How to Approach and Treat Pancreatic Cancer

Intro Welcome back to the Oncology Brothers podcast. I'm Robert Gossain. I'm here with my Co host and brother Rahul Gossain. Today we are focusing on the treatment landscape of pancreatic cancer and to guide us through the current standard of care. We are joined by doctor Eileen O'Reilly, world renowned medical oncologist and also the section head of Hepatobeliary and pancreatic cancer at the Memorial Sloan Kettering Cancer Center. Eileen, thanks so much for being with us today. Speaker 2 Great. Well, thank you both. The pleasure to be here and look forward to our discussion. Speaker 3 Eileen, welcome. OK, so let's start off with the initial work up for a newly diagnosed pancreatic cancer patient. What does it really look like in your clinic for a newly diagnosed pancreatic cancer patient? What does it really look like in your clinic? And can you also touch on the importance of germ line testing here? Speaker 2 Yeah, thanks. So this is an important practical question for a person who comes in the door. We're suspecting this diagnosis. We want to get optimal imaging, so CT pancreas angiogram which allows fine cuts through the pancreas with contrast including chest and pelvis that will cover the imaging. And from the lab perspective, just getting regular labs in terms of CBC, comprehensive panel, getting a CE A/C N 99, importantly glucose, right? Well, for a lot of that, these individuals will see that there's been some prodrome in terms of elevated HBA 1C and or glucose. So understanding that and being mindful of that. And for anybody who were suspecting anything pancreas related, we will want to get comprehensive genetic testing. As you pointed out, getting germline testing using ideally a panel which will cover bracket one bracket 2 Lynch genes, ATM, PAL, B2 and and some of the other core genes and tumor based somatic testing in these days often complemented because of the tissue acquisition challenges of utilizing CTDNA. It's not a perfect tool, but it can be very helpful in in these days where we now want this information as early as we can as we're thinking about hopefully more targeted treatments integrated into first line decision making. Speaker 1 Thank you for covering that, Eileen. Well, we don't have good screening tools for pancreatic cancer in general. Early stage pancreatic cancer As a result, when we do diagnose, we diagnose them in locally advanced or a lot rather metastatic stages. But before we dive into that world, let's go where to our early stage where we do get lucky and do diagnose them at an earlier stage. What does your treatment paradigm looks like, especially from adjuvant therapy trans standpoint? Speaker 2 Yeah, So for a person with resected pancreas cancers or they've been able to undergo surgery and have no visible evidence of disease, you know, international standards of care guidelines would support multiple multi agent chemotherapy and for a fit individual that's modified for Feranox and a couple of things about the modified version of for Feranox in the adjuvant setting is just being mindful of the dose of irinity. Can we do see more diarrhea in this patient population possibly related to the surgery and absenting any, you know, specific UGT one O 1 consideration or you know, the very rare DPD consideration. But even even there just to always be conscious of that and no bolas 5F you in the adjuvant setting. The things that that I think about when weighing up what's the right time to start is to ensure that somebody's wound has, you know, heals. That's obviously straightforward, but to make sure that they have adequate nutrition. That's really key. This is a, you know, a stiff regimen at the best of times. And when a person is not eating and hydrating well, it's it's a set up for for trouble and early hospitalization. So ideally they're, they're maintaining their weight and even starting to gain weight in the post op setting and in parallel with that, right, that they have a level of functional recovery in terms of day-to-day activities. So I think all of those three things are the milestones that we look for to make sure that a person is is going to, you know, to tolerate adjuvant therapy. Speaker 3 Eileen, thank you so much for laying that foundation. Modified Fofirinox bolus and leucovorin You touched on this No 5 FU bolus. Is that the case throughout the paradigm where you're not using any 5 FU bolus given the data does not really support and then use of Leucovorin? Speaker 2 Yeah, good, good questions. I think no real consensus on this, but many of the adopted versions of modified Fofirinox in the metastatic setting do not use bolus 5 FU. And if you don't give bolus 5 FU, right, what's the value of Leucovorin? It's really modulating the bolus and I can't say we're always consistent in that. And you know you see that too some of the other regimens, but that's that I think is a very real approach. Our version of modified for Fairanox is