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Pancreatic Cancer Progress: Expert Insights on Treatment Choices and Collaborating with Patients
Released: September 04, 2025
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Zev Wainberg (University of California, Los Angeles): Hi. My name is Zev Wainberg from UCLA GI Oncology. I am pleased to be joined by two close colleagues: Mark O'Hara from Penn and Paul Oberstein from NYU, also GI oncologists. And we are here to talk about a disease that really we are all struggling with, which is pancreatic cancer. I think we know that pancreatic cancer continues to rise and incidence in the Western world, particularly the United States, for reasons not entirely clear. We also know that the treatments of it remain a challenge.
There has been significant changes and the treatment, the landscape, the risk factors for the disease over the last 30 years. If we think about the challenges of cancer, this is top of list. I am going to just start by throwing a few ideas out there. Mark and Paul, feel free to chime in. I think that what we have got is a situation where, by and large, the cancer is diagnosed too late and the treatments are often, while somewhat effective, not effective in the way we think we want to be in terms of getting rid of it. It is always about chasing it. This is a cancer that chasing it eventually becomes very challenging. Mark or Paul, do you want to chime in on some of your thoughts about how we confront this situation?
Dr. Mark O'Hara (University of Pennsylvania Perelman School of Medicine): I think that overall, you hit the nail on the head. Overall, most patients are unfortunately diagnosed with the metastatic setting. We are talking about palliative treatment options, and looking at palliative chemotherapy unfortunately is our mainstay. Overall, having some options available to some advancements in our options over the last 10 years, but nothing that has necessarily broken the barrier to be drastically changing. We are improving survival by 1% to 2% a year. That is not necessarily what we want to do. In this terrible disease, we want to make drastic changes. I think that is anyone of us that do pancreatic cancer, that is what we are hoping for and actually see that hope potentially in the near future.
Dr. Wainberg: Paul, one of the challenges here in the disease, is that you are starting at a baseline oftentimes are the patients symptomatic from the disease. In a lot of cancers, as you guys know, you know patients are diagnosed. They do not have a huge amount of symptomatology necessarily from every single cancer it is found, whether it is screening or otherwise. You have some leeway with which to treat a patient, so to speak. Here I find the majority of patients, not the minority. Majority of patients, there is already symptoms from the cancer. Paul, you have a lot of patients with advanced pancreatic cancer. Do you find that to be your struggle also?
Dr. Paul Oberstein (NYU Langone Health): Yeah. I completely agree with your point. I think it is always hard for us to know what is causing it. It seems in some ways, like everything about pancreas cancer is bad. The ones who are resected, who have surgery, the rate of recurring is much higher than other cancer. There is early metastasis in pancreatic cancer that is out of proportion to the stage. What you pointed out is absolutely correct. Very often, especially patients with locally advanced or metastatic disease. By the time we meet them, they have already suffered quite a systemic insult from their cancer.
Sometimes you can measure that in terms of weight or inflammatory markers or cachexia. Something we look at muscle wasting. Sometimes it is much less tangible than any of that, but often it limits what we can do for them from a treatment standpoint. I would say rarely we see patients who get chemo and respond, and that is how they respond by coming back to life almost. Eating more, gaining weight. That is the minority. Most people never really get there. I think there is a ton that we still do not know about the mechanisms of that, what cytokines or what inflammatory pathways are happening, and what we can do to treat those. There is a lot of exciting research in that, but I think we are still not where we need to be at all.
Dr. Wainberg: I think the reality is chemotherapy is still the mainstay of this disease. The patients that we see who show up in our office usually ask us, "What are our options? We are left telling them, for better or for worse, that chemotherapy is the only thing at this point in time, in 2025, for the majority of patients, that is been shown to impact survival. I have these very candid discussions. They say, "Why am I doing this? Just to live a couple extra months?" The usual conversations obviously are all about it is not just the months, it is about the palliation and about the symptomatology control.
I think in that respect, we have made some progress. It is very rare that I see nowadays a patient who is decent performance status, who is like, "Gosh, I do not want to try anything." We can always persuade them. I think, for better or for worse, to try some chemotherapy regimen because we do believe overall as oncologists that overall we are helping patients with chemo, even if it is a grind.
Discussions about two drug regimens, gem-nab-paclitaxel, three drug regimens FOLFIRINOX, NALIRIFOX, with recent data set. These are all top of mind, and laying out a combination of efficacy data and toxicity data. Markin your average patient, how much time are you spending talking about side effects versus Kaplan-Meier curves or median survival numbers?
Dr. O’Hara: I think overall the median survival numbers Kaplan-Meir curves helped us decide is this therapy potentially a useful therapy? When ultimately we are we are sitting in front of the patient, those numbers actually do not necessarily discuss flat out, because every patient is going to be different. Every decision we are making is going to be pertinent to that patient and what side effects they have, as we have discussed, and what side effects we expect to see with the chemotherapy regimen. Balancing then the potential benefits in terms of symptomatology improvement, and then hopefully leading to also an overall survival benefit versus the side effects that I am expecting to see with these chemotherapies, because unfortunately, every therapy we give, it is very, very, very rare to see a patient not have any side effects unfortunately.
