Introduction: Initial Management of Pancreatic Adenocarcinoma (PAD)

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice, and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is the eighth of 11 meetings we’re holding here at the ONS Congress. This is our seventeenth year joining the congress. This evening we’ll be focusing on pancreatic cancer.

We have a great faculty this evening: Ms Caroline Kuhlman from the Massachusetts General Hospital in Boston, Ms Amanda Wagner from the Ohio State University in Columbus, and Dr Farshid Dayyani from the UCI Chao Family Comprehensive Cancer Center at the University of California Irvine in Orange, California, and Dr Philip Philip from the Wayne State University in Detroit.

As in all of our programs here, we will be talking about the use of unapproved agents and regimens. So please consult the package-insert information for more data on the various agents we’re going to talk about today.

Check out our new podcast, Oncology Nursing Update. Just take your phone, go to podcasts, hit search, type Oncology Nursing Update, and follow us. We have a couple programs on there now and we’re going to add all 11 of these programs onto the podcast as well as a number of other programs moving forward.

As I mentioned, we have 9 programs. This is the eighth one. We view this really also as an oncology emersion experience. We’re really here to talk to the faculty. I always loved making rounds when I was training. We brought that idea into all of the education programs we do. We have a fantastic faculty this week. And we’re really looking forward to hearing from our faculty tonight about pancreatic cancer.

Here's where we’re heading. We’re going to chat a little bit before we get started, just, we’re going to go through a case. And then, we’ll dive into the management of pancreatic cancer. First, the first-line treatment of metastatic disease. Selection of treatment of relapsed disease. We’ll talk a little bit about palliative care. Also, PARP inhibitor therapy in pancreatic cancer. We’ve already talked about that in breast cancer, prostate cancer, and then this afternoon in ovarian cancer. And then finally, we’ll talk about some new strategies and new agents coming along in this difficult disease.

Let’s start out with a case. And, Mandy, this is a 42-year-old man, young man who presented to you. One of the themes we have, in general, we’ve had over the years, is the biopsychosocial circle around the patient. And a question we have, and I’m going to ask you this question about this man is, what made it different taking care of him than another patient in the same oncology situation but a different person? Older, different family situation, comorbidities, social support, et cetera. So let’s hear a little bit about this 42-year-old man, Mandy.

MS WAGNER: Yeah. So this gentleman, 42 years old, no significant past medical history. He was actually at church with his family and had a syncopal episode, and was taken to a local ED, which was actually pretty rural. There, his labs showed he was acutely anemic with a hemoglobin of 7 and had hyperbilirubinemia with a total bilirubin of 7. And prior to him passing out, he had over the past month or so been feeling more fatigued, feeling weaker, losing weight, his urine turned dark, and he had started having some abdominal pain. So once in the ED, he had imaging that showed a pancreatic head mass with associated biliary ductal dilation as well as several lesions in the liver concerning for metastatic disease. We underwent an EGD and EUS, which showed an oozing pancreatic mass that was invading into the duodenum. That’s what was causing the bleeding. And the biopsy showed adenocarcinoma. He also, at that point, had been transferred actually to our facility, had the ERCP as well to have the biliary obstruction relieved and underwent a liver biopsy. He had further testing. This was not found to be genetically linked. It was just, it had happened.

So in our first appointment, we spend, as nurse practitioners, a lot of time just kind of assessing the patient, assessing their symptoms to try to figure out kind of what is going to be the best option to present to the patient as far as treatment goes. So as I said, he had lost weight, he had a very poor appetite, he was fatigued. He was still trying to work. He worked as a contractor, had 3 little kids. His pain was better since they had placed the biliary stents and the dizziness was better after the blood transfusion. So very anxious, obviously, regarding this devastating diagnosis. His wife was also extremely anxious, very tearful during that appointment.

DR LOVE: What kind of work did he do?

MS WAGNER: He was a contractor, self-employed.

DR LOVE: And did he have a lot of questions? Did he know much about pancreatic cancer?

MS WAGNER: He didn’t really ask a lot — he seemed more withdrawn. It was more his wife and father who was with him at the appointment that were asking the majority of the questions. And his mother couldn’t be at the appointment either because she had just recently been diagnosed with cancer herself.

DR LOVE: So, Caroline, a very challenging situation here. We’re going to get into some of the medical aspects. But just taking a step back. When you’re here thinking about, of course, this is a younger patient, 2 young children. That’s actually been something we’ve talked about quite a bit over the years here is patients with minor children or grandchildren. We had a patient earlier today who took care of a grandchild, a sole caretaker of the grandchild. Any thoughts about what you think about when you know you have a situation here of an incurable situation with young kids? Any special services at Mass General for this situation?

MS KUHLMAN: Yeah. It’s an incredibly tough situation. We do have a program through our social work department. It’s called Parenting at Challenging Times. And it is designed to offer parents support around navigating a new diagnosis of a serious illness with their young children. They don’t actually see the children, but they offer strategies to the parents about how to talk about the serious illness and prepare them, and also to help the parents understand developmentally how they might interpret the news, how they might deal with the changes that are about to happen within the family structure. But so important to remember that the kids will have unique needs and the parents themselves are going to need support around giving them what they need.

DR LOVE: Philip, any thoughts about when you know you’re about to see a patient with a new diagnosis of metastatic pancreatic cancer, now you hear these details in terms of the patient’s family, some of the things that are going through your heads, the kinds of questions past patients ask you in that situation? And also, any comments about the presentation here, the biliary stent placement, also the new diagnosis of diabetes?

DR PHILIP: Thank you very much for asking this important question because, Neil, also diabetes is considered to be kind of a risk factor for other things. But it puts us in a challenge because every time you diagnose a new patient with diabetes, it’s difficult to think that they will have pancreatic cancer because most of them, they don’t. But something to keep in mind in the absence of family history of diabetes or something else.

The patient’s mother had uterine cancer. So you would think, is there a link between the two? And the link is the obvious one is the Lynch syndrome, which can happen. But I see that the genetic testing was negative.

From my own experience, so this patient was diagnosed 3 decades earlier than the average time we diagnose patients, which is 71, 72 years of age. And I have to deal with really the important challenges that come with this diagnosis. Number 1, I see sometimes patients have delayed their diagnosis. They’re young, they’re working. So you really have to be careful about that because sometimes, those patients take a while to come because they don’t think. The other important thing is that they go to their doctor and because they’re young, cancer is not always thought as important in the differential diagnosis. But certainly, in a patient like this, we really have to be very, very aggressive in supportive care. And you know how I feel very strongly about palliative care, supportive care for patients in general. But in a patient like this, it becomes even much more important from day 1 to be very aggressive with that, the supportive care. Because I’ll tell you, it’s very difficult to deal with a patient who is 42 and tell them that you have an incurable disease.

The other point to make is that those patients, because of the track record of the chemotherapy we have nowadays, we always have to think of clinical trials also. Because they tend to be, in fact, healthy in general. So it’s really something to keep in mind. So overall, the management of this patient may not be different than the 72-year-old, but there are aspects of it that have to be more enforced to do that.

DR LOVE: Just out of curiosity, any exciting trials that a patient like that would be eligible for at your institution, Philip?

DR PHILIP: The trials that currently are of interest in patients like him would be, I’ll touch on it later on, would be, for example, the KRAS mutation. So the patient did have KRAS mutation. And there are ongoing trials in the different lines of treatment. Although the frontline is a bit less developed because they’re working on the second-line. So that’s something, which is a KRAS mutated. And I would say that for the oncology nurses, you’re the advocates of the patients. And one has to be aware of the existence of these possibilities because that will really be very helpful.

DR LOVE: Yeah, we had an incredible case presented at lunch today of an ovarian cancer patient, a little far advanced disease, went on a clinical trial, is doing very well. Farshid, again, any thoughts about sort of the psychosocial issues in a patient like this? Anything you want to say about the clinical presentation? One of the themes that we’ve been talking about that goes throughout all oncology is biomarker assessment, as you just heard Philip talk about. This patient had KRAS G12C. Farshid, how often do you see that? TP53-positive, we talked about that last night in CLL, for example. And low TMB microsatellite stable, kind of tying into what you were saying in terms of potential for Lynch syndrome. MSI-high tumors, very, very uncommon but we need to make sure we identify them because they’re exquisitely sensitive to immune therapy checkpoint inhibitors. How often, Farshid, do you see MSI-high pancreatic cancer, incidentally?

DR DAYYANI: Less than 1% of the cases. This is a classic presentation in a very unusual patient because he’s so young. KRAS mutations in more than 90%. And as Dr Philip noted, in a young patient — so the approach is reverse what you can reverse by time and then put them on a trial that might change the trajectory of the disease. For example, at our institution, we have KRAS and MEK/ERK inhibitors combined with chemo, for example, with 5-FU/nanoliposomal irinotecan in the frontline setting for KRAS mutated. We have antibody-drug conjugates with Claudin 18.2 with chemotherapy. So really, the same way, the way you try to reverse the obstruction by putting a stent, the first thing you want to do is give your best systemic treatment, control the disease, reverse the course, reset the clock, and then see how you can really change the trajectory with a clinical trial. So that’s the message for this patient.

