How to Manage & Treat Pancreatic Cancer

Intro Hello and welcome back to the Oncology Brothers Podcast. I'm Rohit Ghosain here with my Co host and brother Rahul Ghosain. We are practicing General Medical oncologist in the community and our goal with this ongoing series of treatment algorithm is to reiterate the current standard of care and appreciate the treatment landscape for each disease site. With that in mind, today we'll be covering pancreatic cancer. To walk us through this, we are joined by Doctor Emma Lu, a medical and neuro oncologist with focus in GI malignancies from University of Minnesota. Before we get started, is it important to address your Twitter or X handle MO? Definitely jealous, but cancer assassin. Speaker 2 Yeah, at the outset of social media I tried to come up with something clever and memorable, and I'm glad it has the case of plus decade plus. I think that in the era of targeted therapy, the ideal to aspire to is to protect the patient, get rid of the cancer, which is the enemy, and spare the patient as much as possible. So that's something we should always all right to in any drug developments. I think we're all cancerous assassins in that we're trying to improve quality of life and get rid of the cancer. Speaker 3 I love it, Emil. Thanks for joining us. You know, Emil, whenever we're talking about our treatment algorithm series recently, we've covered breast cancer, bladder cancer, even upper GI malignancies. Pancreatic cancer treatment landscape We're often touching on the latest drug approval or another upcoming FDA decision based on one more positive study. But when it comes to pancreatic cancer, it feels like we're still waiting for its turn to have that breakthrough moment, be it through precision medicine or that one antibody drug conjugate that's going to make an impact. And to be honest, I don't mean to start on a somber note, but we all are eagerly waiting for something big to happen in this disease site. All right, we have a lot to cover, so let's dive in for early stage disease. Early stage pancreatic cancer If surgery is an option, this ends up being the mainstay. But systemic therapy, be it a neoadjuvant or adjuvant, still plays a big role. MO What's your treatment approach for this particular patient with early pancreatic cancer? Speaker 2 Yes, So thank you. I want to echo what you're saying is that the three of us are waiting. The whole world is waiting, patients and their caregivers are waiting and the breakthrough is haven't come fast enough. And so through drug development, understanding of biology, one will not be able to be in isolation from the other. And I think that plays into this idea. I mean and and our colleagues who are working in the screening sphere are obviously working very hard to make this a cancer where we can have an effective and validated screening test. And so that's why only 10 to 15% of all these pancreas adenocarcinoma is approximately 45,000 new cases the US each year, only 10 to 15% being able to diagnose the time where they're potentially resectable at time of diagnosis, right. So that's an unacceptably low number. But when we do have the opportunity to be able to tell a patient this, there is opportunity for resection with intent to cure and obviously still a high chance of coming back, we have to go for it for patients who want as aggressive a treatment as possible. So you know, with our friendly neighborhood surgeons obviously are absolutely key and and our radiology in a multidisciplinary, you know, tumor board approach, the conversations and formal tumor boards and in between. I absolutely rely on my surgeons and radiologists to pinpoint to me the things beyond that I already know. So we talked about the difference between a resectable tumor versus borderline can be millimeters. The evolution of adjuvant chemotherapy It's like real estate, the location maybe not so much even the size in some cases for the great vessels, the superior mesenteric artery or vein and the portal system, which I think is remarkable. In the time I trained and more so academic cancer centre, amazing internationally renowned leaders, they would be the first to say wow, things have changed in the sense of this evolution where it was resection, a small number of patients. That part hasn't changed so much, but what you give after evolved from gemcitabine. There was an era earlier part of the 21st century, maybe 15 to 25 years ago. Radiation was explored, very controversial, multiple studies reporting detriment and now the use of resection followed by adjuvant chemotherapy, which I always explained to patients with the effort to risk reduce that surgery has already taken out what's there. But so much of the shift over the last decade to neoadjuvant. At my center at the University of Minnesota, we've nearly entirely shifted new adjuvant intent therapy over the last 10 years. So we rarely see, but if you look in the NCC guidelines, it's still listed and we have to be able to address it. But with the trials that were seated and started more than a dozen years ago reported more recent years, we have the opportunity to treat in the post doctor setting with modified folfiranox or gemcitabine with kepsitabine. Speaker 1 