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Evolving Paradigms in Pancreatic Cancer: Frontline Treatment Regimens

Published Online: May 13,2016
Overall, 19.5% of patients in the FOLFIRINOX arm had lung metastases versus 28.7% in the control arm (P = .05). The median age of patients was 61 years, and nearly all had an ECOG PS of 0 or 1 (99.3%). The median number of metastatic sites was 2. CA19-9 levels were elevated ≥59xULN for 41.5% to 46.7% of patients, in the FOLIRINOX and gemcitabine arms, respectively. 

In the study, the median OS was 11.1 months with FOLFIRINOX compared with 6.8 months for gemcitabine alone (HR, 0.57; 95% CI, 0.45-0.73; P <.001). Median PFS with FOLFIRINOX was 6.4 months versus 3.3 months with gemcitabine (HR, 0.47; 95% CI, 0.37-0.59; P <.001). The investigator-assessed ORR was 31.6% in the FOLFIRINOX arm versus 9.4% with gemcitabine arm (P <.001). 

There were significantly more AEs in the FOLFIRINOX group versus gemcitabine, including febrile neutropenia in 5.4% of patients (TABLE 1). However, at 6 months, 31% of patients treated with FOLFIRINOX had a definitive degradation in quality of life versus 66% in the gemcitabine (HR, 0.47; 95% CI, 0.30-0.70; P <.001).
 

TABLE 1. Grade 3/4 AEs in PRODIGE 4/ACCORD 11

  FOLFIRINOX Gemcitabine
Neutropenia 45.7% 21%
Fatigue 23.6% 17.8%
Vomiting 14.5% 8.3%
Diarrhea 12.7% 1.8%
Thrombocytopenia 9.1% 3.6%
Sensory neuropathy 9.0% NA
ALT increase 7.3% 20.8%
Anemia 7.8% 6.0%
Thromboembolism 6.6% 4.1%
Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; NA, not applicable

Nab-Paclitaxel/Gemcitabine

In 2013, the FDA approved nab-paclitaxel plus gemcitabine as a first-line treatment for patients with metastatic adenocarcinoma of the pancreas, based on the phase III MPACT trial.5 The approval of this combination displaced single-agent gemcitabine, which had been the standard of care for more than 15 years. 

The phase III MPACT trial enrolled 861 patients who had not received prior chemotherapy for metastatic pancreatic cancer with adenocarcinoma histology. Patients were randomized in a 1:1 ratio to receive weekly intravenous nab-paclitaxel at 125 mg/m2 plus 1000 mg/m2 of gemcitabine for 3 weeks followed by 1 week of rest (n = 431) or 1000 mg/m2 of weekly gemcitabine for 7 weeks with 1 week of rest followed by the same schedule as the investigational arm (n = 430). The primary endpoint of the trial was OS.

Patients were primarily enrolled in North America (63%) at community and academic centers. All patient characteristics were well balanced between the arms. There was no upper age limit for enrollment in the study, and 42% of patients were ≥65 years in age. The trial included those with a KPS of 70 to 100. Thirty-nine percent of patients had lung metastases, and 14% of patients had ≥3 metastatic sites. CA19-9 levels were ≥59x ULN for 52% of patients. 

The trial found a PFS advantage favoring the nab-paclitaxel combination of 5.5 months compared to 3.7 months (HR, 0.69; 95% CI, 0.58–0.82; P <.001). The combination also demonstrated a superior overall response rate of 23% compared with 7% for gemcitabine alone (P <.001).

In a long-term assessment, the nab-paclitaxel arm demonstrated a significantly higher OS than gemcitabine monotherapy (8.7 vs 6.6 months; HR, 0.72; 95% CI, 0.62–0.83; P <.001).6 Four percent of patients in the nab-paclitaxel arm lived beyond 3 years versus none with gemcitabine alone. OS was consistent across stratification factors (TABLE 2). 

TABLE 2. Median OS in Prespecified Subgroups

  Nab-paclitaxel
Plus Gemcitabine
(months)
Median OS Hazard Ratio
Age <65 9.2 6.8 0.65 (95% CI, 0.53-0.79)
Age ≥65 7.8 6.6 0.81 (95% CI, 0.63-1.03)
KPS, 70-80 7.6 4.3 0.61 (95% CI, 0.48-0.78)
KPS, 90-100 9.7 7.9 0.75 (95% CI, 0.62-0.92)
Australia 9.2 6.7 0.67 (95% CI, 0.45-1.01)
Eastern Europe 7.7 5.9 0.84 (95% CI, 0.58-1.23)
North America 8.7 6.8 0.68 (95% CI, 0.56-0.82)
Liver metastases 8.3 5.9 0.69 (95% CI, 0.59-0.81)
No liver metastases 11 10.7 0.86 (95% CI, 0.56-1.33)
Abbreviations: KPS, Karnofsky performance status; OS, overall survival





The most common grade ≥3 AEs with nab-paclitaxel/gemcitabine versus gemcitabine alone were neutropenia (38% vs 27%), fatigue (17% vs 7%), and neuropathy (17% vs 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the nab-paclitaxel and control arm, respectively. At a median of 29 days, grade ≥3 neuropathy improved to grade 1 or lower. 


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