And in terms of social — psychosocial, we have the PROMISE 5 screening tool for all new patients. And that sort of captures all these social issues. And if they score low, then that triggers an automatic referral to social work, for example. So then, we can follow up with that and address those issues.

DR LOVE: So Mandy, let’s continue on. But also, what was involved in, this patient, as you can see, presented with hyperbilirubinemia, also anemic. Was he transfused? And what was involved with the stents? Do you see infections with these stents?

MS WAGNER: Yeah. Actually, this stent did become infected and he developed something called cholangitis where that bile duct was infected. They can get really sick really quickly. And at that point, he was actually — this happened recently back home 2 hours away. There was not a bed available at OSU. And they did not have any advanced endoscopists at his institution. So they ended up putting a percutaneous drain in, which then he was left with, you know, for, I think, many weeks, at least 10 to 12 weeks so it can cannulate. And then was transferred to OSU. So unfortunately, in that situation, because of where he was living, he couldn’t get the — have the ERCP to have the stent removed.

DR LOVE: So I see he was started on NALIRIFOX. Can you explain what that is? We’re going to go through what it is and the clinical research, but maybe just sort of a brief intro. How it’s delivered and how he tolerated it.

MS WAGNER: Yeah. So NALIRIFOX consists of, it’s a triplet drug cocktail, liposomal irinotecan, 5-flurouracil and oxaliplatin. So we generally reserve our more what I would call aggressive treatment options, so this triplet therapy, for somebody with less comorbidities, a good performance status, somebody that we think can handle it because they do — can have significant side effects, nausea, vomiting, diarrhea, neuropathy or numbness and tingling. So because he was so young and healthy, he was started on it. Did well. He only had mild side effects as far as the GI symptoms as far as some diarrhea and nausea that were well-managed with antiemetics, antidiarrheals. He did though develop, as everyone does who gets oxaliplatin, neuropathy in his hands and feet. And being a contractor, he really needed good use of his hands and feet to prevent, you know, power tool injuries. So after I think it was probably 4 months of therapy, we did discontinue oxaliplatin.

DR LOVE: So he’s continued to work?

MS WAGNER: Yeah. Because once he started treatment, we saw a significant improvement in his symptoms. So his energy got a lot better, his pain improved, he started gaining weight back, and felt more like himself again.

DR LOVE: Can you talk a little bit more, obviously, this was a tremendous shock to him and his family, about sort of what’s happened over the ensuing months? What kind of questions have they been asking you?

MS WAGNER: So I think initially, it was just coping with that massive diagnosis of you have, you know, a terminal diagnosis and what this kind of means for me and my family and just kind of grasping at that and absorbing it. And then as he’s felt better, we’ve been able to kind of provide those supportive services through our psychosocial oncology to kind of help cope with everything.

DR LOVE: How old are the children? And did he and his wife ask any questions about what to say to them? Do they know what’s going on?

MS WAGNER: So not at that initial appointment. I think they’ve been talking to the kids now. I know they’re under 10. I don’t know their exact ages though, but they’re young.

DR LOVE: Caroline, again, any thoughts about what you’ve heard up until now? And what do you see in terms of patients in all situations trying to cope with this type of diagnosis? One thing we hear a little bit about is reorientation of goals, focusing more on short-term goals. What are some of the typical ways you see people react to this?

MS KUHLMAN: Yeah. It’s shocking news for these patients. And the conversations you have initially, it’s more than 1 conversation about prognosis and timing because we always tell patients we’re terrible predictors. I think it’s important for patients to know they have a disease that’s treatable, but probably not curable, but not curable, probably, but not curable. It’s important for them to have that information. But in the initial visits, the need to say exactly what that number is if they don’t specifically ask, that’s an ongoing conversation. I think you have to be ready at any moment for the patients to come to that realization of, well what is the number? And then sort of help them view their lives a little bit differently, which is we’ll see how the treatment goes. If you respond, every 4 cycles, so every 2 months, we’ll do a scan, to kind of think of your life in those increments for now and that we’ll see how the treatment — how you respond to treatment, and that will dictate prognosis.

DR LOVE: Philip?

DR PHILIP: In my practice, I do not give them survival numbers, months. And I tell them clearly, I’ve been doing it for a long time and I’ve seen people — you need to know that while patients — they say, is it possible for me to live several years? I say it’s possible. Because in my practice, I’ve seen that. Because they want that hope. They want that kind of encouragement. But also, there are other drugs coming along. The field is becoming so active. So I keep that also in their minds that there’s no time I can give you. Unfortunately, sometimes, they come and someone told them that the median survival is this or they read it on the internet. But I make it clear to them that’s just an average. And I’ve seen people who do well. That’s what they need to know, that yes, can I do well? Do you think I can survive several years? Yeah, I’ve seen people doing that. I don’t lie to them and say everyone is really doing that, but give them that kind of encouragement.

DR LOVE: Yeah. And that’s a realistic issue, the possibility of new drugs coming along. Again, we had a case just presented at lunch of a patient that ran out of options, ended up being treated with T-DXd because it was HER2-positive ovarian cancer, and went into a great remission and a remission right now that was not available, like, a year ago. So that hope does always exist. And we’ll talk a little bit more as we go along today about another thing we’ve talked about a lot over the years here, which is what we call “the bond that heals,” and the idea that regardless of what kind of antitumor strategy you have, the patient is going to value the relationship they have with you. And we often value the relationship we have with them.

Clinical Presentation and Prognosis of PAD; Recent Advances in Up-Front Treatment for Metastatic PAD

DR LOVE: Alright, Amanda, let’s hear a little bit about pancreatic cancer with that as background.

MS WAGNER: Okay. So we will kind of take a step back here and kind of talk through just, first, pancreatic cancer statistics. So pancreatic cancer, and we’re talking about adenocarcinoma, is the tenth most common cancer in the US. It’s the third leading cause of cancer death. In 2024, the SEER database estimated about 66,000 new cases of pancreatic cancer. They comprise about 3.3% of all new cancer cases. Survival is grim, as you can see. It’s at 12.8, 5-year survival. People’s overall lifetime risk of developing pancreatic cancer is 1.7% by age 75.

And now, we’ll start talking a little bit about risk factors. So some of the clinical risk factors for pancreatic cancer include acute and chronic pancreatitis, smoking, alcohol use, obesity, diabetes, and then these cystic tumors, these intraductal papillary mucinous neoplasms and mucinous cystic neoplasms. Sometimes, those people, we know they have them. At our institution, we do have a pancreas clinic. So those are followed by a gastroenterologist and they do imaging and kind of monitor those to see if there is concern for them turning into pancreatic adenocarcinomas.

There’s also some inherited risk factors. So these are germline alterations that patients can have that they may know about or they may not know about. And sometimes, they’re not discovered until they are diagnosed with pancreatic cancer. And for every patient in our practice, we do offer genetic testing to assess for any of these. The most common ones I see in my practice are the hereditary breast and ovarian cancer syndromes, so your BRCA1, BRCA2, PALB2. And then we see a fair amount of Lynch syndrome as well.

So pancreatic stage distribution at diagnosis. So as you can see, the majority of cases, so about 80%, are locally advanced or metastatic at the time of diagnosis. So there’s only about 14% of patients whose cancer is localized at the time.

And as you can see, the survival based on their stage at diagnosis is also grim. So the patients with metastatic and regional disease, their 5-year survival is as low as 3.1% for metastatic disease, 16.2 for regional. And then if we are fortunate enough to find it localized, still it’s not great, it’s only at 44%.

So a lot of times, we don’t find pancreatic cancer until it’s too late. And the reason is a lot of times, they don’t have symptoms until the cancer has either metastasized or what we call locally spread. So there might be regional lymph nodes or this tumor might be encompassing vessels, making it unresectable. So some of the symptoms that they can present with, anorexia and weight loss, so loss of appetite, fatigue, abdominal pain, back pain, and that can be kind of mid-back pain, so more kind of around the bra line, which I’ve had patients before that they’ve had all this imaging of their spine and they can’t find it, can’t find it, and come to find out, they have a pancreatic mass causing their symptoms. They can have muscle pain or muscle weakness and wasting. They can present with jaundice, so if a pancreatic head mass is pressing on the bile duct. They can also have change in bowel habits. And specifically, pancreatic insufficiency symptoms. So our pancreas is a digestive organ as well. It helps us break down our food and releases enzymes to help us break down our food. So when we’re lacking those enzymes, they can have lots of gas a bloating, floaty, oily stools. So sometimes, that’s how they find their cancer. They can have indigestion or new or worsening onset diabetes.

DR LOVE: So before we go on to another case of metastatic disease. Farshid, even though it’s a small percentage of pancreatic cancer, as we saw on that diagram that Mandy just showed, you do see patients who present with localized disease. Can you talk a little bit about the use of neoadjuvant chemotherapy in those patients, both who are not resectable in the hope to make them resectable and even in patients who appear to be resectable?