dose adjustment of all components as opposed to singling out individual ones. And if you look at the original phase three, the the median dose intensity over time was about 80%. So that's very reassuring. Speaker 3 And again, for our community listeners, this has been the case where 5 Fe bolus is not compromising any outcomes. It tends to increase more side effects. So throughout the GI paradigm, we've seen that omitting 5 Fe bolus is actually safe. Coming back here when it's borderline resectable disease, we do have a few options, and this can start to get complicated very quickly. How do you decide which treatment, how you're deciding the number of cycles? Is that dictated by the overall response? Is it by our surgical colleagues? Any role of radiation here? Can you walk us through this space before we switch gears to metastatic disease? Speaker 2 Yeah. So thank you for this. This is again an important practical day-to-day question, right. Management of locally advanced pancreatic cancer How, what are the best strategies for management of locally advanced pancreas cancer? I think one key point is the multidisciplinary approach. We like to have our surgery colleagues in close collaboration and often our radiation colleagues too, and have a consensus paradigm in terms of how we approach this group of people. And remembering that this is a spectrum right from locally advanced, which can include to complete vascular encasement as in arterial encasement, where there's very unlikely to be any local operative potential to the group of people that have, you know, maybe a fairly high chance of going to surgery 6065% in the in the more borderline resectable approach. And this can be very, very nuanced with more, you know, potential for operation in in the setting of venous vascular involvement as opposed to extensive arterial involvement. So with with that, I think first and foremost is the functional status of the individual and their nutrition. So they're more general themes as we you know drill down to the individual treatment regimens with choices as you're alluding to with modified for fair NOx and gemcitabine and apaclitaxel and potentially Nalerifox too these days, although data there is in the in the metastatic space. So you know mostly for fit younger individuals it will be using modified FOLFIRINOX. That's where we have the bulk of the data. But it's a very reasonable approach to use gemcitabine, apaclitaxel and those suggested strategy, you know, two weeks on, a week off or even every other week in the older less fit individual and you know, patients preferences are important here, right? The considerations of ports and frequency of infusion visits and considerations of you know, alopecia. All of this factors into what might be an optimal decision, but I think you know weights in favour of gemcidibi, napacki, taxol and the older and less robust population and certainly strong weighting in the direction of modified full fair anox for the younger fitter group of people. Speaker 1 And I knew as you leaded to that modified FOLFIRINOX initially, at least in young fib patients. Modified FOLFIRINOX vs. paclitaxel But sometimes we do see that they won't even respond to modified FOLFIRINOX where CA 19-9 won't budget too much. And on repeat imaging at least the scans are not showing progression. Do you usually change your course to gym side to being that paclitaxial and then see the responsiveness based on that? Speaker 2 Yeah. I think this is another very important point is when should we make that decision to potentially adjust treatment. And couple of things that keep keep in mind as I think about this is at the beginning at the time of diagnosis, right, This disease can often be biologically very active. It's making people very sick and you know, appetite down, pain down, sugars haywire, etcetera. It can take some time to just get the cancer under control and get things stabilized. And we all wanted to be better yesterday, of course, most of all the person in the family. But it does take some time. So I'm always a little bit cautious about changing treatment quickly unless it's truly very clear that it's not working. So we use all the clues, right? And the clinical ones are, are, are, I think prime here. If a patient's pain is getting better, that's a very important positive thing. And if they're starting to feel better and there's nothing subtle about this, when it works right, we see it, it's very gratifying and it's, it's evident to all. But it does take typically, you know, sometimes four to six weeks, 2 to 3 doses of treatment to, to get in. But if one is reaching the, the two-month mark and, and things haven't changed and, or, you know, CN 99 is going up, you know, we can't be naive about us. And we certainly have to consider, and increasingly, I think there's comfort with us. And we know biologically too, this makes sense, right? There's some tumour types or subtypes that can underpin differential response to, to