Factors Determining Frontline Therapy Selection for Pancreatic Cancer

Evolving ParadigmsPancreatic Cancer

A multitude of factors contribute to the selection of frontline treatment for patients with advanced pancreatic cancer, specifically in regard to selecting first- and second-line therapies.

To explore the multiple factors, a study looked at the effectiveness and supportive care utilization associated with first-line treatment with nab-paclitaxel/gemcitabine or FOLFIRINOX for patients with metastatic pancreatic cancer.8In this retrospective cohort study, data were selected from an electronic medical record platform involving patients throughout the United States. This analysis provided real-world data to support decision-making, including sequencing, in an era of expanding second-line options.

The main objectives of the analysis were to determine time to treatment discontinuation (TTD), database persistence (a proxy for survival), adverse events, supportive care before and during chemotherapy, proportion of patients receiving second-line therapy, time to next treatment, and duration of first- and second-line treatment.

Data were assessed for 122 patients treated with first-line nab-paclitaxel and gemcitabine and 80 treated with FOLFIRINOX. Patients treated with nab-paclitaxel/gemcitabine were significantly older (67.0 vs 61.4 years;P<.001) but, otherwise, the groups were similar.

The median TTD was 3.4 months with nab-paclitaxel/gemcitabine and 3.8 months with FOLFIRINOX. Database persistence also did not differ between the two groups, at 8.6 months for both arms.

FOLFIRINOX was associated with a higher incidence of all-grade adverse events (95% vs 84%) and significantly greater prophylactic use of G-CSF and other supportive care medications (TABLE). In the FOLFIRINOX arm, 39% of patients utilized an average of 4.41 doses of G-CSF per patient per 100 days. With nab-paclitaxel/gemcitabine, just 8% utilized G-CSF an average of 2.02 doses per patient per 100 days (P<.01). Additionally, a significantly greater number of patients required erythropoiesis-stimulating agents in the FOLFIRINOX arm (0.9 vs 0.13 doses per 100 patient days;P<0.01).

TABLE. Number of Doses Per Patient Per 100 Days

Nab-paclitaxel Plus Gemcitabine



















Abbreviations: ESA, erythropoiesis-stimulating agents; G-CSF, granulocyte-colony stimulating factor

Approximately one-third of patients initially treated with nab-paclitaxel/gemcitabine received 5-FU—based second-line treatment, and about half of the FOLFIRINOX group received second-line gemcitabine-based regimens. Duration of treatment in second-line was similar between the groups (about 8.5 months). Database persistence was 12.7 months for the nab-paclitaxel/gemcitabine group and 9.3 months with the FOLFIRINOX group, a difference that did not achieve statistical significance (P= .48).

When considering the overall cost of care, supportive care and other considerations should be taken into account. With this in mind, nab-paclitaxel and gemcitabine could be the most cost-effective option for the first-line treatment of patients with metastatic pancreatic cancer, according to a recent health resources management study.9

In the study, the costs and clinical outcomes of nab-paclitaxel/gemcitabine versus erlotinib plus gemcitabine were assessed using drug cost per cycle multiplied by the median cycles delivered from clinical trials. The comparison included the cost of the drugs and expenses related to administering the therapy and managing adverse events of grade 3/4 severity. These costs were based on 4 months of therapy for nab-paclitaxel/gemcitabine versus 3.9 months for erlotinib/gemcitabine.

In this comparison, the costs associated with the nab-paclitaxel regimen were $24,984 versus $23,044 with erlotinib. When considering the respective survival advantages, the nab-paclitaxel arm showed a $15,522 per life year benefit versus the erlotinib group.

In a separate analysis,10FOLFIRINOX was considerably cheaper in upfront costs compared with nab-paclitaxel/gemcitabine, since gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin are available in generic form. However, when considering the need for G-CSF, infusion costs, hydration, and the management of additional AEs, the cost associated with FOLFIRINOX was similar to nab-paclitaxel/gemcitabine. When taking these factors into account, the total cost for gemcitabine alone was $8,567 versus $31,761 with nab-paclitaxel/gemcitabine and $67,299 for FOLFIRNOX. In addition to dose modification strategies, a panel of experts also explored factors that influence frontline treatment decisions. This conversation included input from Thomas A. Abrams, MD, Dana-Farber Cancer Institute, George P. Kim, MD, Mayo Clinic, and Caio Rocha Lima, MD, Gibbs Cancer Center & Research Institute.

Q:What factors influence your frontline treatment selection?

Abrams: The FOLFIRINOX trial, or the PRODIGE 4 trial, differed from the MPACT trial in patient selection. Patients in the FOLFIRINOX trial really all came from France. They had, for the most part, a better performance status than the folks in the MPACT trial. They were ECOG 0 and 1, whereas the folks in MPACT were KPS 70% and above, which really doesn&rsquo;t necessarily translate evenly, but may in fact show that there were a little bit poorer performance status patients getting the gemcitabine and the nab-paclitaxel. But, on the other hand, both control arms were gemcitabine, and the overall survivals were essentially identical. So, it does make one question whether they were really truly meaningful differences in the trials with respect to the patients.

That said, clearly, the FOLFIRINOX patients had more in the way of toxicity, slightly more in the way of neutropenia and diarrhea than those in the MPACT trial randomized to the experimental arm. And they had a much higher overall survival: 11 months versus 8.5 months. I think based on those data, most people feel that FOLFIRINOX might be a little bit more effective, might have a better response rate, but it&rsquo;s again with the proviso that cross-trial comparison is very, very difficult and fraught with landmines.

Kim:It depends on the patient. What does the patient want to do? Does the patient want to wear a pump and have potential toxicities, be hospitalized, need Neupogen, Neulasta? Or do they want to get treated weekly, maybe come in every week and go home, stay at work and still be able to support their family and get their insurance?

I think it depends on what the patient wants and what best fits them. I&rsquo;m going to stir the pot a little bit. There are good survival data. There&rsquo;s this kind of urban legend that we&rsquo;re supposed to use FOLFIRINOX in the really good performance status patients, but there are data out there in the ECOG 0 patient that survival can be as high as 12.6 months with nab-paclitaxel/gemcitabine, and that data is out there in the public domain.

You can use gemcitabine/nab-paclitaxel, especially out in the community. I think there is some fear that if you don&rsquo;t have the support for FOLFIRINOX, you run into side effects. Gemcitabine or nab-paclitaxel is a very reasonable option in that population, that good performance status population. I think the other end of it is, the poor performance status patients we always think, well, let&rsquo;s just give them gemcitabine. But you can give them gemcitabine and nab-paclitaxel, and there does appear to be a benefit to that group of patients as well.

Lima:We are moving to a new paradigm now. We&rsquo;re thinking about sequence. We actually have the option in pancreatic cancer, believe it or not, so it&rsquo;s going to be a discussion further along among us.

Now we have irinotecan in a new formulation that showed a benefit in survival combined to 5-FU in second-line gemcitabine-pretreated patients. It threw us off a little bit in how to choose the first-line because if you pick FOLFIRINOX, you don&rsquo;t have randomized phase III data with gemcitabine/nab-paclitaxel in second-line. But you now have randomized phase III data with 5-FU and the MM-398.

I tend to go for sequence, because I think I would also diminish the risk for toxicities for the patient, and I&rsquo;ll be basing phase III trial in my first-line and second-line treatment.

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