DR DAYYANI: So the first thing we have to understand, it’s early metastatic disease in the majority of the patients. We’ve been doing surgery for 40 years and we’ve cured the minority of them with surgery alone. So there’s early metastatic disease. And we’re getting better and better at determining early dissemination. So that’s where the concept of neoadjuvant systemic therapy comes. Because you don’t give the chemo to remove the primary tumor because the surgeon cuts it out. They get it all, all the time, right? So you give the chemo to kill the micrometastatic disease before it exponentially grows. And I think in 80+% of the cases by the time they’re diagnosed, as we heard, they’re probably metastatic already, maybe micrometastatic disease. So that’s where the concept of presurgical or neoadjuvant comes. Because from the data, from the adjuvant trial data, we know there’s a subset of patients where adjuvant chemotherapy cures them compared to surgery alone. Again, the tumor is out, so the chemo only killed whatever already had spread. So if you take that concept and you say, okay, earlier treatment is associated with better outcomes, as we do in other GI cancers. So that’s where the concept of neoadjuvant chemotherapy comes in.

Now we have pretty good data that for anything beyond very early-stage disease, let’s say less than 2 cm, Stage I. Anything beyond that probably neoadjuvant treatment to best response followed by surgery is as good, if not better, than surgery followed by adjuvant because it’s much more difficult to tolerate chemotherapy when the pancreas is missing and you’re recovering, and half of the patients won’t make it, right? What we do have is in very early-stage disease, we don’t have the data yet that perioperative chemotherapy is any better than adjuvant. The question begets, do we really need, in a subset of patients, chemotherapy or are they cured with surgery alone? We don’t have the biomarkers to determine those patients, so right now, everybody gets chemotherapy. And we have ongoing trials for very early-stage disease like the Alliance trial where we randomize perioperative to adjuvant to see which one is better. But for anything beyond really small pancreas-confined, if there’s lymph node involvement, if the tumor is a bit larger or even locally advanced and not resectable up-front, really, systemic treatment is what the patient needs to go to. And the 1 thing to tell the patient and the family is if this tumor grows through those 2 or 3 months of your best systemic treatment, you should have gone to surgery in the first place. Because that tumor would have come back within a month. So when they understand that, then they are much more willing to actually do the right thing, which just means early systemic control.

DR LOVE: So let’s hear about another case, Mandy. This is a 54-year-old man, again, pretty young.

MS WAGNER: Yeah. So this man had a history of substance use disorder. And he, last year, had developed epigastric pain, and was diagnosed with pancreatitis and received conservative treatment. But he kept coming back to the ED with these similar symptoms. And they kept saying you have pancreatitis again, you have pancreatitis again. He actually did have an EUS with a biopsy that there was no evidence of malignancy on the EUS, but there was also some new indeterminant liver lesions. So 2 months later, came back still having the same pain and those liver lesions got a lot bigger and he had, as well as the pancreas looked a little bit more suspicious actually for a tumor. And he underwent a biopsy of both the pancreatic mass and the liver lesion, and was diagnosed with metastatic pancreatic adenocarcinoma. His NGS did show an indeterminant variant in DPYD, which we weren’t really sure was going to mean anything at initial, you know, looking at his, reviewing his sequencing. His germline testing was also negative.

He, at his first appointment, was very symptomatic from his cancer. He had worked as a barber, but wasn’t able to work anymore. He had uncontrolled abdominal pain. Fortunately, through his hospitalizations and his history of substance use disorder, he was discharged with follow-up with we have a harm reduction clinic. So they follow patients with a history of substance use disorder to treat their pain. So was started on buprenorphine and morphine for the pain. And fortunately, they were doing a good job at managing his pain. He had a lot of constipation issues as well. Psychological symptoms, he was very depressed regarding his diagnosis. Like I said, he was married, he worked as a barber. But he had been sober and clean for over 20 years.

DR LOVE: So without substance abuse.

MS WAGNER: Yeah.

DR LOVE: This is a history, in the past.

MS WAGNER: Yeah, history, in the past.

DR LOVE: And what was the substance he used?

MS WAGNER: Cocaine.

So we started him on first-line treatment with NALIRIFOX. And after a couple of doses of treatment, developed mucositis and neutropenia and diarrhea, to which we were like let’s look more into this DPD. So he was noted actually to have a DPD gene mutation, which can be associated with poor tolerance to 5-FU. So now, we’re able to find this activity score, and his was kind of lower. So we were able to dose reduce his 5-FU by 20% with resolution in his symptoms. And within 3 months of chemo, his symptoms related to the cancer have gotten a lot better. He’s eating, he’s gaining weight, he’s been more active. They just went on a trip to New Orleans and he was able to do anything and everything they wanted to do. And he’s doing great right now.

DR LOVE: I want to hear a little bit more about him and his circle of — family circle and friends. But, Philip, can you explain a little bit more about what DPD gene mutation is and how it affects the use of 5-FU?

DR PHILIP: So basically, simply put, the DPD mutations — so DPD is an enzyme. And when we give a drug, 5-FU is one of the drugs, we need the DPD to break down the drug, not let it stay in the body longer. So we don’t want to get overdosage of the drug in a given patient, individual where their enzyme activity is deficient basically, is not working well. So if that happens, just think of it like they get an overdose of the 5-FU or any of the related drugs. For example, capecitabine is another one. So it comes to the same thing.

In some countries in the world like France and the United Kingdom, it’s now mandatory not to start any 5-FU treatment without doing DYPD. And at least in France, it was prompted by a VIP dying of the complications. It can be very, very severe and patients can die, especially if the patients don’t get supportive, early, very early, like with the diarrhea, mucositis and all that.

Now in my practice, we changed in our hospital last year that it’s — we do it routinely. There were challenges. And I have to warn you about the challenges because sometimes it’s an insurance issue. Now that’s not our discussion today, but I’m just giving you that headline to follow up on. The other thing we do is UGT1A1, which is the one that does the same thing, same principle for the irinotecan or liposomal irinotecan, as you know. So these 2 things we do ahead of time. And in fact, our nurses now, they check on it before they give the treatment because it’s become part of our workflow. It requires some arrangement to do that, but we do that.

And in this patient, something which comes up when we’re seeing these young patients is that we have to prepare when the family comes to you after 3 or 4 months and say, what about my children? What do I do with my children? How do you counsel them? Because they, are they at risk of pancreatic cancer or any other cancer? That becomes also something to keep in mind.

I also want to add something else. When we see in oncology, obviously, especially in pancreatic cancer, you have someone with liver metastases, our mindset is chemotherapy, experimental treatment, drugs, et cetera. But down the road, if you give someone a treatment like, let’s say, NALIRIFOX, and they respond very well, because we’re getting better treatments, we also have to think of what we do, for example, in patients who have 1 or 2 lesions in the liver. Those patients, you can either ablate, resect or give radiation. So that really brings me back to the point that patients have to be really under a multidisciplinary treatment.

DR LOVE: Right. And we were talking about the treatment of what’s called oligometastatic disease yesterday with prostate cancer.

So Mandy, again, can you maybe just briefly comment on his situation, how it compares to your previous patient? He was in recovery. Was he going to AA or any other groups?

MS WAGNER: Not at that point because he’d been clean for over 20 years. But it kind of ties into a bit of a stigma, right? Not only did, we talked about this yesterday at ONS but we worry about treating him differently because we knew about his substance-use disorder. But he has a reason to have a significant amount of pain. And I’m not sure, could that have been part of the reason that it took so long to diagnose him? He just kept coming back, kept coming back. And they were like pancreatitis, treat it conservatively. But yeah.

DR LOVE: Great point. Alright, Farshid, let’s talk a little bit about this, both these patients got a therapy that wasn’t used more recently. Philip?

DR PHILIP: Just a quick point. I was reading recently an article and this is a fact that people who have recurrent pancreatitis, think of the possibility of pancreatic cancer. Don’t let it just go as only pancreatitis if it’s recurrent.

DR LOVE: Great point. Farshid?

DR DAYYANI: So our recently hired pancreatic surgeon with a 5-year-old calls me and says Farshid, the mother of one of the mothers who goes to the same kindergarten like my kid diagnosed with pancreatic cancer wants a second opinion. So a 72-year-old lady from Fiji, but I think is South Asian ethnicity, family history of pancreatic cancer. No significant past medical history. She has some diabetes, but well-controlled. Basically, a 20-pound weight loss. Not a lot of pain, weakness, fatigue. Ultimately, gets a work-up and has, unfortunately, as you can see here, this 4 cm pancreatic tail mass. Not clearly visible on CT scan but when we updated her imaging based on a CA 19-9 of 19,000 on MRI of the liver, small lesions that were suspicious for metastatic disease. As we would do for diagnosis, we do endoscopic ultrasound and fine needle aspiration or biopsy of the mass. Unfortunately, it shows moderately differentiated adenocarcinoma. A CA 19-9 of 19,000 basically means the patient has Stage IV disease even though the patient doesn’t want to know it, the involved daughters don’t want to know it, the son-in-law doesn’t want to know it, the husband doesn’t want to know it. Nobody wants to know it, but it’s there. Preserved performance status. As I said, she has some comorbidities, but they are well-controlled. And obviously, she wants to be super aggressive because, believe it or not, she wants to go to surgery.

