So, this is a fairly typical case of a patient with pancreatic cancer66 years old. She presents actually with jaundice and some abdominal discomfort. She gets worked up and found to have, on CT, a pancreas mass, and the mass is big enough that it has now pinched her bile duct. And so, she&rsquo;s jaundiced, and her labs show that. Her cancer marker is elevated and so she goes to GI. She has an upper endoscopy, an ERCP (endoscopic retrograde cholangiopancreatography) stent is placed, and brushings are taken. At that point, she is diagnosed with pancreatic cancer.

Now, typical imaging is doneusually CT and endoscopic ultrasound is standard&mdash;and she&rsquo;s found that maybe she might be surgically resectable. And so, she heads off to the operating room, and the findings at surgery, unfortunately, are that she has metastatic disease to her liver at that point. And so, the surgeon appropriately opts to not do an operation, sews her back up, and sends her to the medical oncologist.

She shows up a few weeks later, and about a month later, initiates treatment with systemic chemotherapy. And the choice that was made was nab-paclitaxel, or Abraxane, and gemcitabine combination, a 2-drug combination; that gets initiated. She tolerates it pretty well. She has some mild nausea, which is pretty easy to control, and she has some fatigue that is typical of the cancer and the chemotherapy. But she also has a little bit of neutropenia, which is managed through our usual routes, sometimes using growth factor support. She tolerates it pretty well, in general, and undergoes repeat scanning a month or so later. And she actually has a really nice response. Liver lesions are no longer visible and the pancreas mass remains fairly stable. She continues on treatment for a little while longer and eventually develops a complication of some diabetes. She gets admitted to the hospital for that. Not an uncommon problem that we see when we&rsquo;re beating on people&rsquo;s pancreases, with chemotherapy, and all of that for them to get some diabetes, lose glucose control. So, in that evaluation, she&rsquo;s also found to have some progression of disease.

And so, new liver lesions, new-onset diabetes, it&rsquo;s time to change therapy. And nowadays, of course, we have a variety of choices in second-line therapy. But because of this woman&rsquo;s ageshe&rsquo;s under the age of 70, good performance status still&mdash;the doctor decides to give her full monty chemotherapy of the combination regimen of FOLFIRINOX in the second-line setting. And she&rsquo;s off that treatment now.

So, this is a fairly typical patient presenting with pancreatic cancer. She has already got symptomsjaundice, probably some pain, and doesn&rsquo;t feel right. And this cancer, almost in everybody, brings them down a rung or two on the performance status tier. This patient is no different. Also, being 66, it&rsquo;s important to recognize that fairly aggressive chemotherapy such as FOLFIRINOX may not be all that well-tolerated and may be difficult to get into her. And so, I put those pieces of the puzzle together and say that this is a good case for gemcitabine/nab-paclitaxel frontline therapy.

You want to ask some other deeper questions, too, about a patient. Lives alone or not? How much support does the patient have? Really, how well are they? What are the other comorbidities? All of that factors into a decision as to how one picks what you&rsquo;re going to use in frontline therapy.

Pancreas cancer&rsquo;s terrible. The problem with this disease is it has a very short timeline in terms of overall survival. We are doing better. If a patient really asked and wanted me to pin this down, under 1 year is typical survival. There are a few patients who make it longer than a year with metastatic pancreas cancer. And that&rsquo;s really coming on the backs of successful first-line, and now second-line, chemotherapy. So, her overall prognosis is not good. There are a few lucky folksthey&rsquo;re what we call &ldquo;the tail on the curve&rdquo;&mdash;but there are some on the other end that really never respond to treatment and don&rsquo;t do well at all.

