, you know, nowhere near lung. But you know we always have hope. Melanoma wasn't melanoma until 10 years ago, so you know we always have hope.
Speaker 2:Was that a segue into my last quick bite, kate? Which is, in fact, melanoma. Well done. So this is a paper in JAMA Oncology Long-Term Survival in Patients with long-term survival in patients with advanced melanoma. So this is from Dutch Melanoma Treatment Registry. Good on the Dutch, they're great at doing some of these prospective registries.
Speaker 2:So this is the largest report of long-term follow-up patients who received ICI for melanoma, some 2,500 patients who have been treated with first-line ICI for melanoma, some 2,500 patients who were being treated with first-line ICI, either IPI single agent, a single NEVO single agent or the combination. And then looking at the long-term follow-up and so the overall survival for all patients at three years was 44% and at five years 35.9%. So this is some sort of real world evidence that people who treat melanoma can discuss with their patients. If patients achieved a PR or a CR, then they also had a secondary analysis looking at factors associated with likelihood of progression, if achieved, to PRS-CR and they were three or more organs involved. And then when you dive into the details, so the curves are very interesting.
Speaker 2:Again, this is not randomized data, this is retrospective analysis. But patients who received combination ipinevo seem to have a true plateau on the curve with long-term survival. But in fact at an early stage the curves cross. So the patients who receive single agent nivolumab do better initially and then on the tail of the curve there's a. There's a small difference between the two, but we're talking about a 2% difference in the five-year survival. So that comes down to this. You know kind of concern about early toxicity with the combination, which may be a trade-off between the toxicity and then potentially slightly better long-term survival. So just an interesting paper, I think, for people who do look after patients with melanoma or for those who don't, to be aware that now with melanoma and immunotherapy we're getting long-term cure rates, probably five years in real-world cohorts of about 35% of patients. So just a bit better than a third of patients may be cured, which is amazing to think about where we were with melanoma not so many years ago, which was median survival was less than 12 months in most studies.
Speaker 3:Makes it really hard when it doesn't work. Up front, though, craig, you get disappointed now.
Speaker 2:That's correct. And then, lastly, just a little segment we haven't done for a little while, but this is called PBS Up Deep. But I just wanted to mention three recent additions to the PBS on this side of the ditch. So carbazantinib for radioactive iodine refractory or ineligible patients with differentiated thyroid cancer, so this is an option for people who failed RAI. Larotrectinib, now on the PBS, it's a tumor agnostic indication for people with tumors with NTRK gene fusions. And then, lastly, we talked about Caspian study in the post-ASCO bodies, so Divolumab's been put on the PBS for the extensive stage small cell lung cancer patients and I'm sorry that's again not of relevance to the other side of the ditch, but there is hope that there is new patients coming and that's again just to make people aware that there is increasingly options and the care of cancer seems to be becoming a little bit more narrow and specialised.
Speaker 3:I'd love for us to talk about the tuberectostic indications on my episode, craig, and really dive into that. I mean, as a melanoma in colorectal dot, I'm reminded of the B-REF story which of course, in melanoma it just works spectacularly in 95% of patients and in colorectal cancer it's a total dud and I think it's a bit mixed in other cancers. So cholangic carcinoma you don't get the same response in B-REF that you do in melanoma. So I really struggle with the whole idea of you've got a target, therefore you must target it. I think the parent ways are a lot more complicated than that and I think we still need clinical data. And again I struggle with the term actionable mutation. I think it's no, we've got evidence of a driver mutation. It doesn't follow that giving a targeted therapy to that will improve a patient's outcomes. So I still think we have to resist that urge to go straight to the idea of a tumor agnostic indication through.
Speaker 2:Omoco that enables testing for everybody and then plugging them into clinical trials. So I'm not saying that you have a mutation, you can have the treatment. We still need the trial data and we need second generation NTRK fusion inhibitors et cetera so that we can start seeing those hopefully, the curves like we've seen in melanoma.
Speaker 4:So hot off the press. Esmo have one of their always really interesting special articles. It's called the ESMO Tumor Agnostic Classifier and Screener Tool for Assessing Tumor Agnostic Potential of Molecularly Guided Therapies and for Steering Drug Development. The group is chaired by Vivek Subia. It's on my list of things to read only published this week, so I think that might be something to discuss in a future episode.