It is extremely important this multidisciplinary tumor board approach with regards to surgery, Ripple surgery is not the easiest one to go through either. Yes, it even in my practice we tend to rely on neoadjuvant. But again going through surgery is very difficult. Supportive care aspect comes in with pancreatic enzymes or right nutrition is extremely important. Now working with CTDNA, NGS or germline testing, these are hot topics which are rather being mentioned in all solid malignancies. CTDNA, NGS, and Germline Testing Any role of CTDNA here or anywhere in pancreatic cancer? And also if you could please touch on your practice with regards to NGS or germline testing. Speaker 2 Absolutely. I'll start the the 3rd and germline testing and work way backwards in your question. So ASCO in the last five to six years comes out with consensus guidelines based on evidence like NCCN, the level of guidance and level of the level of evidence versus less from evidence. But there was a mandate at least for ASCO to really offer germline testing and I think with good reason with GRACA one and two and PAL B2. And I think, I think that indication will expand even more in the years to come. And so I always quote for patients and whether patients ask it or or if they haven't thought about it yet, Ioffer just outright that only 5 to 10% of patients with pancreatic carcinoma might have a hereditary component of germline mutation to be uncovered. But nonetheless, it can be very important following the aftermath of the POLO trial, potential implication for actual treatment, which you can't always say with germline testing. In this case you can, but also the implications for first degree relatives always talk about younger adult patients, diagnosed parents, siblings and of course children and potential implications for grandchildren as well. So I always offer cancer next counselling leading to germ like testing for all of my pancreas patients at our first meeting for next generation sequencing and now really with expanded testing at lightning speed in the last five years, I stopped using the word NGS and say comprehensive genomic profiling where clearly 500 more tests become more cost effective. There's no reason not to do it for pancreas carcinomas like with other gastrointestinal and many other types of cancers. At the same time, I also balance it with teaching patients and educating them. Although things are changing at such an impressive pace with tumor agnostic approvals, the chance that a result would come back that would have direct implication for clinical decision making. I would say generously under 15 to 20% and I might even say realistically under 10%. CTDNA is fascinating and you know, I, I'll, I'll to say it's controversial. I know people would say it's less controversial for non spousal lung cancer. I think it's been at the leading of the field. I will say it's controversial, at least in my view as a scientist for colorectal cancer, despite assertions by many other colleagues who I'm happy to debate what's interesting about pancreas adenocarcinoma from the biology of it, this dense desmoplastic reaction, it creates a hard shell for itself. So that has direct implication in my view for ACT and DNA at the biological level. Does pancreas carcinoma shed cell free DNA effectively enough to be picked up and get accurate results? Where it's interesting and where I deploy it most commonly is pancreas carcinoma, the cancer top of my list where there's insufficient tissue at my attempt to request comprehensive generic profiling or NGS and then they got the result or notification back. Insufficient tissue quality not sufficient. And I will try cell free DNA testing from commercial entities. It doesn't always come back with a full panel, but pancreas carcinoma less so than other types of carcinomas, but it's better than nothing at this point. I think the technology is just improving and it will for pancreas carcinoma in the years to come as well. Speaker 3 These are the same struggles we're seeing in other disease sites as well. Coming back to pancreatic cancer, before we move on to borderline resectable, when you're using Fulforonox, is there any role of leucovorin if there is No 5 FU bolus? Leucovorin in Borderline Resectable Pancreatic Cancer In my practice, if there's no bolus, there's no Leucovorin. Speaker 2 Yeah, correct. And that's consistent with my practice as well. I have a excellent pharmacy team that I always, I, I always tell about like among other specialists, I'm their number one customer. I'm always peppering them with questions and they always educate me so well. It's interesting that practices even within my institution and amongst institutions, sometimes people will use Leucovorin and not. I know there was a nice paper in JNCCN at the tail end of 2024. It was a retrospective study of 10s of thousands of cases large again towards colorectal. But I think it's the same principle, four or five FU combination regimens that in absence of using bolus, which is how the FOLFIRINOX regimen was designed, there's really no protective or extra protective role for leucovorin. So in absence of bolus and only infusional 5 FU, there is no indication or no proof of benefit. Speaker 