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Evolving Paradigms in Pancreatic Cancer: Frontline Treatment Regimens

Published Online: May 13,2016
The majority of patients with pancreatic adenocarcinoma are diagnosed with late-stage, unresectable tumors, a setting in which combination chemotherapy is the mainstay. Although progress has been slow, new drugs have become available, important research questions are being addressed, and treatment strategies are continuing to evolve. 

In the advanced stage, pancreatic cancer primarily metastasizes to the peritoneal cavity and liver, with other sites including the lungs, bone, brain, and other organs. For patients with stage IV disease, treatment may consist of surgery, radiation, chemotherapy, biological therapy, or a combination of these strategies. 

According to the SEER database,1 between 2006 and 2012 the 5-year survival rate for patients with pancreatic cancer was 7.7%. For those with localized pancreatic cancer, which is more amenable to surgery and comprises 29% of patients, the 5-year survival rate is 29.3%. In those with metastatic disease, which is 52% of new diagnoses, the 5-year survival rate is just 2.6%. 

In this issue, we will focus on pivotal data from randomized controlled trials, which are starting to make progress toward improving long-term outcomes. Additionally, the review will provide expert opinion, subgroup analyses from large prospective studies, real-world evidence supporting optimal sequencing approaches, new therapies for advanced pancreatic cancer, and novel options on the horizon, including immunotherapies and cancer stem cell inhibitors. 

Frontline Treatment Regimens 

Frontline therapies for patients with metastatic pancreatic cancer have advanced in the past 5 years, with the FDA approval of nab-paclitaxel (Abraxane) plus gemcitabine (Gemzar). These advancements branch off the established treatment paradigm of gemcitabine monotherapy, which showed a significant extension in overall survival (OS) compared with 5-FU alone in a phase III study.2 

In the 126-patient trial that established gemcitabine,2 the agent was administered at 1,000 mg/m2 weekly for 7 weeks followed by 1 week of rest then weekly for 3 weeks with 1 week of rest (n = 63). 5-FU was administered at 600 mg/m2 once weekly (n = 63). The Karnofsky performance status (KPS) was 50 to 70 for approximately 69% of patients enrolled in the study. 

In data from the trial, which were published in 1997, gemcitabine demonstrated a 1-year OS rate of 18% versus 2% with 5-FU (P = .003). Median OS was 5.7 months with gemcitabine versus 4.4 months with 5-FU (P = .0025). The clinical benefit rate with gemcitabine was 23.8% versus 4.8% with 5-FU (P = .0022). 

After a significant lull in new approvals for patients with advanced pancreatic cancer, several new regimens have become available including the chemotherapy combination FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin), the combination of nab-paclitaxel and gemcitabine, and the second-line combination of irinotecan liposome injection, 5-FU, and leucovorin. 

Erlotinib Plus Gemcitabine 

EGFR is often expressed by pancreatic tumors, leading to the investigation of the EGFR-targeted TKI erlotinib (Tarceva) in combination with gemcitabine. In a phase III study reported in 2007,3 patients at a median age of 64 years were randomized to receive erlotinib plus gemcitabine (n = 285) or gemcitabine plus placebo (n = 284). Gemcitabine was administered at the dose and scheduled approved for single-agent use and erlotinib was given at 100 or 150 mg per day. Patient characteristics were well balanced between the two arms, except for gender. 

Median OS was 6.2 months with erlotinib and gemcitabine versus 5.9 months for placebo and gemcitabine (HR, 0.82; 95% CI, 0.69-0.99; P = .038). The 1-year OS rate was 23% with erlotinib versus 17% with gemcitabine alone (P = .023). Median progression-free survival (PFS) was 3.8 months with erlotinib versus 3.6 months with gemcitabine (HR, 0.77; 95% CI, 0.64-0.92; P = .004). The addition of erlotinib led to significantly more adverse events (AEs). 

This trial was the first demonstration of improved OS with the addition of a second agent to gemcitabine. Although this regimen is rarely used in 2016, this work set the stage for other novel combination approaches with gemcitabine. 

FOLFIRINOX

FOLFIRINOX demonstrated superiority versus gemcitabine monotherapy in the phase III PRODIGE 4/ACCORD 11 trial,4 which was conducted only at French academic centers in a selective patient population (ECOG 0-1; age ≤75 years). Based on this data, the regimen became commonly used, although it is not FDA approved. Each of the individual agents in the FOLIRINOX regimen are generic and approved to treat cancer. 

In the trial, 342 patients from French centers were randomized to receive FOLFIRINOX (n = 171) or gemcitabine (n = 171). FOLFIRINOX consisted of oxaliplatin at 85 mg/m2, irinotecan at 180 mg/m2, leucovorin at 400 mg/m2, and fluorouracil at 400 mg/m2 bolus followed by 2400 mg/m2 infusion. Gemcitabine was administered at 1000 mg/m2. The primary endpoint was OS. 



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Evolving Paradigms in Pancreatic Cancer: Frontline Treatment Regimens
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