Speaker 2:Yeah, let's do it on the next episode. Fantastic Sounds great.
Speaker 3:Craig, I've got two quickies to run through. Yes, please, lovely, excellent. Well, you've got to love the Dutch. They've got a massive esophageal audit database of 5,000 patients over 11 years and this was patients who were mainly treated with a cross regime, which was five weeks of induction radiotherapy with carboplatin AUC2, with paclitaxel 60 mm2, quite a gentle induction regime and that, compared to surgery, was better and it's been subsequently superseded by the FLOT-based chemotherapy regime. What was really interesting about this was they looked at timelines, so from when you were first diagnosed to starting has largely diagnosed to starting on chemoradiotherapy, and then when you were first diagnosed, when you had surgery. So looking at the time interval because of course these cancers can behave in certain ways and time does matter and what they found was that if you started chemo, if you had surgery less than five weeks after your radiation, you had fewer complications overall and less of an estomotic leak. So starting sooner is better than waiting slightly longer, eight to 12 weeks. So because it's a slightly lower dose, less definitive quote-unquote regime, it should be treating your patients a little bit more quickly, which I think is an important thing, and we can all do that differently. And the last one I wanted to quickly cover off was Canadians. I'm so in love with Canada. I love Canada so much. Some of my best friends are from Canada and we should definitely have a Canadian on the OJC podcast at some point very soon.
Speaker 3:A Canadian study published and first presented at Astro in October 2023, which looks at oligoprogressive disease and whether or not SABRE should be used. This is on the back of the CURB study, c-u-r-b study, which is a randomised phase 2 study in breast and lung cancers, which showed if you gave SABRE to oligoprogressive metastatic disease, there was a PFS gain in lung cancer but no overall survival gain. This particular study randomized patients in a one to two fashion, whereby patients who had less than five sites of progression on chemotherapy either continued standard of care, which could include a chemo switch, or had SABRE the primary outcome goal of PFS. Not quite sure why. I think it's a pretty poor primary outcome, but anyway they did and they found that basically, adding in SABRE did get superior lesional control, but there was not any improvement in overall survival. So I think that's quite interesting 90 patients, 127 lesions Lung, kidney, prostate and breast Mostly only had one lesion and the per-protocol analysis.
Speaker 3:There was no PFS difference. So SABRE for olivoprogressive disease Doesn't appear to be a clear standard and we still have to investigate this group More carefully. In clinical practice we sometimes use SABRE as a chemo sparing. So we'll see someone progressing at one or two sites and we'll give them Sabre and then stop all treatment, then wait for them to progress and then switch at that point and I'll be interested to hear what others do about the place too- Chris, one of the things I find fascinating about radiation oncology trials is they always have a local control as part of the endpoint.
Speaker 4:My concern with SABRE trials is I'm not sure that's needed anymore. We know this is a very good ablation technique. What we need to understand is when we should be pulling it out, not could we? We know we can. It works beautifully, but does it matter? And I think that's the trick in these trials need to be designed beyond lesional control, because that question has been answered. We, like you, use it for people to buy a chemo holiday or maybe push their having to have chemo down the track a tad, or if they're a chemo averse. I understand the lung doctors use it slightly differently, but I don't treat lungs.
Speaker 3:I think the other thing that struck me about this paper, kate, was that the lesional control, like you say, they report that was only 70% in those targeted lesions, which I thought was lower. We would generally think of it in the high 80s to low 90s in terms of lesional control.
Speaker 4:So when they record it and that it was lower than I expected, I think that would be interesting to have a radiation oncologist on board, because there's Sabre and there's Sabre. We could ask, but I think there's a difference between techniques and doses and schedules that there's sabre and there's sabre.
Speaker 3:There's a Jedi one, and then there's a dark side of the force one. Is it red or is it green?
Speaker 2:Great discussion. I'm already looking forward to the next episode where Kate's going to tell us all about tumour agnostic approaches. Done everybody? Thanks to all our listeners. Spread the word about the podcast if you're enjoying it. We've been getting some lovely feedback, which is nice, and thanks once again to Rachel trying to keep us under control and mixing the sound.
Speaker 1:My pleasure.
Speaker 2:So see yous later, ciao.
Speaker 1:Mate wa. Thank you for tuning in to the Oncology Journal Club podcast. So see yous latercomau. 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.