So that’s where we started with. What options do we have? So 15 years ago now, this is kind of depressing because when I was a fellow, this was very new data, the PRODIGE out of France trial showed for the first time that we can improve survival meaningfully over palliative gemcitabine alone with the FOLFIRINOX regimen. Now it’s important to see FOLFIRINOX back then was highly fit young patients with no major comorbidities, great organ function who received oxali at 85 every 2 weeks, irinotecan at 180, full dose, and then they got a 5-FU bolus with leucovorin of 400 and then a 24-hour — 64 — 46-hour continuous infusion of 5-FU. So really full dose FOLFOX or FOLFIRI, what you want, and then you add the third drug as well. Obviously, clear improvement in overall survival, progression-free survival. That became the de facto standard of care for really fit young patients. The problem is the majority of those are not young fit patients. As Dr Philip said, median age of onset is late-60s, early-70s.

So very, very quickly based on single arm data from a very big cancer center, people started to adopt the modified FOLFIRINOX. It was never actually shown to be noninferior to the FOLFIRINOX regimen in a clinical trial. But as you see, irinotecan was dropped. There is different variations of that, but the most common one is irinotecan is dropped from 180 to 150, the 5-FU bolus is omitted. So that’s what you end up with the modified FOLFIRINOX. That’s sort of de facto what people use when they want to give an aggressive regimen. So that’s one of the options. Again, never a Phase III noninferiority trial to show that it’s actually different than the — or the same as the FOLFIRINOX regimen.

The majority of our patients were not candidates for that. So a couple years later, 2013, we had the MPACT trial coming, Dr Von Hoff, out of Scottsdale that showed a regimen of gemcitabine/nab paclitaxel 3 weeks on, 1 week off compared to the standard, again, palliative gemcitabine. Now this was a much more inclusive study. Performance status KPS 70 or more, sort of ECOG I/II to 0. No age limit, 40% of the patients were actually 65 years or older. Adequate organ function. Prior chemoradiation was allowed. Again, this is from a time where we might have given more liberally radiation in the adjuvant setting. So older patients, less good performance status. And this trial showed also that the combination regimen improved overall survival over gemcitabine, and progression-free survival also improved. So now, we have 2 regimens, gem/nab versus gem, and FOLFIRINOX, FOLFIRINOX versus gem. Both trials have the comparator of single agent gemcitabine with a median survival of 6 months. That became our de facto standard of care. And saying if they’re fit, we give FOLFIRINOX. But we don’t give FOLFIRINOX. We give modified FOLFIRINOX. And if they’re not fit, we’re going to give gem/nab. But after a month or 2, we’re going to switch the regimen of gem/nab from 3 weeks on, 1 week off to maybe every other week or 2 on, 1 off because they can’t take it.

So that brings us to NALIRIFOX. So now the liposomal irinotecan is not irinotecan, as the same way a Trojan horse is not a soldier. Within the Trojan horse, you have the soldiers, but they get in easily and then they unleash havoc. So that’s what happened. Irinotecan, the topoisomerase inhibitor, was encapsulated in the lipid bilayer. This lipid bilayer secures and protects the molecule while it’s in the bloodstream. So it doesn’t get degraded as soon as you give it IV, and only a fraction of it gets to the tumor. So you have much more intact molecule being delivered into the tumor with a longer half-life. And what happens is in the pancreatic macrostoma, the macrophages and the phagocytes, they eat up these liposomes, they degrade them. And that’s where you release the irinotecan. That’s the Trojan horse. Now suddenly, the soldiers come out. So you deliver more drug at a higher concentration to where the tumor cells are. So the enhanced stability, penetration and retention in theory should improve the efficacy of nanoliposomal irinotecan over naked, what we call, irinotecan. So the proof is in the pudding, right?

So that was the NAPOLI-3 trial. The NAPOLI-3 trial was not drawn out of the hat. There was actually an extensive Phase I/II trial to establish the most efficacious and tolerable combination of nanoliposomal irinotecan, oxali and 5-FU. We were fortunate at UC Irvine to be part of all of those. So the NALIRIFOX regimen, as you can see here, uses liposomal irinotecan at 50 mg/m², oxaliplatin not at 85, at 60, leucovorin at 400. You don’t have a bolus and you give your 46-hour infusion of 2,400 of 5-FU every 2 weeks. And that was compared for the first time and only time in a Phase III superiority trial in first-line against the doublet chemotherapy, gemcitabine/nab paclitaxel. It was a superiority trial, global, multicenter, academic and community sites. As you see, range, all the way — there was no age limit, 50% were 65 years or older, 1 in 14 were actually 75 years or older.

So this trial improved overall survival for the first and only time against an active doublet regimen with a hazard ratio of 0.83. What you see below is the progression-free survival. And that brings us to the question in 2025. We don’t talk about median survival. We talk about the probability of being alive and without progression at 6, 12 and 18 months. Because I guarantee you in 6 months, I’m going to have molecules and trials that I don’t have today. And that might change the outcome. So that’s what I put in the table on the right side. If you look at the NALIRIFOX group, almost half of them were still alive at 1 year. That’s a median survival with the other regimens that are your standard of care so far. And 1 in 4 were still alive at 18 months. And without progression, almost 1 in 3, 27% were without progression. So that buys you time to come up with the next trial. A 42-year-old guy, he needs to go on a clinical trial. So the longer he is in remission with preserved organ function, the higher the probability to change the trajectory of his disease.

So when we say, oh, there was never a comparison of FOLFIRINOX versus NALIRIFOX. I say there was never a modified FOLFIRINOX against FOLFIRINOX in the first place. But absence of data is not absence of evidence. Were there trials where actually FOLFIRINOX was combined to gem/nab? This is some of the data that we pulled and a paper we just published in the Journal of Pancreas with one of my talented internal medicine residents. So there are actually prospective trials that compared modified FOLFIRINOX to gem/nab. And look at those. Both of them are negative. In the locally advanced setting at the left side, the JCOG1407, there was no difference between modified FOLFIRINOX and gem/nab. And in the JCOG1611 that was presented at ESMO as an abstract, the paper is not out, it was a randomized Phase II/III 3-arm trial. Nab pac actually had a median of 17 months versus modified FOLFIRINOX, 14 months. I’m not good at math, but I can do that much.

So if FOLFIRINOX is better than single agent gem, and nab pac is better than gem, and based on the data I showed you, modified FOLFIRINOX is about the same, if not worse than, gem/nab. But then, you have NALIRIFOX that shows superiority to gem/nab. By deduction, which one do you think is better? NALIRIFOX or modified FOLFIRINOX? It’s not the same drug. And the clinical data don’t support that it’s the same. So if you want to give your patient the best benefit of the doubt and maximize the outcome, you go by the data. So that’s why we chose for this lady the NALIRIFOX regimen.

DR LOVE: I love that analogy of the Trojan horse. And really interesting, again, we’ve talked in many of the programs so far about the challenge when you don’t have the comparison between some of the things you want to see a comparison of, and you have to indirectly compare it. And you can see how oncologists sort of go through these data. Another issue there too though is tolerability. And, Caroline, you’re going to get into that in a second. I’m just kind of curious though. I think you mentioned the patient is interested in surgery. Do you think she has an unrealistic thought about her future or what’s she thinking?

DR DAYYANI: She underwent surgery, believe it or not. Not at our institution.

DR LOVE: Really?

DR DAYYANI: She got into a CR and she went to a different institution and she got the surgery.

DR LOVE: Wow. With metastatic disease? She had the primary?

DR DAYYANI: Well, the liver mets disappeared, CA 19-9 normalized, and you know. She recurred. She should have never gone to surgery, but she went to surgery.

DR LOVE: Wow, interesting.

DR PHILIP: They have only 1 chance, right?

DR DAYYANI: But she had — yeah.

DR LOVE: Interesting. Interesting. Well, again, patient involvement, another thing we’ve talked about. People, some people are very proactive, others are not. This lady and her family sounds quite proactive.

Alright, Caroline, let’s talk a little bit about some of the issues that come up in managing these patients’ symptoms.

MS KUHLMAN: Yeah. So I think also, I’m going to touch on a little bit about how we sort of pick a regimen for patients, you know, what’s the algorithm. And I think we’ll touch on some institutional differences in approaches to what our choices are for first and second-line therapies.

So I’m going to start by presenting a case of an 81-year-old lady who presented with newly diagnosed diabetes, diarrhea, some unintentional weight loss of about 30 pounds. Went on to develop abdominal pain, which prompted a CAT scan. It demonstrated a pancreatic mass in the head and multiple liver lesions. She had very high tumor markers and she also had biliary obstruction as evidenced by her elevated alkaline phosphatase and her Tbili of 2.3. She underwent an EUS. Found out, you know, biopsy confirms that she has adenocarcinoma. At our institution, we also do baseline DPD and UGT1A testing, and she was a normal metabolizer of 5-FU and an intermediate metabolizer of UGT1A. So when we talk about this patient, some other things to consider. She was a very fit lady.