3 And then initially you alluded to this role of radiation or concurrent chemo radiation, be it resectable, borderline resectable, we know this is a systemic disease. Radiation and concurrent chemotherapy Is there a particular patient where you'll lean on to radiation or concurrent chemo Radiation in pancreatic cancer? Speaker 2 So I think radiation oncology colleagues might feel differently, but the span over the last 20 years with SPAC one, the first one looked in the adjuvant setting and reported detriment, overall survival and more toxicity. People will debate that the design of the trial was not good. At the end of the day, the absence of a good design does not provide proof to use something or so the and then followed by 2010. Afterwards a new adjuvant intense setting shifted analysis of potential user radiation to that new adjuvant setting. Doctor Katz from Emmy Anderson LED an excellent cooperative group trial published in 2022 in GEM Oncology. In that study, hyper fractionated radiation, five day course or stereotactic body radiation was used. If you look at the numbers, there's no advantage but maybe even lower survival associated with the radiation. I think radiation still continues to be in the resectable or potential conversion of a borderline resectable case to a resectable case, which might happen in one and three. There continues to be no firm evidence in support of radiation, especially if there might be detriments. What's also interesting and I think our radiation oncology colleagues have made a lot of advances in the modalities of radiation intensity, modular radiation, SRT. But I don't doubt that with maturation of that in the right setting, with the right trial design, that part of that might change in the years to come. As we're sitting here today, I think there is not a strong evidence to add radiation to chemotherapy, especially in pancreas carcinoma more than any other cancer. We take data from stage 4 metastatic setting, We borrow it and some of the studies, retrospective and the prospective ones retrofit it to examine what people are doing in more common practice. Nothing better as an example like that in new adjuvant intense use of chemotherapy for resectable or borderline resectable than that. Speaker 1 The majority of our patients when diagnosed with pancreatic cancer are in either locally advanced or metastatic settings. Prognosis and treatment of metastatic pancreatic cancer If you have this patient sitting in front of you where we have established diagnosis of metastatic pancreatic cancer, what numbers are you sharing with them from prognosis standpoint, median overall survival standpoint with treatment? And then we'll dive into the treatment algorithm from metastatic space. Speaker 2 Yeah, absolutely. It's very individual dependent. There's a lot of mantras. I'll say to a patients, no person is a statistic, but there are many statistics. I can cite as much as you want and some people will tell me I don't want to know. I completely respect that. I don't have the right to tell someone how long they have to live. From the human side of medicine, especially in pancreas carcinoma, we all know results are dismal. The five year overall survival rate is approaching and bordering on 10%, which is a whole lot better than the five, 6% of decades past. It's still not much more than that and other times patients do want to know. So I quote statistics in that manner and I'll quote the studies. That is also a mandate where studies have been done to say that we as oncologists traditionally haven't done a good enough job specifying the terms palliative intent, chemotherapy versus curative intent. When we talk about risk reducing chemotherapy in the post operative setting, only 10 to 15% of pancreas carcinomas are resected. Post operative chemotherapy is given to risk reduce and this the whole shebang is given with intent to cure. And I use the words palliative intent because it is challenging if a patient misunderstands after many months of treatment and I still see this to the day despite my best efforts. I use that as opportunity to try and improve my language and sharing information in as clear language as I can that a treatment isn't over after six months for metastatic cancer. The only way to potentially go for a cure of an aggressive disease called pancreas anticarcinoma has to include the foundation of surgery. So to convert a tumor that's not resectable, it's really a low chance. But going for it over the span of time from diagnosis, six months later, the six month point is the point of no return. If it has not converted resectability by that point, then we are clearly moving forward with palliative intent. If the disease like this is stage 4 at the time of diagnosis, it is clearly palliative intent. As an oncologist, I try to make greater effort to make sure I'm balancing that also with hope and saying quality of life improve the progression free and overall survival. But I'm setting the exact statistics might depend on what the patient tells me that they want to hear or their caregiver when we know know Larry Fox, Volfury Knox, I think virtually, although the comparison are mentioned, those individual trials was single agent