treatment. We need to ideally know this upfront and that's another discussion. But I think increasingly there's going to be some selection using these tools to say that this person apart from their clinical characteristics is going to be perhaps better suited to receiving X regimen versus versus Y. We're not quite there yet. Also just to, to make note is that the CN 99 can go up a bit initially and especially in the metastatic disease setting when people have a very high burden of disease, you know, it can go up quite significantly over the first month. And just always, you know, advise people just to, to give it a little time and, and see. And I would say, you know, often not always that will bear out. But yes, I think just careful consideration of all the information at hand, the clinical factors, what the lab trends in terms of tumor market trajectories, not you know individual numbers, but overall trends are telling you. And of course imaging and just keeping in mind that imaging can lag a bit, especially at that first assessment points for the, you know, locally advanced and even in the metastatic setting. Speaker 1 Marlene, thank you so much for covering that. Now an important question that is rather the more common entity unfortunately, which is a metastatic pancreatic cancer where in fact the median award survival is just about a year time. Metastatic pancreatic cancer Can you please walk us through your treatment paradigm here and also answer some of the important questions that would be any role of testing for NGS for somatic mutations outside of clinical trials and of course the choice of modified FOLFARINOX. Now Larry Fox, based off of your study, Will and gemcitabine nab paclitaxel treatment options. Speaker 2 Yes, thank you again. So for assessing frontline metastatic disease, I do think comprehensive genetic testing is warranted today, right, as in October 2024, we still are, you know, in the realm. It's a relatively small subset of patients that will identify actionable findings. But I think the field is very hopeful that that is changing with, you know, Ras therapies entering the clinic. So while it's not prime time yet, but going back to the selection of chemotherapy choice, I think the factors are somewhat similar to localized disease is functional status, nutrition, patient preference. And you know, perhaps this is even both in an academic and A and a community setting, just, you know, how close or not you are to your treating centre and the the support mechanisms available cause some of these, you know, have significant toxicities and, and that's important. But typically it's multi agent cytotoxic therapy as our go to approach in the metastatic disease. And for fit people once more modified Folfaranox and now Larafox, as you mentioned, is recently FDA approved and guideline endorsed. When to use Larafox vs. Modified Folfaranox And often a question comes up when might one choose that over modified Folfaranox? And I don't think there's a black and white issue, but one that I keep in mind as I think about it is if a person has previously undergone resection and had adjuvant therapy and then at a later time point their disease occurs, it makes sense to revisit the regimen. It's been some distance. Maybe a logical consideration is to use a different version of a regimen. That's so that would be 1 context and similar paradigm for locally advanced and then later disease progression. We do also have to be mindful that our goals are, you know, for the most part, non curative here and again, really important to understand the person, their social supports and their individual preferences. And, and some people will say, listen, I hear you. But, you know, something that gives me more less more flexibility, more time with my family, less time in the clinic. And there's a milder regimen that can be a very, of course, legitimate option. And I had a very, you know, kind of heartening discussion on this topic with a a young man. And one might have imagined that that would be the person that would, you know, push the envelope to the to the end degree, but very thoughtful, you know, reasons as to why that wasn't going to be the right choice. And so these are, you know, very important, very practical discussions. Speaker 3 Eileen, thank you for touching on that. A common scenario also ends up being a patient that ends up in our clinic with high bilirubin. High Bilirubin In that scenario, do you lean towards those adjusted gem nepaclipaxel? Do you reach out for SALI Platinum in that settings 'cause this is not an uncommon scenario in our clinic? Speaker 2 Indeed, it's a. It's a very common one under 2, two contexts to this. The one that's the more common is in people who have obstructive jaundice related to tumour or nodal disease at the head of the pancreas or the portal hepatitis. And that's a reversible consideration. So they're thinking about Bill, your intervention, your intervention radiology if it's not accessible