The patient that we&rsquo;re presented with is a 63-year-old gentleman who presents with the typical symptoms of pancreatic cancer. They&rsquo;ve had changes in their appetite and weight. They have weight loss and pain, and they also have jaundice. So, it&rsquo;s a very typical presentation for a pancreas cancer patient.

He presents to his primary physician who works him up. Common things being commonperhaps they&rsquo;re concerned about reflux, acid disease&mdash;but eventually, he works his way to imaging. In this instance, he undergoes an MRI that identifies a tumor in the pancreas. It&rsquo;s causing symptoms, it&rsquo;s causing obstruction, that&rsquo;s why he&rsquo;s jaundiced. So, that&rsquo;s where we have our diagnosis. Many times, a CAT scan will be performed. Sometimes a PET scan can be performed in that setting. He also has laboratory studies that are done that reveal abnormalities obviously in his bilirubin, his liver enzymes, and these are important when we start talking about our treatments because many of our treatments have to have good, pristine liver function. His primary physician also sends off for tumor markers, and these are elevated. His CA 19-9 is quite elevated at 12,000 U/mL, which is very concerning for advanced disease. His CEA is also elevated.

So, when we work folks up, again, symptoms and jaundice require further imaging that will probably require endoscopy and endoscopic ultrasound looking at the pancreas and determining whether there&rsquo;s a mass present. They&rsquo;ll go on to ERCP (endoscopic retrograde cholangiopancreatography) because this patient is jaundiced and a stent is needed to relieve the obstruction caused by the mass in the pancreas affecting his liver outflow. We need to get him stented and symptoms relieved, and then we can start moving toward discussion with regards to treatment.

The patient presentation is very typical for folks that are diagnosed with metastatic pancreatic cancer. They have pain, they have changes in their appetite, they have abdominal symptoms such as vomiting, nausea, early satiety, cramping, and diarrhea, and our patient also has jaundice. So, again, these are all very common side effects from the cancer. And we really have to do a good job of managing many of these comorbidities or consequences of the tumor in the pancreas.

For this individual, we really want to provide antiemetic supportdegassing agents, pain control, monitoring, making sure they&rsquo;re on good pancreas enzymes allowing them to maximize their intake, their nutrition, and then managing their bile ducts with stenting. This patient is very typical of a person that presents. And overall, his performance status is a 0 to 1, because he does have symptoms relating to his cancer. And so, the patient is one who typically presents in the clinic.

Unfortunately, the scans that were done reveal a mass in the pancreas. We&rsquo;re also informed that he had metastatic disease, and so we start thinking about palliative approaches to systemic chemotherapy.

Case Presentation for Metastatic Pancreatic Cancer

The diagnostic workup for patients with pancreatic cancer will start with how they present. So, for our patient, he presents with liver enzyme abnormality. His bilirubin must be greater than 3 mg/dL because he&rsquo;s jaundiced. We&rsquo;ll start with simple chemistrycomplete blood count&mdash;seeing whether or not he&rsquo;s anemic. Does he have leukocytosis in reaction to the tumor? And then, we&rsquo;ll move on to additional blood work that might include tumor marker, CEA, and CA 19-9.

Just a note on CA 19-9, it&rsquo;s not a great screening test. It depends on the patient having a Lewis antigen. If they don&rsquo;t have a Lewis antigen, they will not express CA 19-9. So, many times, we&rsquo;re left with the quandary of: &ldquo;You&rsquo;ve got a mass in the pancreas, lesions in the liver, but the CA 19-9 is normal.&rdquo; It&rsquo;s because the patient does not have a Lewis antigen, and so that&rsquo;s why their CA 19-9 can be a little confusing. It&rsquo;s not carcinoma, a known primary, it really is metastatic pancreatic cancer.