gemcitamine really or it was interesting that for those populations 11.1 months. And then I think the point I approach it is it's not years, it's measured in months. And so however, I tailor that to the individual patient. I think we have to keep that in mind and then as researchers trying to improve upon that. Speaker 3 And now with all that in mind, how are you picking sulfur Anox, Niluri, Fox, gemnapaclotaxel? How to choose the right chemotherapy regimen for your patient Because as a clinician we're stuck with cross trial comparison. BRE was first approved in second line. We have strong data in first line. Now it is approved there. But this was compared to gemnapaclotaxel. We also have sulfur Anox. How are you picking that particular regimen in your clinic? Speaker 2 Right, I wish you were more scientific. I'll just say full fear Knox and gem that back tax will just start thinking chronologically how they came about in the last decade plus. I think my practice falls in line with I take polls and ask, go into meetings or otherwise and then say someone has an outstanding performance status. Let's do full fear Knox and see what happens. See how they do and and adjust in real time accordingly. If there is any reason where I mean and and not to generalize, but if someone is is elderly, other severe comorbidities, they have severe cardiovascular risk factors. If if I find a tiebreaker, then I would maybe err on the side of a GEM napacotaxel. One thing to think about that I do stayed upfront with patients is not necessarily always better, but you're using a very potent regimen in FOLFIRINOX. What is the standard of care second line gem that's said to be napacotaxel. What do you do after that? Then it's really clinical trial or both really they're favored third line would be whereas strategically and sometimes patients feel reassurance of this. If you start with gemnapaclotaxel which has virtually identical response rate is Volfurinox and metastatic setting 30%, which to me means a lot for the neoadjuvant setting as well as a metastatic setting. Then if you follow the paradigm, you can go second line liposomal or inu TCAN with infusional 5 FU and then oftentimes Falfox can be very useful in the third line setting. So that provides a three line strategy and sometimes especially if you go into more in depth conversations that patients want to know the future. I will explain it that way. Some patients might feel more comfortable or oncologist might feel comfortable that we're in it for a longer haul. Hopefully having a third line available that standard of care might buy some more time before we need to go to something uncovered by comprehensive genetic profiling or clinical trial opportunities with Nellary Fox. I think also in this era of financial toxicity, I do have concerns about Nillery Fox's expense. It's expensive, not that any of this cheap of course, but with a cross trial comparison, same overall survival, there's nothing that stands out more. We know from the Nillery Fox trial that just broadly compared to FOLFIRINOX, the risk of some cytopenia is like neutropenia, febrile neutropenia and some GI disturbance issues were reported to be less in the Nillery Fox trial that examined that led to FDA approval then the the PRODUCE trial, the lepto FOLFIRINOX, that might be a consideration as well. That's some of the ways I approach it. Speaker 3 And again, before we move on to what's available next, you mentioned FOLFOX, that's another regimen, especially if your bilirubin's high. What is available in metastatic or new Edeman setting These are the patients where you can run into that. Yes, you can use Gemnop, paclitaxel. You have to be very careful with the dosing, but FOLFOX have used in that particular setting as well and you can buy some more time. Speaker 2 Absolutely. I'll just add something that's a favorite of mine. Tonyos Beke Saab when he was at The Ohio State University, yeah, I remember that just included GIS Co symposium in January 2015 and subsequently published with Daniel on and team and Tony a few years later. It was a retrospective study at Ohio State acknowledging single institution. I found it very helpful, the time and something that I instituted into my practice pretty much immediately after hearing that and then decades since metastatic or new Edeman setting is dropping Day 8 at the outset. Speaker 3 As opposed to. Speaker 2 The reaction because there's so much neutropenia, these these port patients show up from day one almost consistently every single time. And I just found that patients tolerate so much better and we're not losing efficacy. And there's some evidence from that study. And I know in personal conversations with him that he has done that since. I just find it interesting. If patients get a second opinion, I will hear even from major institutions that will not be named here. The doctor said that you're doing it wrong. So I always proactively say, if you ever talk to anyone, go on the Internet. I'm telling you what I'm doing and why. Speaker 3 No day one and day 14. Speaker 2 Yep is so I proactively dropped AI just tell people it's easier logistically every 14 days. I'm telling you why I'm doing it and I think that's. Speaker 3 Really