Diagnosis and Treatment of Metastatic Pancreatic Cancer

We&rsquo;ve got choices now for managing frontline metastatic pancreas cancer, and so it really falls on us to work with our patients to understand what the best, say, frontline therapy is. And when I approach this, I think about a 3-drug cocktail (the FOLFIRINOX regimen) or a 2-drug cocktail (the nab-paclitaxel/gemcitabine regimen). We have to remember that they&rsquo;re not very different in how well they work, but they are very different in how well they&rsquo;re tolerated. And so, there tends to be this drive to say, &ldquo;Well, in a very good performance status patient with a lot of support, I&rsquo;m going to go with the 3-drug regimen first because I can.&rdquo; We tend to favor that. But I do really think we have to have a good discussion with our patients. What is their level of support? How will they do with an infusion Mediport pump at home? Neuropathy, the oxaliplatin neuropathy, is it immediate and significant? The nab-paclitaxel neuropathy is later and cumulative and fades. So, you want to make that decision.

I think it&rsquo;s even harder in a case like this, where it&rsquo;s localized disease, where you think you might maybe just convert a patient to resectability. Now, we have to remember, in our case, they found liver metastases, so we&rsquo;re probably not going to go to surgery. But there are a lot of times of locally advanced pancreas cancers where we still cross our fingers, and if we get a good enough response, we might take them to surgery. And here, we tend to want to go to 3-drug cocktails. But quite honestly, the 2-drug cocktail performs very nicely in that setting, too. So, it&rsquo;s working with your patient, understanding what their support is, what they&rsquo;re willing to put up with, and making your best clinical judgment.

So, when a brand new pancreas cancer patient comes to see us in the clinic and has metastatic diseaseand we&rsquo;re trying to really set expectations, what are our goals, how are we going to go forward, what are our expectations of treatment&mdash;I really do start with some language around the severity of the disease, that this is a serious cancer, that it is life-threatening. Most of them honestly have done a little clicking already so they know something about what they&rsquo;re facing. But I just want to level set with them where we are.

We want to manage their symptoms, tell them we&rsquo;re going to take care of them forever, and make sure they&rsquo;re doing the best they can. And then, we turn to the positive side of this, and that is, we&rsquo;ve got new treatments. Those treatments, by themselves, are not curative. I often will use language of, &ldquo;The only way we know to cure this disease is through surgery,&rdquo; and then say, &ldquo;But you&rsquo;ve got too many spots for surgery.&rdquo; So, I don&rsquo;t actually say, &ldquo;You can&rsquo;t be cured,&rdquo; but I let them figure it out on their own. Maybe I&rsquo;m just a chicken and should just come right out and say it. But they understand what I mean by that.

And then, with that, we talk about survival, we talk about the positives and the impact of treatment. I usually dive right in to discussing the regimens that are used: that the 2 main regimens are the 3-drug regimen (FOLFIRINOX) and the 2-drug regimen (nab-paclitaxel/gemcitabine). And I usually start with the 3-drug regimen. I describe what a Mediport is, how one is put in, why it&rsquo;s a nice thing to have. I then describe the regimen in some detailhow much time, how often they come, what the side effects are&mdash;and this takes some time, and I really feel that it&rsquo;s important for us to take this time. Different practices do this differently. Sometimes doctor practices will have their nurse practitioner or their nursing core do the describing of that. But I actually think it&rsquo;s really important for the doctor to sit down with a patient and try and describe what it&rsquo;s going to be like, how they&rsquo;re going to feel&mdash;not just the 2 days on the treatment, but a week later&mdash;and how many good days, how many bad. Because that patient is having to make some decisions about their life. If they&rsquo;re working, for example, can they continue to work? Are they going to need a ride back-and-forth from treatment? And they&rsquo;re doing all of that math while we&rsquo;re describing this neuropathy and that nausea, etc.

We also have to remember that almost everything we tell a patient, particularly on that first visit, they forget or they didn&rsquo;t hear. And so, if there&rsquo;s not somebody sitting right next to them writing everything down or they&rsquo;re recording you on their iPhone, then make sure that they get written information, tell them you&rsquo;re going to discuss it again with them, in detail, because they will have forgotten a lot of the detail that you think they&rsquo;ve gotten.