Dr. Wainberg: I always talk about weighing the side effects of the therapy versus the side effects of the disease. Because the patients some of them think that their quality of life is going to be better without cancer chemotherapy. The reality is that, the majority of studies, with rare exception, the patients on chemo feel better than the patients off chemo. That was studied in the early days, and that has been studied in just about every recent study is that the reality here is that the cancer does not grow in a vacuum. As the patients are not being treated, they are progressing. That is why I always have that approach when I talk about a patient.
Dr. Oberstein: I can just echo that. I think that it is the case. Sometimes people have a sense that they could either have, three or six great months and travel the world or nine to 12 months with chemo. Of course, that is not the reality. It is they are not feeling well when they come. They are not just going to start feeling better. It is true that when chemotherapy in many studies has shown efficacy. It also shows noticeably improvement in quality of life but less decline in quality of life.
I think the other thing that I do in my practice a lot is we are very quick to make adjustments in chemotherapy. There are settings where you are doing curative intent, chemo for some cancers where you do not want to change anything. Here the whole goal of chemo is really palliative what is going to help the patient live the longest, live the best. We have to have those conversations. It is not easy, and it takes patients time to start thinking about those questions. We are very quick to adjust chemo or delay a couple of weeks for vacation or a wedding or an event, and try to get them the maximum benefit from what they can get.
Dr. Wainberg: I think that is a good point, and we are always using that in practice. We are trying to be driven by data, too. There is always this balance between, "Oh, you want to intensify the chemo to see a better response, drop that number lower," whatever it is. Then, the reality is that in just about every clinical trial ever done, modifications are constant. The patients that we treat in the real world are often somewhat reflective of what is done in the studies, because no patient on the study is necessarily getting full-blast chemo for the entirety of their regimen.
I find that the clinical trials like NAPOLI 3, which I like the fact that there were lower doses of oxaliplatin from the get-go, I feel that is more reflective of a reality, and also, I like the fact that gem-nab modifications were left to individual site discretions. Because if it is preconceived that every doctor is going to manage every single patient the same way with the dose modification. it is not reflecting reality. When you allow some flexibility in patients based on toxicity management, it is overall better for patient care. That has always been my thought about clinical trial design. Mark, you have a patient with let us say NALIRIFOX has neuropathy starting to get there. You will stop oxaliplatin, I assume, and approach it the way we would with the standard of care FOLFIRINOX type of regimen.
Dr. O’Hara: Exactly. As Paul said, quick to adapt to these regimens so that you are not necessarily leading to more permanent side effects with the oxaliplatin neuropathy itself, unfortunately, can linger for so long. When it starts getting bad, I am very quick to first dose reduce, but then actually take off the oxaliplatin with possible reintroduction down the road if we actually see an improvement in the neuropathy, but close monitoring overall, similar to what we would do with FOLFIRINOX in general.
Dr. Wainberg: In second line Mark, it is obviously, the toxicity parts of the discussion are even more front and center, I would imagine for you, because now it is not just about the chemo as I tell my patients, chemo has diminishing returns. When you get to second line, it is not usually working as well as front line. That is the reality. The toxicity things, I am sure, for you in your discussion with patients take a more prominent role.
Dr. O’Hara: Certainly, I do not think any one of us has a defined paradigm. Every pancreatic cancer patient, first line gets this, second line gets this because it really that second line decision is based off of what toxicity occurred with the first line therapy? If they have neuropathy avoiding it, maybe doing a FOLFIRI or 5-FU, nal-IRI. If diarrhea was a big side effect with the first regimen, maybe avoiding irinotecan and going to maybe gemcitabine-nab-paclitaxel or something like that.
Looking at their side effects and also looking at that point, unfortunately coming into second-line therapy, their cancer is progressing and they are going to have new cancer-related side effects as well. Balancing the potential benefits you can get from second-line therapy, unfortunately, with diminishing returns compared to first line, but some potential benefits you may be able to get versus the risks associated with each one of these regimens.
Dr. Wainberg: The landscape is changing quickly. We have got new drugs that are disposal, hopefully in the next few years. Paul, I know you have worked on a lot of RAS inhibitors and other stuff. What excites you?
Dr. Oberstein: I am easily excitable person. I would definitely say to me, the most exciting thing is that for a long time we were doing these trials of third-line pancreas cancer, where we were throwing, I will say, marginal drugs in settings where we had no hope, and we would take very little for success, and none of them succeeded. Now we have got really biologically plausible and good drugs which are not yet proven, but are much more exciting. Both the KRAS inhibitors, which we have both all three of us have worked on a lot, and we are using a lot of PRMT5 inhibitors for MTAP loss patients with very occasional good responses.
I think the most exciting thing to me about these is that I think these drugs are going to come in earlier settings. They have got toxicities, but they are not necessarily overlapping with chemotherapy. If we could find a way to both identify the patients who will benefit and then figure out how to use them in first-line or neoadjuvant or adjuvant settings, I think there will be a lot of differences in how we treat pancreatic cancer.
Dr. Wainberg: Yeah, I agree. I think, in some ways this is the most optimistic I felt about this disease and patients know it too. I am sure Mark and Paul, you get patients coming in asking for things. We never used to see that in this disease coming in and asking for specific drugs and KRAS inhibitors, or immunotherapy drugs that you know. This is an opportunity for us to catch up to some of the other precision therapy, cancer-related treatments. I think we are all really excited about what the future holds and the field is moving so fast. That is one amazing thing. It is amazing how fast the drug development is going right now in pancreatic cancer.