Marshall Explains Recent Trial Data in Terms of the Evolving Landscape of Pancreatic Cancer

John Marshall, MD

John Marshall, MD

During aTargeted Oncologycase-based peer perspectives program, John Marshall, MD, reviewed his clinical considerations for the management of pancreatic cancer. Marshall, chief of the Division of Hematology/Oncology, Medstar Georgetown University Hospital, and director of the Ruesch Center for the Cure of GI Cancers, Washington, DC, discussed his treatment options and other factors that go into his decision making with the group during the meeting based on 2 case scenarios of patients with pancreatic adenocarcinoma.

Case 1

April 2015

A 66-year-old female presented to her gastroenterologist with jaundice, weight loss, upper right quadrant abdominal pain, and diarrhea. She continued to carry out normal activity but reported requiring rest on most days. Her carbohydrate antigen (CA)-19 was 2296 U/mL.

Abdominal CT findings showed an expansive lesion measuring 39 x 26 mm between the pancreas and inferior vena cava, below the portal vein; enlarged para-aortic lymph nodes; and stenosis of the common bile duct. An endoscopic retrograde cholangiopancreatography was performed, and the patient was referred for surgery.

An explorative laparotomy revealed an inoperable mass due to local vascular infiltration and liver metastasis. From the pathophysiology, she was diagnosed with pancreatic adenocarcinoma; stage T4N1M1.

What is the prognosis of this patient?

The prognosis is dismal, but this is not actually what you are going to tell your patient.

What factors would guide the choice between front-line options nab-paclitaxel (Abraxane) and the chemotherapy regimenleucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX)?

FOLFIRINOX is a regimen that is a 2-day recipe of 3 drugs. It is fairly toxic and usually requires growth factor support. However, it does have a good response rate relative to what we had before. Gemcitabine plus nab-paclitaxel is a 2-drug cocktail. It is pretty easy to give everyone and most people can handle it. However, it has a lower response rate. The decision should be based on response and toxicity.

Do you consider opportunities for sequencing therapy when deciding on upfront treatment?

There are 5 drugs currently in play, and you probably want to get them all in, if you can. One very interesting phenomenon that I've come to recognize is that if you compare our shop to the shop at the Washington Hospital Center, we have a very different patient population. Our patient population tends to bring in journal articles and are very informed, whereas the other center has a 30% no-show rate at the clinic. Now, the Washington Hospital Center is trying to educate and get more support for those people.

When we talk about second- and third-line options with our colleagues at the Washington Hospital Center, they say that they are never able to get their patients that far along before they are too sick and their cancer gets too far. Whereas, in our practice, we have second- and third-line clinical trials because our patient population finds the cancer a little earlier and tends to have more support. These patients need a lot of help and assessing them for sequential therapy is important.

How do you communicate with your patients regarding the goals of treatment?

If this 66-year-old patient decided not to have treatment, she would have 2 to 6 months. If she decided to go through with treatment, she would have 9 to 12 months. We sometimes tease these patients and tell them 12 to 18 months. It is still bad, but the difference of a few months versus maybe a year seems a lot better. And there is a tail on the curve for these patients.

When you have a patient who comes in to your clinic, you should go into the room with 1 of 2 strategies. One strategy is to go in and educate your patients. You tell them how much you know about the disease and the different choices. You can set them up to pick, and then they tend to respond with: what would you do? Then you make the decision. On the other hand, you can go into a room and already know what you are going to give that patient. Then, you would need to sell that 1 recipe to the patient. But you've made a decision before you even go into the room.

May 2015

The patient was started on gemcitabine plus albumin-bound nab-paclitaxel. She complained of mild nausea and moderate fatigue for the first 4 weeks of therapy that was managed with antiemetic therapy. Neutropenia was also managed.

What is the optimal supportive care for patients with metastatic pancreatic cancer?

I would say radiation oncologists are very useful. Nutrition is also something we utilize because a lot of these people have malabsorption because they are talking creon, and they are losing weight. We have to bring that into the picture. It is also good when the patient has a spouse, and a spouse who can drive is even better. Having a partner to drive them back and forth to treatment is a great thing. It should always be a red flag to all of us when a patient comes in and we find out they live alone and their daughter lives in California.

What has been your personal experience with this regiment in terms of efficacy and tolerability?

The regimen is 3 weeks on and 1 week off, but almost no one can keep up with that long term. They will get cumulative neuropathy, for example. So, we make long-range decisions to modify treatment either earlier or somewhere along the way.