Her past medical history was pretty unimpressive. She walks a couple miles a day. She does yoga. She’s very active in her church. She — sorry, was a retired music teacher. She has a husband who has Parkinson’s disease, and part of her drive for her fitness it to be available to him because she cares for him. He is a chronically ill guy who gets intermittently hospitalized for falls at home. She is his primary caregiver. She has 3 adult children and a lot of grandchildren, good social supports there. So our thought for her is, you know, what do we pick for this lady?

She’s extremely fit, very motivated. She wants to be around to care for her husband. We considered the options of FOLFIRINOX as a first-line versus NALIRIFOX versus gemcitabine/nab paclitaxel. We actually chose FOLFIRINOX for this patient. Again, our institutional bias is that we think of them as equivalent. There have been studies that suggest that they are in terms of their — there was really no difference with FOLFIRINOX and that the toxicity was fairly similar, the cost is quite different. The liposomal irinotecan is quite expensive. So we did start her on FOLFIRINOX. She — let me just go back to her original.

We did start her on FOLFIRINOX, and she actually tolerated it pretty well. We dose reduced her irinotecan to begin with because she was a UGT1A intermediate metabolizer, so we gave her 150. We gave her 85 of oxali. We dropped the bolus of 5-FU and gave her the 1,200 per day — sorry, per m² per day of the continuous infusion 5-FU x 2 days. She generally tolerated that pretty well. She did need additional adjustments in the oxaliplatin, we dropped it to 65, and the irinotecan. She had an initial response with a lowered CA 19-9 and CEA.

Her major side effects were — sorry, her major side effects were fatigue, she had diarrhea, suffered from pancreatic insufficiency, she had some weight loss and anorexia. We worked really hard to manage her symptoms with GI working with stent replacements and social work as well as palliative care for pain.

So the side effects that we encounter with these regimens. She actually went on to progress, unfortunately. And a second-line therapy for her was gemcitabine/nab paclitaxel. To start with, the most common side effects we see with NALIRIFOX or FOLFIRINOX are the lowered blood cell counts. At our institution, we give growth factor on day of disconnect. That’s actually becoming harder to get approved by insurance, but we still continue to do it. Nausea and vomiting, obviously, are issues with this chemotherapy. And we premedicate patients pretty aggressively and then we send them home with a very detailed description of how to use nausea medicines at home. Diarrhea is a big concern particularly related to the irinotecan. And we give them aggressive management instructions for use of loperamide. We use second-line diphenoxylate and atropine.

And in extreme cases, we add deodorized tincture of opium, DTO. Neuropathy is a huge problem with this regimen. People get the acute cold-induced neuropathy. So lots of instruction about avoiding cold exposure in the days that follow therapy. This can transition into a chronic neuropathy where patients have pretty significant numbness in their fingers and feet. This can really limit their function. So we’re taking detailed histories every time, remembering that our goal with the therapy is palliative and we don’t want to leave people unable to function optimally. Less common side effects we can see are arterial vasospasm from the 5-FU. That can be managed when you consult your cardiology colleagues. In rare cases, we can see really severe diarrhea. And that requires dose reductions in the irinotecan and really close monitoring of fluid and electrolyte status. We can see allergic reactions, particularly to oxaliplatin. And those can be managed when you consult your allergy colleagues. It’s rare, but we can see severe side effects with these regimens that can lead to death. And it’s important to tell patients that that is a risk of the chemotherapy.

This just summarizes in the PRODIGE-4/ACCORD-11 trials what the common side effects were and what we just discussed.

Again, how do they compare? Well if you compare FOLFIRINOX or NALIRIFOX to gem/nab paclitaxel, you’ll see there’s more neutropenia when you give more drugs in chemotherapy. There’s slightly more febrile neutropenia with FOLFIRINOX. We give growth factor so that’s less of an issue. The diarrhea is more common. Fatigue, more common. And interestingly, you can see pretty moderate neuropathy also in the gem/nab paclitaxel.

So that’s a summary of some of the side effects we see in the NAPOLI-3 trial.

So again, the major side effects are — I mean, the major concepts in managing these sides effects, it’s really good patient teaching. Really, a lot of anticipatory guidance, being sure you give patients explicit instructions about how to use the medicines in their toolbox. We write out schedules for them so they know what to take and when. And we give them specific instructions about when to call. And it’s really important that if they experience a side effect they didn’t expect or they don’t know how to manage that they contact us. No symptom or if they’re worrying at home, we want them to let us in. So when they’re aggressively managed, patients even 81 years old can tolerate these regimens.

So in summary, the FOLFIRINOX/NALIRIFOX, it is the most effective active regimen in these patients. And we use it in fit patients, but fit can have a lot of definitions. And then we use the gem/nab paclitaxel in our less fit patients. But we utilize dose adjustments with palliative intent in mind.

And this is just another summary of the side effect management and sort of the elements that are very important.

DR LOVE: So there’s probably no wrong answer. There are 3 potential combinations that are used up-front. It’s the art of oncology and talking to the patient about which one is going to be used. You can go to practice guidelines and see that all 3 have evidence that’s positive. We just like to do surveys of experts and say, what are you doing, just to inform oncologists. We are seeing more use of NALIRIFOX. It’s a relatively recent regimen. But again, very important point you make. This is palliative therapy, so there’s really maybe no real right or wrong answer there what’s best for any individual patient.

Selection and Sequencing of Therapy for Relapsed/Refractory Metastatic PAD

DR LOVE: So let’s talk about second-line therapy for patients who are able to get to second-line therapy. And Farshid, we talked about a situation where a patient gets gemcitabine/nab paclitaxel. As Caroline was saying, not uncommon for that to be used in older patients, poor performance status with the thought that it may be better tolerated. Although you do see neutropenia there as well. And then, these patients often, if not always, will progress. And a common second-line therapy is the same agent you just talked about, the Trojan horse theory with NALIRI and 5-FU/leucovorin. So can you talk again about the clinical trial evidence we have, about what to do in this situation, how often patients actually get to second-line therapy, and how you make this decision?

DR DAYYANI: So if you play your hands right, the majority of your patients will make it to second-line. Meaning, don’t push until their bone marrow is wiped out and they can’t walk anymore and they don’t tolerate any more disease — anymore treatment even though you have other options. So that’s the one point. And neuropathy and cytopenia, these are really the rate-limiting stops for second-line treatment after first-line something that includes a taxane or a platinum that causes neuropathy.

So let me talk about this gentleman. What you see here, this big dark thing is his stomach. A 74-year-old gentleman. He had, as a teenager, testicular cancer. Doesn’t play a role here. Cured with chemotherapy and surgery. But then, he comes back with this gastric outlet obstruction, huge stomach. Has a stent placed. Whipple was aborted because he was found to have locally advanced pancreatic adenocarcinoma. He comes to see me. He’s 74. He had some chemo decades before. Performance status reduced. The LAPACT trial was a single arm Phase II trial of gemcitabine/nab paclitaxel in about 80 to 90 patients with locally advanced. Locally advanced is a euphemism. Locally advanced, it’s a Stage III and patients get happy. I’m like sorry, it’s the same as Stage IV in terms of treatment. But there’s a nonzero chance that you still get them to surgery with adequate systemic control and reduction of the tumor in locally advanced. Maybe that’s the light at the end of the tunnel. But clearly, for this gentleman, gem/nab pac at full dose was appropriate. He was interested in aggressive treatment. So we started him on gem/nab. And his CA 19-9 was elevated at 1,200.

Again, in the setting of normal bilirubin, that’s invariably an indicator of more advanced disease. After 5 cycles of treatment, 5 months, his CA 19-9 normalizes to 18. He has to stand in place. He’s eating. He’s getting better. What you see a lot of times on imaging, the primary tumor will not necessarily shrink a lot because there’s a lot of dense fibroblastic stroma in that tumor. That’s not tumor cells. So even if you kill those tumor cells, the size of the tumor might not necessarily shrink on imaging. But biochemically, ctDNA and CA 19-9, he clearly had a good response. Now obviously, after 5 months of nab paclitaxel, he starts to have peripheral neuropathy, as we heard. And that started to bother him. That led to some adjustments in the nab paclitaxel dose adjustments. But ultimately, at some point, another 3 months or so, his CA 19-9 starts to slowly go back up. And we repeat imaging. And now, unfortunately, the pre-present liver lesions that were not visible, now they become visible. Hypodense lesions in the liver. He has early metastatic disease. So what do we do? Not a trial candidate or maybe we didn’t have a trial at that time. He has neuropathy, but he’s otherwise interested in treatment and in good shape. So that’s where we discuss nanoliposomal irinotecan with 5-FU/leucovorin or the NALIRI regimen.