So, first I describe the 3-drug regimen in some detail. And then I say, &ldquo;Or behind curtain number 2, we have a 2-drug cocktail.&rdquo; And then I actually go into not only the specifics of the 2-drug regimen, but how they&rsquo;re different. Why would anybody pick 3 versus 2? And why do we think that there&rsquo;s a little bit of superiority to the 3-drug regimen than to the 2? I describe actually the clinical trials, how one was done versus how the other was done, saying that that&rsquo;s really not quite a fair fight when we do comparisons. And I essentially tell patients that there&rsquo;s not much difference, clinically, in outcome between the 2-drug regimen and the 3-drug regimen.

If I have a patient where they&rsquo;re very symptomatic, a lot of tumor burden, hurting from it, and they&rsquo;re young enough and fit enough, that&rsquo;s a patient I&rsquo;ll try the 3-drug regimen in because I want every percentage point of response I can get in that patient. But for me, and almost everybody else, I&rsquo;ll tend to use the 2-drug recipe as initial lines of therapy, mainly because I find the FOLFIRINOX regimen, for all the machismo out there, difficult to give to patients over a long haul.

So, in summary, I spend the time, I describe the 2 regimens in detail and so that they have a pretty clear understanding. And then, of course, what happens is the patient says, &ldquo;Well, what would you do?&rdquo; And I&rsquo;m like, &ldquo;Oh God, I don&rsquo;t know what I would do.&rdquo; I then do a gut check and think, what would I do if I was sitting over there? And then I make the recommendation to the patient going forward.

Choosing Chemotherapy for Pancreatic Cancer

We prescribe a whole lot of chemotherapy, but most of us have never taken it or taken it home with us, for example. And so, we have this idealized vision of what it&rsquo;s like, and we mostly see that patient like 2 weeks later after they&rsquo;ve recovered, so we&rsquo;re not seeing them at their worst, typically. I think that&rsquo;s a great oncologic trick. So, as best we can do, we need to describe to patients how they&rsquo;re going to feel.

For me, the gemcitabine/Abraxane is really a pretty easy regimen to describe how one feels cause it&rsquo;s quite predictable in terms of the acute side effects. They are very manageable, the nausea is minimal. Most people, I say, can drive themselves back and forth to get the treatment. I talk about cumulative side effects and the need for blood counts. And then I talk about the different regimens, different recipes: the 3-weeks-on/1-week-off, the every-other-week, and the 2-weeks-on/1-week-off. Because patients are setting in their calendars these regimens, and a lot of times we look up, &ldquo;Okay, it&rsquo;s 3 weeks on, 1 week off.&rdquo; Well, if everything in that patient&rsquo;s life is set for that and then on week 3 they can&rsquo;t get the treatment cause their counts are too low, their whole world is now in turmoil. So, giving them a sense that this is flexible and we change on the fly, I think is really important for that regimen.

I also emphasize that we&rsquo;re going to do this for a couple of months. We&rsquo;re going to follow your marker, we&rsquo;re going to follow you, and we&rsquo;re going to then do repeat scans and see if it&rsquo;s working or not. Depending on how you&rsquo;re doing and how the scans are doing, we&rsquo;ll make a decision about going forward beyond that.

The FOLFIRINOX is a little bit more time-consuming and challenging to describe because you have the mechanics of the treatment itself: half a day or more in the infusion chair, getting the oxaliplatin and the irinotecanthe premeds that are required&mdash;taking home an infusion pump for 46 hours, and the post medications that are really required to keep people&rsquo;s nausea down. And then, the fatigue that comes, what I call the &ldquo;disconnect day.&rdquo; So, that second day, third day of treatment, patients, I tell them the couch looks really good, feels really good, you can get around, but you don&rsquo;t really want to. Eating&rsquo;s kind of off. Not so much you&rsquo;re throwing up, but you just don&rsquo;t want to eat for a few days. And then you start to feel better. A week later is when the diarrhea hits. Everybody&rsquo;s thinking diarrhea, but you actually are constipated for the first 3 or 4 days because of the antinausea meds. Then, diarrhea a week later, if you&rsquo;re going to get it, and then you worry about low blood counts, too.