What other diagnostic studies are performed? Well, we move on to our imaging evaluations. We do a CAT scan ideally with IV and oral contrast. Sometimes you won&rsquo;t see the mass in the pancreas and you&rsquo;ll have to do a pancreas-dedicated CAT scan, which takes more slices through the pancreas and really delineates what is normal and what is abnormal in the pancreas. Many institutions will do MRIs; again, really getting a close look at the pancreas. And then, obviously, we&rsquo;re looking at the liver, we&rsquo;re looking at the lungs, and we&rsquo;re also trying to look at the peritoneum for metastases.

Other imaging studies are PET scans. I think PET scans are useful in the very beginning, especially when we&rsquo;re trying to find out if the patient is resectable and trying to find occult metastases. So, PET scans are useful in the diagnostic evaluation. It may not be so great in terms of restaging patients. Other diagnostic procedures are endoscopic ultrasounds, where our gastroenterologists get involved. They go down into the stomach, look at the pancreas, and are able to retrieve tissue. ERCPs are important for symptom relief and also to get some brushing. And then, we move on to other studies with more advanced evaluations, especially if we don&rsquo;t have a diagnosis or we can&rsquo;t get tissue. Ideally, if you do have a patient with metastatic liver disease, you go after a biopsy of a lesion in the liver. Those are most easily approachable from a percutaneous approach. And so, those are some of the diagnostic studies that we&rsquo;ll do in the very beginning.

So, an additional diagnostic evaluation is whether or not to do a laparoscopic evaluation, and that&rsquo;s really for patients who you&rsquo;re considering to resect or potentially you believe have curable disease. That&rsquo;s a great way for the surgeons to assess if there is a peritoneal disease that&rsquo;s not picked up on imaging and enables us to really, fully stage the patient. And obviously, if there is something that they detect, they can go in  and biopsy it.

Diagnostic Workup for Pancreatic Cancer

The importance of a multidisciplinary evaluation tumor board involves allowing us to formulate a treatment plan based on the diagnostic and staging information. So, for our tumor boards on Thursday afternoons, it&rsquo;s the medical oncologist, the radiation oncologist, the interventionalist, the gastroenterologist, the surgeons, and the pathologist who all meet and discuss cases.

The multidisciplinary tumor board is very helpful for deciding what patients can go on to surgery and how we will sequence our interventions, and having discussions about patients who may not be ready for surgery now because their tumor may be near an important artery or vessel. It&rsquo;s also important we talk about local advanced disease in which we use combined modality therapies, both radiation and chemotherapy. And it&rsquo;s also important when we are trying to treat metastatic patients. They may have certain situations where our interventionalist may have an opportunity to go after a solitary liver lesion, or a radiation oncologist may have an opportunity to treat the primary and provide patients symptom-relief. So, these discussions occur during the tumor board, and it&rsquo;s very important to have all the specialties involved.

The criteria for resection of pancreas cancer is that the tumor has to be localized. Unfortunately, there are not a lot of patients that fit into this stage. It&rsquo;s roughly 10%, 15%, maybe 20% of the patients, depending on how they are referred and what centers are treating them. The criteria are obviously, and especially in relation to our patient, that the patient cannot have metastatic disease. So, this individual is not eligible for surgery because of the lesions in the liver. You have to have non-metastatic disease.

Now remember where the pancreas is. Most of the tumors will show up in the head of the pancreas, and there are important vascular structures that run through that area, particularly the superior mesenteric artery and the celiac artery. So, the tumor cannot encase these important structures because it&rsquo;s very hard, or it&rsquo;s not meaningful for the surgeon to go in there and take it out. Even if he is able to take it out, the chances of recurrence are very high.

Very similarly, there are the venous structures, the portal vein, the superior mesenteric vein, and the confluence. In certain situations, we can give chemotherapy or even radiation, shrink some of the tumors away from that structure, and have a surgeon who is adept at performing the portal confluence reconstruction and that will enable the tumor to be resected. We do need to obviously reconstruct the veins, put in a graft, and then these folks actually can have very meaningful survival.

So, getting back to the eligibility, you can&rsquo;t have metastatic disease. You can&rsquo;t have involvement of some of the arteries, but there are opportunities with pretreatment, with chemotherapy, or even radiation, that enable these folks to achieve a resectable state, which is very important. It has to be coordinated through a multimodality clinic.