Why did we do that? Somehow, I was fortunate enough to be part of that trial at my previous institution as well in 2012/2013. So the NAPOLI-1 trial, if I’m not mistaken, is maybe the only randomized Phase III prospective global trial that used the doublet versus an active comparator in second-line or post-gem progression in metastatic advanced pancreatic adenocarcinoma. Patients with advanced disease, more than 400, who had prior gem-based therapy. Now this could be in the adjuvant setting and they progressed within 6 months. They were in fact Stage IV. Or they were diagnosed with Stage IV, received gem-based, gem combo, and a subset of them actually had gem/nab paclitaxel in that trial, normal bilirubin, albumin greater than 3, performance status KPS 70 or higher, randomized to NALIRI regimen, nanoliposomal irinotecan, 5-FU/leucovorin or 5-FU/leucovorin, so active comparator arm 1:1 with overall survival as primary endpoint. Importantly, the nanoliposomal dosing in this regimen is 70 mg/m².

Remember in NALIRIFOX, it’s 50 mg/m² because it’s a triplet. So here, it was 70. And as you can see, early separation of overall survival. Separation of progression-free survival. So 10 years or so before the NAPOLI-3 trial, the NAPOLI-1 trial established the NALIRI regimen as a second-line regimen after gem-based progression in metastatic pancreatic adenocarcinoma. You look to the right side, diarrhea, vomiting, nausea, decreased appetite, fatigue, neutropenia, anemia, hypokalemia. Now the description of the AE profile from a clinical trial is not here to make us scared. It’s here to educate and prevent as much as we can. And I would argue cytopenia and diarrhea and nausea/vomiting we call ameliorate or prevent as much as we can. Neuropathy we cannot. We have to dose adjust or dose reduce. So we have to learn from this trial, so our numbers should be better than the ones presented at the trial because the trial didn’t have prophylactic growth factors, maximize antiemetics, bring them on day 3 for extra IV hydration, right? But these are things that you have to tell your patient and educate your team so your numbers look better so your patient can remain on trial longer, right?

So based on the NAPOLI-1 trial, we offered this patient the NALIRI regimen. If you look at the NCCN guidelines, in advanced, locally advanced or metastatic, the NCCN lumps them together, locally advanced and metastatic, for prior gem-based therapy, the only category 1 is actually the NALIRI regimen, 5-FU/leucovorin/liposomal, because it’s a randomized Phase III with an active comparator OS benefit. And even if intermediate PS 2, remember in the original trial, KPS was 70 or higher. The only one that’s recommended for prior gem-based therapy is 5-FU/leucovorin/liposomal irinotecan. So if your patient for some reason starts on a gem-based regimen and they progress and they’re still a candidate for systemic treatment, certainly, the highest-level data is for the NALIRI regimen.

Now the discussion of naked irinotecan being the same as nanoliposomal irinotecan being the same is 10 years old by NAPOLI-1. Oh well FOLFIRI is the same. FOLFIRI does not have the data. All you have for FOLFIRI are single arm retrospective or prospective single arm trials. You cannot derive — there was never a direct comparator in the Phase III to show the superiority. And worse than that, the nanoliposomal formulation is actually different pharmacodynamics and kinetics than naked irinotecan. But if you look here, it’s 8%, median survival, 6.6. In the NAPOLI-1, you had about 10 months survival. But these are all single arm Phase II studies. Yeah, if you don’t have anything else, you can give it. But if you want to be data driven, then you want to go by Level 1 randomized Phase III data.

How about FOLFIRINOX as second-line? So gem/nab, gem combo, they progress. Again, never been a randomized Phase III trial with an active comparator. This is a relatively small Phase III trial out of Korea, 80 patients. Modified FOLFIRINOX was randomized to S-1, which we don’t have in the US. Numerically, a higher response, disease control. But you could argue it’s 3 drugs versus 1 drug. Has nothing to do necessarily with the FOLFIRINOX. Obviously, you have higher toxicities in that setting.

So the sequence if prior fluoropyrimidine to gem-based means, do we have data for gem/nab in second line? Again, we don’t have randomized gem/nab data in second line. There’s clearly some activity, 15% 10 months in single arm. And what you see on the right side is actually another randomized trial, it’s outcome based on ECOG. And as you would expect, better ECOG 0/1 has better survival than worse ECOG 2, which is, we know, one of the most important prognosticators in pancreatic cancer, performance status, right, if it’s disease driven. So if you don’t have anything else, sure, you can use them. But if you want to go evidence based, you usually try to go by what has a randomized Phase III trial.

This is the second-line data for gem/nab post-FOLFIRINOX. As you see, prospective single arm retrospective, prospective 30 patients, 59 patients. NAPOLI had more than 400 patients randomized, right? So there’s some activity, but nothing that would tell you this is clearly better post-FOLFIRINOX as a treatment.

So what factors do I consider? It’s really a multitude. Neuropathy is a big one. No matter what you start with, you have a platinum first-line or nab paclitaxel, if you play your hands right and they benefit, they will start to have neuropathy. They will have cytopenias. Strength of clinical evidence. This is category 1 or no this is retrospective study. Do I really want to maximize survival benefit, because survival benefit means more access to clinical trials. What are the patient wishes? What do the families want? Performance status, constipation, you know, neuropathy. If you have tumor derived pain and you’re on opioids you have more constipation than if you go to another platinum or nap-paclitaxel, and then obviously other factors. So it’s really tailored to the patient but really on the foundation of level of evidence.

DR LOVE: So great presentation. Maybe a little bit of a palate-cleansing story, when I saw your — in fact, this man was cured of testicular cancer 55 years ago, right? He was a teenager.

DR DAYYANI: Yeah.

DR LOVE: He was a teenager. Incredible.

So quick story, for about 10 years, every day I’d get up in the morning at 6 AM and play this trainer in basketball one-on-one for an hour. He was an incredible athlete. I never could beat him. I mean it must be the oncologist in me. I just kept wanting to play, right? So one day he comes up to me and he goes, what do you think about this? I go whoa, what? He had this huge node under his arm. It turns out he had recurrent testicular cancer. He had prior surgery. So he goes and gets chemotherapy, becomes bald, starts losing weight, sick as hell, but he kept playing. I never beat him, never. Can you imagine playing this guy? He was bald and losing weight and whatever. I could not beat him even then, so, the determination of cancer patients.

Importance of Palliative Care for Advanced PAD

DR LOVE: Alright, well, let’s get back to palliative care, a very important and common part of oncology. And Caroline, we asked you to talk about some of the many palliative issues that come up with this cancer.

MS KUHLMAN: So the care of a patient with metastatic pancreatic cancer, it is a team sport. This is something that you have to utilize all your resources to help patients in a difficult situation where there’s not curative treatment, but to help them do as well as they can for as long as they can.

So I’m going to start presenting a case of a 69-year-old man who was newly diagnosed with metastatic pancreas cancer. This guy is married, has 2 adult children. He is retired as a high school English teacher. He lives in New Hampshire, which is north of Boston. He has a big piece of land and he enjoys being outdoors and gardening. He has chickens and dogs. He loves to cook and entertain. The shock of the news of his pancreatic cancer was devastating. He had just retired. They were ready to make a life enjoying their leisure. He was a fit gentleman. We did start him on FOLFIRINOX but this was a challenging regimen for him. He was experiencing, at the time of the start of treatment, abdominal pain, which made it hard for him to be out and about in his garden. He wasn’t eating. He had difficulty sleeping. He would come to visits openly discussing his feelings of depression. He had lost interest in other activities. He wasn’t seeing his friends, his family. He was moody at home, his wife would report, and he was pretty tearful during our initial visits.

So our supportive interventions for a patient like this is we refer him to social work. In fact, we refer almost all of our pancreas cancer patients to social work. Our licensed social workers are also therapists so they would meet with him on his visit days. We referred him to nutrition to talk about strategies for maintaining his weight. We referred him to our palliative care team also, in partnership to manage his pain and also talk a little bit about goal setting and managing other symptoms that he had. We worked with our Interventional Radiology colleagues, our GI colleagues, to manage other symptoms associated with malignant ascites, also the need for intermittent stent changes.

I think the key point I want to leave everyone here today with, this is an old study but it’s so important that I wanted to talk about it today. It is a New England Journal paper that came out of the Mass General Hospital Cancer Center Supportive Oncology Group, in which we did a randomized study looking at early intervention with palliative care versus our standard intervention, which was when the patients got sicker and more complicated to manage, then we referred them to palliative care. This study assigned them to a palliative care intervention at the start of their treatment. They measured quality of life and mood assessments based on standardized tools. They did it at baseline and then again at 12 weeks and they randomized 151 patients. And what they found was that the palliative care group, the early palliative care group, they reported at 12 weeks better quality of life and less depressive symptoms. But what was most compelling to me and to my colleagues is that in the early palliative care group, these patients received less aggressive end of life care, but despite this their median survival was longer, 11.6 months versus 8.9 months. And this was a statistically significant finding. And there have been subsequent studies in metastatic cancers that have supported and validated these results.