endoscopically, but assuming that's a soluble problem often would start for that individual who's otherwise well with FOLFOX and then a scale up with Arena TICA and then modified FOLFIR an ox, the more challenging and problematic set of circumstances. And it's a very classic picture. It usually a left sided body or tail primary and diffuse liver metastasis And there it's not so much an obstructive picture, but it's a diffuse disease infiltrative process that's usually a very concerning set of circumstances, prognostically worrisome and a much more difficult situation to to to treat in many, many regards. That's often a sicker patient population and there gemcitabine now paclitaxel, I think one has to go very carefully with because of poor metabolism, heightened toxicity. So usually in that setting for me, it's always those adjusted falfox to start and then very carefully scale it up. If, if one can get response, one is always hoping in in that setting that maybe there's an underlying, you know, bracket, somatic or germline context that these people will respond and, and sometimes they respond very well, but often it's a, it's a, you know, it's a kind of a spiraling challenging scenario, that latter context. PARP inhibitors in the context of disease progression Absolutely. And then unfortunately we often see this disease progress. So how are you planning your subsequent treatment if the disease has progressed in first line? Can you also touch in the PARP inhibitors here? Speaker 2 Thank you. So in the context of disease progression, we'll, we'll take that first and then go back to PARP inhibitors. Your nice logarithm here speaks to how we think about it in practice and in the world of finite choices. It's sort of the opposite to what you didn't have in in the front line. So for individuals who've had gypsitabine based therapy, it's typically 5 FU based treatments. And usually in that setting we have an FDA approval for liposomal lorinotican 5 FU and that's a good choice or FALFOX in in, in some people for individuals who've received modified FOLFIRANOX and Nalirafox, typically gemcitabine based, I usually will try a combination and certainly favour gemcitabine and Apache Taxol. But other combinations may be reasonable and individuals where neuropathy is a concern or you know, comorbidities preferences in terms of alopecia, etcetera. And and so there's you know, limited, but some variation on the theme there in the in the second line setting. So going to PARP inhibitors, PARP inhibitors really don't work very well in the setting of progressive disease and certainly in the context of platinum progression. So right now they're FDA approved as a maintenance option after platinum based therapy. For a person with you know germline bracket one bracket 2, but we also include people who have oncogenic somatic variants and people with germline or somatic PAL B2 and maybe a few other rare variants in terms of the RAD 51 genes, they can confirm Holocus repair deficiency signature. So the, the best time to use a PARP inhibitor is when diseases debulked, stabilized responding and kind of in a minimal residual disease state in advance of progression. Progression is a very poor surrogate for a favourable outcome with a PARP inhibitor. Uh, but PARP inhibitors are a very nice option as an alternative to ongoing cytotoxic therapy, uh, for that particular, uh, population and you know, offer again, some quality of life, uh, benefits. They don't work for everybody, but when they do, we can sometimes get some extended period of time away from chemotherapy, which is very meaningful and. Speaker 1 This is certainly a tough disease to manage. Well, we have covered quite a bit here. Outro Thank you so much, Doctor O'Reilly for this overview of the current landscape for pancreatic cancer for our listeners. Let us recap what the key points from this talk today. In today's discussion with Doctor Eileen O'Reilly from Memorial Sloan Kettering, we covered the current standard of care treatment for pancreatic cancer. We emphasize the importance of a thorough initial work up, including genetic testing, which can significantly impact the treatment decisions. We discussed the management strategies for resectable, borderline resectable, and metastatic disease, highlighting the role of neoadjuvant therapy, surgical approaches, and importantly, systemic treatment options in this space. Speaker 3 In this discussion, we also had a chance to touch on the emerging role of targeted therapies and the potential of NGS to look for these actionable mutations in pancreatic cancer. The multidisciplinary approach involving case collaboration with surgical and radiation oncology colleagues still remains crucial, especially in optimizing outcomes for our patients with early disease. Thank you so much for joining us, and don't forget to check out our other episodes covering conference highlights, recent approvals and treatment algorithms. We're at the Oncology Brothers.