Multidisciplinary Assessment of Pancreatic Cancer

The prognosis for this specific patient is that we have treatments that are meaningful and helpful, something that we didn&rsquo;t have even 5 to 7 years ago. Obviously, the patient has stage 4 cancer, whether it be pancreas cancer, lung cancer, or colon cancer. It&rsquo;s an advanced setting and our treatments are really to palliate and prolong time.

So, the prognosis, based on it being stage 4, is a concern and can be considered poor. But we&rsquo;ve got to get over that nihilism of pancreas cancer in particular. We are still benefiting patients with our treatments. We are still getting patients to important anniversaries, birthdays, and births of grandchildren. These are very important events in the lives of our patients, and also in the survivors of their family. Their family members are very important events that still can be achieved by prolonging time and maintaining quality, even though the prognosis is poor.

For this patient, obviously, there is metastatic disease. And so, we start thinking of systemic treatments and chemotherapy, and that will help the patient. Our goals and our patients&rsquo; goals are to maintain and preserve quality of life. We want to maintain their dignity. We want to prolong time. We want to give them more time that they may not have had in prior eras when we didn&rsquo;t have as active chemotherapy. And then, there are patients&rsquo; concerns regarding side effects: &ldquo;What is the impact of the chemotherapy on my quality of life? Am I going to be sick in the bed without any quality of life, coming to the doctor every week, or am I going to be able to function, go to work, be able to go on vacation, and spend time with my family?&rdquo; These are all very important endpoints that patients have told us are important to them, and it&rsquo;s our responsibility to provide those outcomes.

The treatment options for this patientas we discussed, he does have metastatic disease, he is not a resection candidate&mdash;we need to treat the whole extent of the tumor burden. So, chemotherapy in this setting is appropriate. In 2017, chemotherapy involves 1 of 2 regimens. There is the Abraxane, or nab-paclitaxel, with gemcitabine combination. And then, there is the FOLFIRINOX regimen. Gemcitabine combined with Abraxane was shown to be superior to gemcitabine alone in terms of overall survival. The toxicities are known and are well-managed. FOLFIRINOX also has been shown to provide a survival advantage over gemcitabine alone. Remember that we&rsquo;re using full-dose 5-FU, full-dose leucovorin, and full-dose oxaliplatin and irinotecan. So, it may be a more intense regimen, but those are the 2 standards that are useful or that can be considered for our patient.

Treatment for Metastatic Pancreatic Cancer

The patient has a choice of gemcitabine/Abraxane versus FOLFIRINOX. Those are the 2 standard treatments available in the metastatic setting. How do you go about deciding which treatment is most appropriate for the patient? This really could be a dissertation, but I&rsquo;ll just try to summarize what&rsquo;s important. So, our patient has a good performance status. They are in their early 60s. They have a performance status of 1. We&rsquo;ve corrected their biliary function, meaning we put in a stent. They&rsquo;re less jaundiced; their liver function as improved.

You have to present to the patient that we have these 2 treatment options. Gemcitabine/Abraxane is given weekly. It does have side effectsthe typical myelosuppression, it does cause peripheral neuropathy. You do not necessarily have to put in a port. You don&rsquo;t have to wear a pump for 48 hours as you do with FOLFIRINOX. Gemcitabine/Abraxane was tested in the United States in the majority of the patients. It was tested in the community. So, the point is that it may be a more amenable combination to use for those patients who are not treated only at academic centers.

In contrast, FOLFIRINOX does require full doses of all the drugs includedoxaliplatin, irinotecan, bolus 5-FU, and leucovorin. So, it is a more intense treatment. Patients do have to wear the pump, they do have to have a portacath placed, and the schedule is every 2 weeks. But typically, patients do have to have an extra couple days after the treatment is given to recover. So, you think about it being every 2 weeks, but they can be out of work, for example, for up to 1 week. Giving a weekly combination of Abraxane/gemcitabine, patients may feel nausea for 1 or 2 days, but are hopefully back to work for the remainder of the week. And, certainly, they can be monitored more closely because the treatments are being given weekly as opposed to administering all the chemotherapy and waiting for the next 2 weeks to see how they do.

