Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine

Abstract

BACKGROUND In a phase 1–2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel–gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel–gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel–gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel–gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel–gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.)

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…PDAC is also among the deadliest forms of cancer, with a 93% mortality rate in 5 years following diagnosis 33, 34, 35, 36. Current approaches to treating PDAC include cytotoxic chemotherapy, ionizing radiation, and surgical resection 37, 38. One possible reason these therapies are unsuccessful in achieving long‐term survival is that they fail to treat cachexia, which is a key underlying cause of PDAC morbidity and mortality 10, 11, 12, 39.…”

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

“…PDAC is histologically characterized by a dense desmoplastic reaction surrounding malignant epithelial cells that plays a critical role in tumor progression, invasion, metastasis and drug-resistance by providing a mechanical barrier. Nab-paclitaxel has been proposed to disrupt the PDAC stromal architecture, causing increased perfusion and drug-delivery [12]. Our laboratory has shown that the nab-paclitaxel is the most effective single agent cytotoxic agent in comparison with gemcitabine or docetaxel [10].…”

“…FOLFIRINOX, a combination of chemotherapy agents (oxaliplatin, irinotecan, 5-FU/leucovorin), nearly doubled the median survival of PDAC patients (11.1 months compared with 6.8 months in the gemcitabine group), but this regimen is highly toxic with serious side effects [9]. Nab-paclitaxel (NPT), a water-soluble albumin-bound paclitaxel, has recently shown efficacy against advanced PDAC [10, 11], and nab-paclitaxel in combination with gemcitabine demonstrated 8.5 months median survival compared with 6.7 months after gemcitabine alone [12]. Considering these trial-based moderate improvements in PDAC prognosis, there is an urgent requirement for novel therapeutic strategies to improve overall patient survival.…”

Human pancreatic cancer progression: an anarchy among CCN-siblings

“…Currently, there are a few FDA-approved efficacious therapies for chemo-resistant patients that help improve survival for 4-11 months compared to the old standard of care (gemcitabine therapy) (Conroy et al 2011;Han and Von Hoff 2013;Von Hoff et al 2013;Von Hoff et al 2009;Wang-Gillam et al 2016). Thereby, chemoresistance is still a challenging task for PC therapy.…”

“…The median overall survival (OS) in these therapeutic groups remains modest, varying from 4 to 12 months with degradation of quality of life (Conroy et al 2011;Mohammed et al 2015;Von Hoff et al 2013;WangGillam et al 2016). The limited efficacies of these drugs are due to the acquisition of chemo-resistant characteristics of PDAC.…”