It&rsquo;s one of the few regimens, as a GI oncologist, in which I routinely give growth factor. In most patients, that means bringing them on day 3 to have the growth factor administered. Different doctors in different offices manage that in different ways, but we routinely add growth factor in. We, too, plan for about 4 rounds of that. So, we see them every 2 weeks, we check their labs, we adjust accordingly to how much their side effects were, we adjust the doses, and then, again, watch markers, watch patients, and watch scans. And depending on how they&rsquo;re doing, set off for more treatment with that. It&rsquo;s very hard to give much more than about 8 rounds of FOLFIRINOX total, and I tell that to patients up front. We have some specific goals we&rsquo;re setting: we want to get the cancer back; we want to drive it back. With gemcitabine/Abraxane, it&rsquo;s much more of an open-ended scenario. If this is going well, we&rsquo;ll just keep it going. With FOLFIRINOX, to me, it limits setting. I&rsquo;ve got about 8 cycles I can give.

We have to remember the initial clinical trials were different. So, the FOLFIRINOX clinical trial done in academic centers, PS 0 and 1, had an age cap. Not that these people were marathon runners, but they were the best of the best and they were managed in academic centers where they have disease-specific teams. The gemcitabine/nab-paclitaxel clinical trial was a community-based study. You could have a performance status all the way down to 2, and there were plenty of patients over the age of 70 in that clinical trial. I always think of that as more real-world pancreas cancer. Pancreas cancer is different in my center than in our community centers, for example. The patients who can make it to me typically have a better PS, typically are younger, etc. Whereas the patients who make it to their community doctors are a little older, have more comorbidity. So, anyway, the gemcitabine/nab-paclitaxel trial is more real world in that. And when they look at those various groups, if you pull out the high performancestatus patients from the gemcitabine/nab-paclitaxel and the FOLFIRINOX clinical trial, those 2 groups perform very similarly.

When you look at the overall clinical trial, there&rsquo;s some debate about whether the gemcitabine/nab-paclitaxel is weighted differently because of the lower performance status and the higher age group. I believe that in clinic and in practice. That&rsquo;s why I say I don&rsquo;t think there&rsquo;s a lot of difference patient-for-patient between the 2 regimens.

Patient Communication on Therapy for Pancreatic Cancer

The patient in our case, 66 years of age, she&rsquo;s feeling her cancer. She has got pain, she has obviously got jaundice. We&rsquo;ve got to fix our jaundice, right? Any of our regimens, whether it&rsquo;s FOLFIRINOX or nab-paclitaxel/gemcitabine, we have to get that bilirubin down to safely administer it. So, on some level, we&rsquo;re waiting on that. She does have pain. This would be a good case for maybe a nerve block, too, as you&rsquo;re thinking about waiting on these patients to recover their jaundice.

But her performance status is falling. She has lost weight because of all of this. You want to reverse that; you want her feeling better. She doesn&rsquo;t have a huge tumor burden. It&rsquo;s not like she&rsquo;s full of cancer. She has actually got relatively small liver metastases, relatively small primary metastases. And so, our goal here is reversing her cancer. You&rsquo;ve got 2 tools that are very similar. I always worry about patients like this, in giving them 3-drug cocktail FOLFIRINOX, of actually making their performance status worse. You want to make them eat better, that they feel better, that they gain weight. So, in a patient where I&rsquo;m in for the long haul with systemic therapy, I like the 2-drug cocktail because it&rsquo;s more likely, in my opinion, to improve their overall performance status because the chemotherapy doesn&rsquo;t beat them up as much. In this patient, her marginal performance status, or falling performance status, loss of weight, pain, etc, make me lean more toward the 2-drug regimen than the 3-drug regimen.