Other important considerations are whether folks need a growth factor. So, do you need Neupogen (filgrastim) with a weekly regimen or do you need Neulasta (pegfilgrastim) with FOLFIRINOX? That&rsquo;s also important when we talk about the cost of the treatments. Supportive care is different in FOLFIRINOX versus gemcitabine/Abraxane, and its supportive care cost can be three-fold as high. Additionally, cost is also important when you talk about gemcitabine/Abraxane versus FOLFIRINOX. Believe it or not, gemcitabine/Abraxane is about $3000 less a month than FOLFIRINOX, which many people would believe is less costly because all the drugs are generic. But, importantly, there is a higher need for supportive care.

In terms of outcome, there is an 11-month survival reported with the FOLFIRINOX regimen as opposed to an 8.7-month benefit with gemcitabine/Abraxane, and so patients will commonly ask: &ldquo;Which regimen will I get more time with?&rdquo; But you have to balance that again with the side effects. And if you go back to some of the trial results, you will also see that patients who were given gemcitabine/Abraxane had good performance status and very similar outcomes compared to the 11.7 months seen with FOLFIRINOX. So, they could achieve outcomes as long as 12.6 months. And so, one can argue that in good selective patientspatients with well-controlled symptoms&mdash;they can indeed reach the outcomes that are seen with FOLFIRINOX.

We discussed the treatment options with the patient, and we talked about the outcomes of the 2 trials and evaluated the 2 regimens. We talked about the toxicities. We talked about some of the cost and some of the logistics of therapy. Our patient needed to continue to be active. He could not be in the bed or sidelined for long periods of time. He did have a good performance status, an ECOG of 1. And so, all of those factors helped usthe patient and the providers. It&rsquo;s never just the providers that make that decision, you need the patient&rsquo;s input. But at the end of the day, it was the patient&rsquo;s decision to go on to gemcitabine/Abraxane. The patient received 2 months of treatment&mdash;2 cycles&mdash;and CAT scans were performed, which revealed tumor response. The patient went on for an additional 6 months of therapy, and, again, had stable disease. So, they clearly benefited. Their quality of life was maintained and they were able to manage the toxicities&mdash;neutropenia, thrombocytopenia, and neuropathy. All of these symptoms were managed and the patient benefited as he responded, and also had stable disease.

Choosing Upfront Therapy for Metastatic Pancreatic Cancer

The toxicity profiles also help us decide which regimen to choose. That&rsquo;s especially true in the community. So, for example, gemcitabine/Abraxane does have mild suppressions, neutropenia, thrombocytopenia, and then the neuropathy. These are symptoms that are well-managed either at a community center or an academic center. In comparison, FOLFIRINOX, if it is not given at the right dose modifications, for example, or if the patients aren&rsquo;t followed closelyespecially in pancreas cancer where, again, the patients start off with a compromised performance status&mdash;patients can really run into nausea, vomiting, diarrhea, dehydration, and neutropenia, which are very significant side effects. They really have to be managed very closely, and they can be catastrophic.

And then, you also have to recognize that pancreas cancer patients, their ability to bounce back and their reserve is compromised. So, if you knock a patient with FOLFIRINOX off their feet, they go to the hospital. Their ability to bounce back and get additional treatment is compromised. And so, you may have one shot to get this right.

With gemcitabine/Abraxane, I think the side effects are fairly well-managed. And, again, the regimen was evaluated in the community in the majority of the patients enrolled. So, we know that this is applicable or very useful for patients that we see in the clinic every day. It&rsquo;s very important in how we select, especially when we&rsquo;re out in the community.