August 2015

A CT scan showed no residual liver metastases; the tumor in the head of the pancreas was unchanged in size. The patient was asymptomatic and continued to tolerate therapy.

June 2016

The patient was hospitalized for high blood glucose levels and diagnosed with new onset insulin-dependent diabetes mellitus. Her CT scan showed appearance of several new liver metastases and she was started on the FOLFIRINOX regimen.

What is the trigger to change to the next line of therapy for a patient with progressive disease?

A CT scan report that says there are new lesions, more than 20% to 30% progression, symptomatic changes, among others.

Case 2

A 64-year-old woman was diagnosed with locally advanced pancreatic adenocarcinoma and referred for consultation at a high-volume center. Her CT findings showed a 2.8-cm mass in the pancreatic body, invading the common hepatic, celiac, and splenic arteries, with abutment more than 180 degrees to the superior mesenteric artery (SMA) but no encasement. A staging laparoscopy showed no distant metastasis; peritoneal washing cytology showed no malignant cells.

What would be your diagnostic workup for this patient? Do you routinely order molecular testing?

The problem with pancreatic cancer is that you will get a small number of cells from a fine-needle aspiration and that is not enough to do molecular profiling. However, there are some interesting data surrounding theBRCAmutation and homologous repair deficiency. There are data to suggest that about 20% of patients have some sort of actionable mutation. Some people do molecular profiling and find this to be useful, while others will wait until later in metastatic disease.

What are the criteria for resectability in patients with pancreatic cancer?

By traditional measures, greater than 180 degrees with no metastasis is generally the rule. Lymph nodes, however, are fine in this case. To make an effective pancreas surgery, the key element is negative margins. If you do the surgery and you get positive margins, you might as well not have done it.

How do you sequence perioperative local and systemic therapies?

A lot of us do chemotherapy for a while to see if the patient responds and then proceed to radiation. That is what this patient did, based on studies done by Memorial Sloan Kettering Cancer Center and other places that provided positive data. This is followed by resection. We do the chemotherapy first to shrink it, then consolidate with chemotherapy and radiation. Then on to resection.

She received FOLFIRINOX for 6 cycles followed by capecitabine and concurrent radiotherapy. A follow-up scan showed the tumor had shrunk to 1.2 cm and the SMA encasement was diminished but still detectable.

She underwent distal pancreatectomy with celiac artery resection; which was completed with R0 margins. A histopathology showed fibrous changes around the celiac artery; Evans grade IIb. There was no evidence of residual tumor of the periphery and 0 out of 8 positive lymph nodes.

What is the standard-of-care chemotherapy for this patient population?

There was a gemcitabine plus nab-paclitaxel induction trial called the LAPACT trial.¹This patient would have been eligible for the protocol of the study. Patients on the trial received full-dose gemcitabine and nab-paclitaxel, and then chemoradiation with follow up. Out of this, there was a decent response rate, which is what you would expect from this regimen. There was a 72% 1-year overall survival (OS) rate. Fifteen percent of these patients converted to resectable disease.

This concept of neoadjuvant chemotherapy, whether it is this regimen or FOLFIRINOX, can be given initially. It gets people to surgery and you have a not so dismal result. There are a lot of these kinds of patients who show up in my office.

The phase III trial of adjuvant modified FOLFIRINOX versus gemcitabine was landmark this year.²The problem is that this is not the current standard of care. The current standard of care is gemcitabine plus capecitabine, which didn't do badly compared to gemcitabine, and the modified FOLFIRINOX regimen for 12 cycles, which is a lot, at least for my practice. For patients with resected pancreatic cancer, the curve looks really good. There is a 40% 3-year disease-free survival (DFS) rate.

If you look at gemcitabine plus capecitabine, it is essentially the same median DFS, but the OS is not quite the same. The debate about what is the correct treatment is unclear. FOLFIRINOX is the winner numerically if you get patients through it, but I have a 75-year-old patient who took 2 months to get better after surgery. She is not getting FOLFIRINOX. She is getting treated with gemcitabine plus capecitabine. We will have a new study coming out soon looking at gemcitabine plus nab-paclitaxel, which may even further confuse our problem with having a third regimen. None of them have been compared head-to-head yet.

References:

1. Hammel P, Lacy J, Porales F, et al. Phase II LAPACT trial ofnab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC).J Clin Oncol. 2018;36(suppl; abstr 204). meetinglibrary.asco.org/record/155730/abstract.
2. Conroy T, Hammel P, Hebbar M, et al. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas.J Clin Oncol. 2018;36(suppl; abstr LBA4001). meetinglibrary.asco.org/record/159164/abstract.