The 2-drug cocktail, the gemcitabine/nab-paclitaxel, I mentioned is a pretty easy regimen to give. The standard dose of 125 mg/m

of nab-paclitaxel and 1 g/m of the gemcitabine is doable in almost everybody. I always wonder why anybody would give single-agent gemcitabine anymore because the 2-drug regimen is more effective and essentially just as easy to give. The big barriers you run into with the 3-weeks-on/1 week off schedule is myelosuppression. Yes, there&rsquo;s minor nausea that&rsquo;s pretty easy to cover. You don&rsquo;t even need big gun antiemetics for it though. There is fatigue, as is common with most chemotherapies, but it&rsquo;s not bad. And then, you have some of the rare side effects, allergic reactions and things like that. Hair loss, probably the biggest thing that upsets patients, does clearly happen with both regimens, but probably more with the nab-paclitaxel.

My biggest struggle with the regimen, honestly, is counts. And getting those 3 weeks in a row at full doses in Washington, DC, in Georgetown, seems hard. It&rsquo;s not uncommon that we&rsquo;ll have to hold that third week. And everybody has different strategies for managing that. I think a very popular strategy is keep the doses full and go to every other week, which is nice on your patients as well. But I will tell you, I set out with a 3-weeks-on/1-week-off schedule and see how they do. Then, I tell patients right from the beginning that this may change over time, depending on how they do, partly, particularly in this patient, because I want her symptoms to improve. So, I don&rsquo;t want to be too kind, too gentle up front. I want the drugs to work, I want to get them. But that&rsquo;s more or less how I manage it. And I will typically see patients at least every other week when they&rsquo;re on that. So, I see them at the beginning of the cycle and on week 3, until I really know they&rsquo;re on a nice plateau. I then start seeing them only about once every 4 weeks.

The patient that presents had diarrhea. Why did she get diarrhea? And one of the things that&rsquo;s a very common thread, that we often miss in clinic, is malabsorption. So, when you have pancreas cancer, particularly with a blocked bile duct or if we&rsquo;ve radiated these people or operated on these people, their pancreases are not making enough enzymes to absorb fats and proteins. This is one you ask the spouse: are they passing a lot of gas? Is it pretty stinky? The spouse is over there going like this, that if you take a good history, you can find malabsorption. And so, we can fix malabsorption through the enzyme replacement. Look for this in a supportive care setting for our patients. We watch their sugars because these are people that can get some adult onset diabetes because of what we do to their pancreas during all of this treatment.

Pain management is critical in this world, and we often forget nerve blocks. They&rsquo;re relatively simple to do. Our IR guys and GI guys like doing them. And so, we need to make sure we use our allied professionals to help with overall symptom management. And then, I would say nutrition support is critical. These people are struggling to keep their weight. They have the malabsorption issue; they might have diabetes. So, bringing in nutrition support is really, really important as well.

I encourage our patients to keep moving. We really want physical activity as much as possible. Keep their heads up, keep smiling, have a plane ticket. Really address their social/emotional needs because what I think we do too often as oncologists is we pin our patients down to our clinics: &ldquo;We want you on time and precise, and we&rsquo;re never going to miss a treatment,&rdquo; etc. That&rsquo;s really not true. We need our patients out there living. The reason we&rsquo;re working on their symptoms and the reason we&rsquo;re treating their cancers is so they can keep living, and so we need to encourage them to do that as well.