With the treatment combination of gemcitabine and Abraxane, in patients with good performance statusPS 1s, and you can actually use in PS 2s&mdash;patients do well. Patients can tolerate the weekly schedule. We may need to make some dose adjustments, especially on day 8 or even day 15. We may have to alter the schedule, implement the week of rest sooner. We may have to change from a 3-week on/1-week off to a 2-week on/1-week off schedule. But these are some of the adjustments that can be made. We can make dose reductions in the Abraxane from the 125 mg/m

, if that&rsquo;s needed. And then, again, patients do fairly well. They do experience fatigue, which is typical of chemotherapy, but it could also be characteristic of pancreatic cancer.

The myelosuppression is well-managed. We can implement growth factors if we need to, either Neupogen or Neulasta. And then, there&rsquo;s the neuropathy. It&rsquo;s important to recognize that 17% of patients do get grade 3 neuropathy, which is characteristic of taxanes. The important consideration here is that patients, if you hold the Abraxane for up to 29 days and just give gemcitabine, the neuropathy will reduce to a level of 1 after that period, and about 44% of patients can go back on to treatment. So, these are all some of the management considerations when patients are undergoing treatment.

Obviously, you&rsquo;re still focusing on what we talked about earlier: the need to maintain nutrition, maintain pain control, and really manage the bile duct stent, making sure it&rsquo;s not occluded. Sometimes we&rsquo;ll have to send in our gastroenterologist to clear out the stent. It does not always mean that the tumor is progressing into the stent, it just may be clogged with debris. And so, these are ongoing issuesDVT considerations, prophylaxis, all of these are the ongoing management that&rsquo;s needed in treating patients with pancreatic cancer.

Managing Toxicities of Therapy for Pancreatic Cancer

The patient begins to show signs and symptoms that he had very early on before we began chemotherapy and before he benefited. We want to assess and restage the patient. Typically, we will use CAT scans with IV contrast and oral contrast. Sometimes we&rsquo;ll use a PET scan to see the extent of whether the tumor has grown. Sometimes we&rsquo;ll use CA 19-9. That&rsquo;ll tell us if it&rsquo;s increasing, that maybe we want to perform restaging studies earlier. We don&rsquo;t want to make treatment decisions, make changes in our chemotherapy based on CA 19-9 alone. That is not sufficient, especially when you think about, again, this issue of managing the jaundice, the biliary stent. Because, CA 19-9 can falsely elevate in that situation.

Our patient presents with an increase in fatigue, changes in his appetite, pain, and the jaundice, and so we&rsquo;re quite concerned about having tumor progression. And as we said, he goes on to have imaging studies that confirm that the liver lesions are progressing, and the mass and the pancreas is also growing. And so, now we have to think about changing our treatment strategy, our treatment.

In this setting, in the second-line, we have several options. Remember, we gave this patient gemcitabine/Abraxane. We know that when patients are treated with gemcitabine-based therapy in the frontline, we can go on to 5-FU-based therapy, and this is following the NCCN guidelines. So, our patient was treated with gemcitabine/Abraxane, and now we can go to 5-FU-based treatments. Now, there is an FDA-approved regimen that is available for our patients. This is a regimen using continuous infusion 5-FU, and combining it with a novel drug, ONIVYDE, or MM-398. It is a nanoparticle irinotecan liposome injection. This was studied in a trial, the NAPOLI-1 study, and when combined with 5-FU continuous infusion, and leucovorin, the drug and the combination showed a 2-month survival advantage. And so, it&rsquo;s very important for people to realize that this drug is FDA-approved for gemcitabine-refractory patients. So, our objective continues to be to prolong time, maintain quality of life, and manage very closely the side effects from our intervention, but also the side effects from pancreas cancer itself. We will continue on to this second-line treatment.

If we had chosen FOLFIRINOX in the frontline setting, what we can use now in the second line is somewhat limited. We could try to give gemcitabine/Abraxane, but FOLFIRINOX carries with it oxaliplatin, which carries with it neuropathy, which is not necessarily reversible. And so, now you try to treat with another combination that has neuropathy associated with it. It&rsquo;s very hard to go from FOLFIRINOX to gemcitabine/Abraxane. You would not use FOLFIRINOX in the frontline setting and then go to nanoparticle irinotecan liposome, or ONIVYDE. That doesn&rsquo;t make a lot of sense.

