Sequencing Strategies for Metastatic Pancreatic Cancer

George Kim, MD:In 2018, the treatments are 5-FU-based therapies—that being FOLFIRINOX or gemcitabine-based therapies; that being gemcitabine combined with nab-paclitaxel. What we have learned is that these 2 regimens were studied in different contexts. The trials are different, the patient selection was different, and the outcomes are different. But, when we try to level the playing field, we do understand the treatments are probably the same; understanding different toxicities, different logistical issues, and so, we have to decide what’s best for this patient.

When we talk about first-line therapy, we’re now starting to think about second-line therapy as part of that strategy; what we call sequencing, something that we had not had in pancreas cancer several years ago. We think about using a gemcitabine-based therapy followed by 5-FU—based therapy, and now we do have treatments that allow us to sequence. I think more and more we’re seeing that approach.

This patient was treated with gemcitabine and nab-paclitaxel, and they benefitted. They were given the standard regimen at day 1, 8, and 15 of a 28-day cycle. He did encounter grade 3 neutropenia, which was seen in about 38% of patients in the MPACT trial. He did not require any growth factors.

What happens when you give Abraxane, nab-paclitaxel chemotherapy is, at about 4 to 5 months, you develop cumulative grade 3 neuropathy; roughly 17% of patients, and that can be a treatment-limiting toxicity. The way to manage that is to actually hold the nab-paclitaxel. If you hold it for up to 1 month, almost 50% of patients can then restart the medication as the neuropathy declines down to a grade 1 level, so that’s very unique. Then you can restart the combination, and hopefully garner benefit for as long as possible.

Now, our patient did develop progression. The chemotherapy was no longer effective, and so we needed to think about second-line therapy. As we discussed, there is an FDA-approved NCCN category 1 treatment called Nal-IRI, which is a nanoparticle liposomal irinotecan injection. It is combined with continuous infusion 5-FU and leucovorin. This has shown a survival benefit in patients that are gemcitabine-refractory. The natural progression in our treatment strategy would be to have the patient treated with this regimen. It does show a survival benefit and is FDA approved. The side effects with this regimen importantly, are not the same side effects that one might encounter with the first-line nab-paclitaxel therapy. In particular, there is no neuropathy seen and there is only a low amount of thrombocytopenia. It makes sense to rest the nerves, rest the bone marrow, and move on to the second-line therapy which provides the survival benefit. That is what sequencing is in 2018.

Had we chosen FOLFIRINOX as our first-line therapy, again, the neuropathy with the oxaliplatin, we would have dropped that. We would have maintained the patient on the other medications, the irinotecan, the 5-FU/leucovorin. The patient ultimately would experience disease progression, and then we’re left with the difficult decision of what do we give the patient in the second-line setting. Obviously, it’s going to be a gemcitabine-based therapy. Would it be gemcitabine/nab-paclitaxel? Unfortunately, they have encountered oxaliplatin neuropathy, now they’re going to encounter nab-paclitaxel neuropathy, so it becomes more and more difficult to proceed in that sequence. That’s why I think this first scenario that we described using the gemcitabine-based nab-paclitaxel, followed by the 5-FU-based, Nal-IRI, 5-FU sequence is becoming more and more accepted in practice.

Transcript edited for clarity.

A 57-Year-Old Man With Abdominal Pain and Unexplained Weight Loss

• A 57-year-old man was referred from his primary care clinician with complaints of persistent pain in his upper abdomen that radiate to his back
• History
  • Former smoker (35 years, quit 5 years ago)
  • Was obese (BMI 29.0), but began losing weight despite not changing his eating habits
  • Reports feeling “tired” despite regular sleep habits
  • Treated for DVT 8 months ago
  • Hypertension controlled on medication, impaired glucose tolerance
  • Family history: mother alive with type 2 diabetes, father died (MI)
• Clinical evaluation
  • CT reveals mass in head of pancreas with metastases in liver and blood vessels
  • CA19-9 level: 55 times upper limit of normal
  • ECOG PS: 1
• Diagnosis: unresectable metastatic pancreatic cancer
• Patient began treatment with IV nab-paclitaxel (125 mg/m²) plus IV gemcitabine (1000 mg/m²) on days 1, 8 and 15 of a 28-day cycle
  • Experienced grade 3 neutropenia; did not require growth factors
  • Had mild peripheral neuropathy that did not progress or require dose adjustment
• At 6 months, patient progressed and received second-line treatment with liposomal irinotecan in combination with 5-FU/LV