helpful, No, Absolutely. Speaker 1 Right. We recently covered a toxic series and that's where the conversation was to utilize it on day one and day 14 with Doctor Schroff and Mala, keeping in mind that this is in palliative care settings, so quality of life has to paramount in this setting. Particularly, can I bring back NGS and germline testing to the limelight because this is an important consideration even in frontline setting. PARP inhibitors for germline mutations We have PARP inhibitors approved along with some given bucket approvals of NTREC and recent approval for NRG 1 mutation starting with BRCA mutation. Do you consider PARP inhibitors for germline mutation or evidence is strong even for somatic mutations? Speaker 2 Yes, now a really good question with the initial presentation of the Polo trial is most prominent in this sphere. The subsequent survival data presented I think was 2022. An update, I always think of trial designs, we hear the presentation, the end result of course what went into it. I'll be very honest with the POLO trial in pancreas carcinoma. I think of FRESCO trial and colorectal cancer as examples. If you have a novel drug and you want to understand the response rate and then potentially implications for progression for your overall survivals. What is a comparator arm Is a comparator arm what we would do anyway Sometimes it's like dealer's choice. You mentioned at the outset my background in neuro oncology and some glioblastoma trials incorporating novel approaches drugs or otherwise we'll compare it to I call it dealer's choice in more late terms. And what would a neuro oncologist do anyway? Some of these studies, you know, I have concerns about comparison placebo because in the setting of metastatic pancreas carcinoma, unless a patient tells me that they don't want to have treatment or they want to have a prolonged treatment break, that's not what I would do anyway. I would not give no absolute anti cancer directive therapy. So I, I just, I think that's like that's it is a important point to make for trials like this for patients that have and I think that as a trial was designed for a germline, not specifically somatic only form of Braca alteration. Braca 2 seems to be more prevalent than Braca 1 in pancreas carcinoma. I think where there's a lot of value from it is sparing patients for some prolonged amount of time from drug toxicities of cytotoxic chemotherapies. I always poll patients you feel confident and want to be taking something oral on their own. As with any oral directed therapy, I think the amount of time that you can get benefit from maintenance sparing them of whatever we might do otherwise. Gem Abraxane. GEM alone, 5 FU, whatever we can concoct as maintenance therapy extrapolating from colorectal and other experiences I think has a lot of value. I think we have objective evidence from Polo for example, there is no difference in overall survival reported from that study using the labyrinth in the maintenance study versus placebo. But the value that I'm hearing from patients is this spared them of the toxicity that they would get from a Pulpyrinox or any other GEM based combination therapy until there is progression of disease on that maintenance. Elaborate at which time we would go back, but they gained A chemo free interval in there. There's value there. Speaker 3 And Rohit, then you touched on Amtrak and RN RG1, which is a recent approval. These are needle in a haystack, but that reiterates the importance of NGS when we're talking about pancreatic cancer. Another thing that should be on our radar is high risk of VTE. We have like risk scores, corona risk score that gives us a chance to be proactive because this in itself is a poor marker. So again, prophylactic anticoagulation and high risk patient is important and all. We've packed a lot in this discussion. We appreciate you taking the time to walk us through the current treatment landscape of pancreatic cancer with us today. For our listeners, let us touch on some key takeaways from today's conversation. In today's discussion with Doctor Emil Liu from University of Minnesota, we had a chance to cover the current treatment landscape in pancreatic cancer. Key Takeaways Rohit, your three key takeaways from today's discussion. Speaker 1 Well, we quote packed quite a bit. Well, we'll start off with number one. That is the most important one for me is managing the side effects and finding the right balance between efficacy and adverse events that come along with our treatment, especially when the intent is palliative. Second, the importance of NGS testing along with germline testing. And 3rd, as you brought it up, keeping VTE in mind when it comes to pancreatic cancer. Rahul, do you want to add anything here? Speaker 3 Yeah. Now Roy, that's a pretty good list. One thing I would add is something that we brought up the importance of multi D in early resectable disease or borderline resectable disease and then managing side effects that come along with Whipple surgery. Thanks for joining us. Make sure to check out our other discussions in GI malignancies and our recent discussion around toxic for common drugs that we use in pancreatic cancer. We are at the Oncology Brothers.