So, that&rsquo;s why when we talked about the treatment options for our patient in the frontline, we&rsquo;re thinking about our treatment spectrum. What are we going to use if and when the patient&rsquo;s tumors grow? What do we use in the second line? The gemcitabine/5-FU-based sequence, gemcitabine/Abraxane, has a survival advantage and is FDA approved. ONIVYDE, or the nanoparticle irinotecan liposome regimen, again, has survival benefit and is FDA approved. That&rsquo;s why that sequence is so meaningful for our patients.

Progression of Metastatic Pancreatic Cancer

The patient progresses and has symptoms that are characteristic of when they initially presentedchanges in their appetite, weight loss, pain, and jaundice. We really have to be active, again, reengaging the patient and managing the symptoms. We have to perhaps intensify our efforts to have them increase their appetite. So, appetite stimulants are very important. Your Megace, your Marinol, some of these agents that are helpful in stimulating their appetite. We have to make sure that it&rsquo;s not just nausea that&rsquo;s causing their appetite to be diminished. We have to really make sure that they&rsquo;re taking their antiemetics and that they&rsquo;re using them on an appropriate schedule, and that it&rsquo;s meaningful.

We also have to review some of what they&rsquo;re eating. We have to make sure that they are getting good, meaningful nutrients. Starches are great. Proteins, meat, fish, and chicken are all still very important. Obviously, they&rsquo;re managing their glucose levels. We may want to be a little loose in that regard, letting the glucose levels ride a little bit above more stringent levels. And so, again, we have to reengage the patient, make sure that they&rsquo;re continuing with the management recommendations that we made in the very beginning. This patient also should be reevaluated in regards to, is the biliary stent functioning? The patient still has a performance status of 1. We want to make sure that patients with good performance status, 0 and 1&rsquo;s, receive second-line treatment. In this instance, it&rsquo;s appropriate for them to receive ONIVYDE, the nanoparticle liposomal irinotecan. The trial looked at patients with ECOG performance statuses of 0 and 1.

I think it&rsquo;s very important in today&rsquo;s practice that we get supportive care. Oncologists are very, very busy in the community managing several different diseases and several different new drugs, all with very broad considerations. So, palliative medicine in this instance has become very important. They enable us to really focus on what the patient is experiencing and how symptoms can be managed. There&rsquo;s also psychosocial support, which is critical for these patients, many of whom have depression, and so palliative medicine is very helpful. And just having good primary medical carenot to wall off the primary care doctor who has been with the patient for years taking care of them before they even developed cancer&mdash;having them remain engaged is very important.

We consider the treatment options for this patient using the standards: gemcitabine and Abraxane and FOLFIRINOX. But we really have to consider whether this patient had an opportunity to participate in research and in experimental trials. Our treatments are more active than they were years ago, but we still have a lot of work to do. And so, when we were considering what options are available for our patient with advanced disease, we really have to go back and think about trying to find them an experimental trial so we can advance the field. That&rsquo;s very important.

Our patient has progressed on second-line treatment. Now we&rsquo;ve run out of treatment options, and that&rsquo;s another opportunity for patients to participate in experimental trials such as phase I studies. They&rsquo;re dedicated to pancreas cancer disease and to pancreas cancer patients. So, in that situation, we can have an opportunity for research and patients can have an opportunity to access drugs that may provide benefit in the future.

Other approaches are some of the genetic, molecular analyses work that can be done. Patients may have a specific mutation that may be actionable and targetable. And in that instance, there&rsquo;s the great work done with PanCAN and the KnowYourTumor program where they actually perform molecular analyses of the tumor, try to identify a targetable mutation, and, again, hopefully allow the patient to continue to benefit from intervention and prolong time.

Chemotherapy for Metastatic Pancreatic Cancer