This is looking at quality of life scores. I’m just showing you that when we look at the standard care versus early palliative care, these patients all reported better quality of life scores. They were less depressed with early palliative care. And their survival, quite compelling. And to me that was really instructive and it has really informed the way I think about palliative care and managing my patients and their symptoms.

The other thing I think that’s really important to think about in this setting is to have serious illness conversations with your patients. The goal of those conversations — it isn’t 1 conversation, it’s several. But the important factors to include are trying to understand as you get to know your patients, what are your goals? What’s important to you? What is it, that you don’t want to be a burden to your family, or is it that you want to live as long as you can to go to see your son graduate from high school? What are your goals? And then I think it’s really important to share your hopes and worries along with theirs. And that can look like, well, we’re going to start a second-line therapy and I’m really hopeful that this gives you some benefit. I worry that your symptoms are getting worse and your disease may progress. And if that’s the case, if you know your time is limited, tell me a little bit about how you want to spend that time? And I think those kinds of conversations really make it possible for a patient, first, to begin to think in those terms, but also to begin to ask themselves those questions and their families.

Supportive care, to a lot of patients, feels like you’re giving up, like you’re stopping. You know, palliative care, I wish we had a different name because the patients just bristle at the notion that I’m referring them to palliative care. But it is the hardest work we do. It is every bit, I would argue, as important or maybe more important than the chemotherapy treatments we give them. The goals, it’s about aggressive pain management, utilizing long-acting opioids, break through medications, but also being thoughtful about the way we deliver those medications. Can the patient swallow pills? Do they have a system where they can remember to take those pills? Should we be thinking about patches for those patients? Should we be thinking about pain procedures? Are they candidates for blocks and those kinds of things? We need to work really closely with our GI and IR colleagues. We need to be thinking about things like common symptom problems like delayed gastric emptying that’s very common in metastatic pancreas cancer. Weight loss is a huge issue for patients. They just are so frustrated by it, and so trying to work with our nutrition colleagues, but also just encouraging small, frequent calorie dense meals and snacks, trying to utilize supplements if they tolerate them, and also pancreatic insufficiency, which for many patients it’s like one of those medicines when I prescribe enzymes, that makes a huge difference for patients. Patients are like, oh my god, I no longer have diarrhea and gas and my stomach isn’t bloated. So remembering to utilize all of those tools in the toolbox.

So this patient had an initial — it helped that he responded to FOLFIRINOX and that helped him feel better. He was really grateful for the social work visits. I did refer him to palliative care. We did a great job with pain management. And because he responded to therapy, we were able to wean him off his long-acting opioid and he uses just 1 short-acting pill a day. I added pancreatic enzymes. It allowed him to be able to eat, have some interest in food, which was so important to him. And I started citalopram, which was also quite helpful. Over the weeks that I saw him, it was quite evident that he was much more engaged, stopped crying during the visits. The wife reported that he was just significantly — his quality of life was just much better.

So again, supportive care with or without chemotherapy. It’s the hardest work we do. It’s a team sport. Use your colleagues and earlier the better because we can help not only make their suffering less, but we can also help them live longer.

DR LOVE: So actually, we had a lung cancer program this morning. Your colleague, Liz Krueger, was here.

MS KUHLMAN: Yeah, yeah, yeah.

DR LOVE: We were talking about, that’s one of my favorite studies in oncology, Jennifer Temel did looking at palliative care. And I know Philip was sitting there thinking you don’t call it palliative care at your place, you call it supportive care. So I like that idea as well.

Role of PARP Inhibitor Maintenance Therapy for Newly Diagnosed Metastatic PAD

DR LOVE: Alright, let’s go on and talk a little bit about PARP inhibitors. Again, we’ve already talked about this a number of times. This is another cancer. We’re saying this patient has a BRCA2 germline mutation. Philip, what do we know about PARP inhibitors in pancreatic cancer?

DR PHILIP: So I’m going to start with this patient. And, again, this is a nursing meeting, so you work with patients, you’re always looking at things sometimes we as doctors may not be focusing on. So let me go through this patient’s history. She’s a 66-year-old female. She has Italian ancestry. And the reason I mentioned Italian ancestry is because she also had BRCA2 mutation, which we know is more common in Italian ancestry and Jewish heritage. She works as a residency training program coordinator, so she’s very active. And she wants to continue working, and that was one of the major things that she has. She had a goal in terms of when you talk about the goals and what they want to do, even with the disease that they have and outcome to the stage of the disease. But the important point is that in 1999 and 2018, she had DCIS of the left breast. And after the second occurrence, they checked her for BRCA2 mutation.

At that point, she had 2 sisters with breast cancer and a father with prostate cancer. So these all can be caused by BRCA2 gene mutation. So she underwent bilateral mastectomy and oophorectomy. So she tried to be proactive by preventing development of cancers there. But unfortunately, in 2025, with abdominal pain and weight loss, she had a pancreatic mass with liver metastases. And that was proven to be an adenocarcinoma. So in a patient like this with Stage IV disease, the goals of the treatment are clear that we want her to have control of the symptoms, but also prolong life. I will add that in this patient who didn’t have that many metastases in the liver, the other goal is to see whether she can be one of the few patients we can even address the issue of the liver. But the problem is with, like, ablation. But then again, we still have a large tumor there which is encasing the artery that cannot be resected.

So this patient who had the BRCA2 mutation, the choice was to give her a — or the standard of care is to give her a platinum-based treatment. And that would be either NALIRIFOX, FOLFIRINOX or even gemcitabine and cisplatin. And then, what do we do after that? So if you look at the point I made initially earlier on in the session is that with time, we’re seeing new treatments. And you can see here that in 1997, we had 1 drug. But if you look at the last 10 to 15 years, we’re having more activity. Some of the drugs we’re talking about here are biomarker-driven, so they have only few percentage of people who can benefit from it. But again, it’s an important development for the treatment of pancreatic cancer.

Now if you — the major message I want to put here to you is that, and again, based on my experience with the patients who come to me as a tertiary referral, still a number of patients come to us who are diagnosed, staged and started treatment, but molecular profiling of the tumor and also the germline testing is not done. So this is now a very essential part, in my opinion, of the initial management. And you are part of the team, so you should be aware of it. The tumor profiling, the tissue that you get from the biopsy, unfortunately, sometimes we don’t have enough to do that. There’s plasma ctDNA which also looks at the next-generation sequencing. And then you have germline testing for either blood or saliva, mostly blood. So what’s the benefit of doing the molecular profiling? We talked about clinical trials. That’s something which is very important. But then again, finetuning the initial treatment is very important sometimes in those patients. Even if you have someone, for example, who has locally advanced disease, you’re choosing between a platinum-based treatment or not. Prognosis, sometimes these are prognostic. And then there’s this thing about the cancer risk in the family if they have a germline mutation.

So PARP inhibitors, I’m sure you’ve heard a lot about it this morning. Basically, it’s an oral treatment that you all know. And the whole idea of the PARP treatment is that you’re exploiting, you’re exploiting a kind of a deficiency of repair in the cell, in the cancer cell. And that deficiency of repair is because of the BRCA mutation and the protein that helps the DNA to be repaired if it’s damaged. It helps to repair it. But if it’s not there, then it's relying on another protein called PARP to play the role. And if you can hit the PARP in a patient that has a BRCA2 mutation, then you can kill the cell. And we call that kind of synthetic lethality. So that’s really the whole idea about it.

Now we have to remember the BRCA mutation also predisposes patients to have cancer because the gene mutations that develop over the years are not repaired well. But then, you’re using that mechanism now coming back to that mechanism which is not a good mechanism that the patients start off with, now we’re exploiting it to kill the cancer cells. So it’s a bit of a smart idea.

So this study, POLO trial, was an international Phase III trial. It took a lot of effort to put 154 patients on it. And it was olaparib, the oral pill, versus placebo. And in this study, they showed that patients who got the olaparib, and I’m going to explain to you now exactly how that happened. So patients had at least 4 months of what we call platinum-based treatment. So it could be, at the time, it was FOLFIRINOX mostly. And after 4 months, if they’re not progressing, everything is controlled or improving, then you put them on a pill called olaparib. And the other arm of the trial was placebo. So you have to immediately think about what you’ve heard up to this point from these medications, the FOLFIRINOX or the NALIRIFOX, et cetera. Patients develop side effects which build over time. So in this group of patients who have BRCA2 mutation, you can immediately think that there might be an advantage of now going on a pill, giving them a break from the chemotherapy. Because the side effects will be less than the chemotherapy and doesn’t involve coming to the hospital every 2 weeks and getting a port. This trial was positive. And, therefore, the FDA approved the drug that is available now for use. It delayed the progression of the disease or the worsening of the disease.

So if you look at this, I just pointed to the major side effects, the ones that you should be aware of as, again, nurses taking care of the patients. Fatigue, anemia and the side effects that were treatment-related were in one-quarter of the patients and less than 10% of the patients had to have the drug discontinued because of side effects. Again, in comparison to placebo. So certainly, something that really helps the patients to be on it for a while, be away from chemotherapy and also help to control the disease to stay longer.