Managing Symptoms and Side Effects in Pancreatic Cancer

If your practice is like mine, you&rsquo;re watching patients pretty closely. You&rsquo;re watching markers, you&rsquo;re doing scans every now and then, and eventually 6 to 8 months into first-line therapy, almost everybody&rsquo;s cancer will start to grow. And so, we&rsquo;re looking for this and we find it. When patients progress, we have now a bunch of second-line choices. Now, if you started with gemcitabine/Abraxane or gemcitabine/nab-paclitaxel in frontline therapy, the way I think about it is I want to go to fluoropyrimidine-based therapy second-line. And we&rsquo;ve got fluoropyrimidine with liposomal irinotecan, a proven second-line regimen. We&rsquo;ve got conflicting data with fluoropyrimidine/oxaliplatin. We&rsquo;ve got 1 positive clinical trial, 1 negative clinical trial. And so, I&rsquo;ve actually shifted some of my enthusiasm from &ldquo;Everybody&rsquo;s got to get a FOLFOX&rdquo; to &ldquo;Everybody&rsquo;s got to get a little FOLFIRI&rdquo; and using more irinotecan-based. But you can do it. There are trials that show you can do it. You can give FOLFIRINOX in the second-line.

No one gives FOLFIRINOX full dose. No one does. We all drop the bolus, we all modify the doses or irinotecan, etc. So, the on-label regimens for FOLFIRINOX are not used practically. When you come to second-line, you also have to be aware of that, modify your doses, and watch your patient closely. I&rsquo;ve got a patient right now who&rsquo;s getting second-line FOLFIRINOX after a frontline gemcitabine/nab-paclitaxel. She did very poorly after 4 cycles, but her cancer responded very nicely. So, we&rsquo;ve essentially gotten her cancer to back off, and now we are resting her with a maintenance approach in the second-line.

In colon cancer, in my world and many other cancers, we, right from the beginning, think about all the different treatments we&rsquo;re going to give this patient. And we&rsquo;re even telling patients that, &ldquo;You&rsquo;re going to get all these drugs and it&rsquo;s just, we&rsquo;re going to play a long chess game and we&rsquo;re going to move them here and there.&rdquo; In pancreas cancer, this is a new idea for us because our concept with these patients is just keep you alive, get you off the ledge as fast as we can and try and keep you therekind of hold on. Well, now we can actually think about lines of therapy in sequence because more and more patients are benefiting from frontline and second-line. We have more and more tools. And so, at least in some patients, particularly our case&mdash;low tumor burden, gonna be around through second-line therapy&mdash;this is a patient where you think about sequential therapy right from the beginning.

And so, that does influence our decision making. The way I think about it is, you want to play a gemcitabine-based regimen, and you want to play a fluoropyrimidine-based regimen in that patient. You want to make sure you get both of them in at some point along the way. And beyond when and how, I leave that up to the doctor, the situation, the patient in front of you. But part of our challenge is to try and get both of those in so we can get the best survival.

So, this patient has had gemcitabine/nab-paclitaxel, she has now had FOLFIRINOX and has progression of disease, and what next? Well, first, is she a candidate for more treatment? At this point, it&rsquo;s unusual to see somebody doing well, but that happens; it does happen. The reality is, we don&rsquo;t have anything routine or standard to give her at this point. Having had FOLFIRINOX, I wouldn&rsquo;t then try the liposomal irinotecan compound in third-line. I don&rsquo;t think that&rsquo;s likely to work any better necessarily than your FOLFIRINOX, and it has some toxicity, so I probably wouldn&rsquo;t go there.

In our shop, this patient would probably go on to clinical trials. We are looking at more and more new therapies in this space. So, if the patient has a good performance status, is doing okay, what I would recommend is doing a new biopsy on that patient, sending that biopsy for broad molecular profile and see if that patient is eligible for anything in the NCI-MATCH clinical trial or the ASCO-TAPER clinical trial or other studies that are out there.

Sequential Therapy for Metastatic Pancreatic Cancer

Diagnosis and Treatment of Metastatic Pancreatic Cancer

Choosing Chemotherapy for Pancreatic Cancer

Patient Communication on Therapy for Pancreatic Cancer

Managing Symptoms and Side Effects in Pancreatic Cancer

Relapsed or Refractory Metastatic Pancreatic Cancer