So based on this, and not only the BRCA2 mutation. In fact, you can make a more general statement because there are other germline mutations that can happen in patients. At this point in time, the recommendation by the authorities or organizations is that to do germline testing for any patient who is diagnosed with pancreatic cancer. So this could be a Stage I patient or it could be a Stage IV patient. And we do this routinely in my practice. All patients, when we see them for the first time, we get all these things done. Because that’s now part of our evaluation of the patient. I think this is probably the last slide I have, yeah.

DR LOVE: So yeah, germline testing also with implications to the family. So, Mandy, we asked you to talk a little bit about nursing issues in patients receiving PARP inhibitors. We’re going to talk about it here with pancreatic cancer. But a lot of what you have to say relates to ovarian, breast, prostate.

MS WAGNER: Yeah. So talking back about genetic counseling. So as Dr Philip mentioned, any new pancreatic cancer patient in our institution as well, we do talk about referring for genetic counseling. So this can be very overwhelming for patients because they want to know, is my insurance going to pay for it? If you do find something, what does this mean for my family and their future implications for becoming insured or having preexisting conditions? So it’s very important to refer them to a licensed genetic counselor to have these discussions. They can talk about risk reduction strategies, any necessary screening should they be positive, the possibility of passing the variant to the child. Then, do their children need to be tested? There can be a referral to support groups to cope with discovering that you do have a germline alteration that led to your cancer.

So talking about maintenance olaparib. So as Dr Philip mentioned, this is for patients with BRCA mutations who’ve received at least 16 weeks of platinum-based chemotherapy, so oxaliplatin, cisplatin. So we do this because, as Dr Philip mentioned, we’re trying to give them a break from systemic chemo, improve their quality of life. So as he mentioned, this is a PARP inhibitor which blocks the activity of the PARP enzyme, which plays a crucial role in repairing DNA. So we’re hoping to kill the cancer cell that way.

So things that I counsel the patients on. And we have clinical pharmacists that work in clinic with us that also do, for any oral chemotherapy agents, do actually go in and counsel patients as well. So a lot of that either I start to do and then they finish or we kind of do a team approach. But talking about fatigue but we hope that that is going to be better than it is with systemic chemo. The hematologic toxicities of specifically anemia, thrombocytopenia and neutropenia. We do recommend doing, obviously, a baseline CBC. And then we will repeat labs every 4 weeks. And then if we do see one of those toxicities, then we do hold the drug. I talk about nausea, vomiting, diarrhea with them. You don’t have to take the medication on an empty stomach or with food, but actually taking it with food may help prevent the nausea and vomiting. I’ve had some patients that they’ve just taken an antiemetic 30 minutes prior to taking the drug, and that’s relieved the nausea and vomiting. Some patients have had URI symptoms of just kind of cough, congestion. Decreased appetite, mucositis, headache.

More serious complications to look out for, although rare, would be symptoms of blood clots or pneumonitis. So I really stress the importance of calling me if you have any new cough or worsening shortness of breath, any new swelling, so that we can get you in for an evaluation. Ensure that the patient has antiemetics and antidiarrheals. Obviously, verify their pregnancy status before starting the drug. And then we already kind of chatted about the CBC.

Promising Investigational Strategies for PAD

DR LOVE: So we’re going to move on now to finish out. We need a little hope infusion here. We’re talking about some tough numbers tonight. There’s a great case, if you check out the slide set, that Mandy wrote up, free to check it out, of a patient who actually got olaparib. But, Philip, let’s talk about a couple of new options for the future, maybe better hope for our patients.

DR PHILIP: So we’re staying on the theme of we’re getting new drugs, but also we’re doing additional testing with genetics, et cetera. So this is another example of a patient who is a 49-year-old actually, auto — car engineer. I’m in Detroit, so I see a lot of, unfortunately, younger people come. Many of them do have engineering backgrounds. Good performance status, a very nice young family, fit otherwise. He had pain for a couple of weeks and then had a CAT scan which showed a large mass in the pancreas that you can see here on the arrow. Again, had the usual work-up, adenocarcinoma. Germline testing was negative. So in a patient like this, the goal was pain control, prolonging life, but again, added to it being possible resection down the road. And if you look at the molecular testing that we did up-front, so he came to us for a second opinion but we said you have to have molecular testing. And it sure enough showed microsatellite instability although he had no germline. So he wasn’t Lynch, but he was somatic microsatellite instability. And also, if you look at the liquid biopsy, it didn’t show it. So that’s the reason why we do both because sometimes, we’ll pick it up in one and you don’t see it in the other.

So this patient, we started the patient on chemotherapy plus pembrolizumab. And he’s doing very well actually. His tumor shrunk down a lot. But unfortunately, it kept on hugging the artery, so he’s not operable. But otherwise, he’s doing well. And we’re thinking of just giving him some radiation.

So there are a number of drugs now, as you know, that target KRAS. KRAS represents 90% of the mutations we see in those tumors. So the number of drugs that you’re familiar with, for example, the KRAS G12C, which we see more frequently in patients with lung cancer, maybe colon cancer, so even in pancreatic cancer. So you have to do the testing because then, you have an option for the patient. If you don’t do the testing, then you miss out on these drugs.

The exciting thing is that there are now almost 30 companies working on KRAS, other KRAS mutations, KRAS blockers. And this is an example of a study that was presented last year. And it’s really showing very interesting results in patients who otherwise we didn’t have any treatment for them. So we give chemotherapy, it works. We heard about chemo working for a while and then patients were dosed second-line. And then, you’re really running out of options. So now, we have this very important development. And in fact, these drugs may even go to frontline. There are studies to start in frontline. And also, even the adjuvant setting. So within the next 5 years, you will see this is going to change a lot of things that we’re doing in the treatment.

This is just a very minor example of the number of drugs, different ways of doing it. This is not something which is in any way exhaustive because this is from an article published a few years ago.

The other thing is that the 10% of the patients who have no KRAS mutation, we call it KRAS wild-type. So we have 90% with KRAS mutation, 10% do not have KRAS mutation. Now these patients also have some interesting mutations that can be targetable. So I treated a patient for over a year with an FGFR fusion inhibitor like we use in biliary cancer, and the patient did very well. He had KRAS wild type. So we have to do these things to really figure out what you can do.

Another opportunity is this recently FDA approved drug, zenocutuzumab, which targets, it’s a bispecific antibody that targets HER2 and HER3. Again, the whole idea here is that you have to do the testing to figure out patients who can benefit. And certainly, there is benefit in patients who have pancreatic cancer with tolerable toxicity. So again, these are really things that we have to keep in mind.

Again, I want to finish off by saying, why do we need to push patients — not push patients, I’m sorry, I used the wrong word. But why do we have to push ourselves to talk to patients in terms of opportunities for clinical trials? Again, you see that the benefit from the existing treatments is somewhat modest. People don’t go on living with this or getting the benefit which was many years. So we need to have better treatments. We need multiple lines of treatment like we did, for example, in colon cancer. But to get to that point, we need to discover new drugs, and clinical trials are important. Unfortunately, 5% of the patients in the United States go on clinical trials for pancreatic cancer. That’s a number that we really have to at least double or triple. And then, a clinical trial itself really is a way for the patient to have access to new unique novel therapies. And again, I talked about one promising drug, which is the KRAS targeting strategy. But there are now a number of other experimental treatments like vaccines, cell therapies and certainly other targets.

What are the challenges that we need to think about? Patient factors. Patients have to be aware of and understand clinical trials. They don’t. Because really, they come, they’re stunned by the diagnosis. They’re really very upset that they have that. It’s not a time that they can think of a clinical trial unless someone really helps them and gives them guidance. Because many of them will think it’s experimental treatment, placebo, et cetera, side effects, cost of it. These things have to be explained to the patients so they understand a clinical trial, what the value of it is. A lot of times, the doctors are busy, they don’t have time to talk about clinical trials. And that’s something which, as I said, we have to push ourselves to do these things. And also, we have to spend time to educate the patients on clinical trials. And that’s a big role for our nursing colleagues because we have all that ability to talk to patients and be part of the team to really achieve those goals. There’s always the logistical issue of sometimes patients have a long distance to go to really go into a clinical trial. They live 2 or 3 hours away, rural patients. Again, the cancer centers are trying to really overcome that kind of limitation. And sometimes, the patients do not get the molecular testing, which is really a prerequisite for going on a clinical trial.

So multidisciplinary supportive care. Yeah, I’m a very strong supporter of it. I think it really helps patients to tolerate the treatment and also helps patients, in my opinion, to live longer. So it’s really very important and it comes in multiple different ways that we can do that.

DR LOVE: So thanks so much, Philip. I don’t know if I ever told you. Zenocutuzumab is my favorite name of a drug. It’s got kind of a little bit of a flair.

Tomorrow morning, 6:00 AM, we’re going to talk about checkpoint inhibitors, immunotherapy. Come on back in this same room. Thanks so much to the faculty. Great job.