Metronomic chemotherapy suppresses growth of primary tumors and established metastases. However, its effect on metastatic progression is essentially unknown. We report the treatment of a metastatically competent model of pancreatic cancer with metronomic gemcitabine and sunitinib. Mice with orthotopic, red fluorescent protein-expressing, pancreatic cancer tumorgrafts were treated with gemcitabine on a metronomic (1 mg/kg daily, METG) or maximum tolerated dose (150 mg/kg twice weekly, MTDG) schedule with or without sunitinib (SU). Rates of primary tumor growth, metastasis, ascites, and survival were calculated. Gemcitabine at a daily dose of 2 mg or greater led to toxicity within 1 month in mice without tumors but METG at 1 mg/kg/d was well tolerated. Mice with pancreatic cancer tumorgrafts died with metastatic disease at a median of 25 days. METG/SU significantly prolonged median overall survival (44 days) compared with control or either regimen alone (P < 0.05). Primary tumor growth was inhibited by METG/SU (P = 0.03) but neither METG nor sunitinib alone. In contrast, treatment with METG suppressed metastasis at multiple sites, an effect enhanced by sunitinib. MTDG with or without sunitinib had the most favorable effect on primary tumor growth and survival, but its antimetastatic efficacy was similar to that of METG/SU. von Willebrand factor expression was inhibited by METG. Antimetastatic activity approaching that of MTDG is achieved with a total dose reduced 42 times using METG and is further enhanced by sunitinib. Our results suggest the potential of this therapeutic paradigm against pancreatic cancer in the adjuvant and maintenance settings.

Importance

Interest in minimally invasive distal pancreatectomy (MIDP) has grown in recent years, but currently available data are limited. Greater insight into application patterns and outcomes may be gained from a national database inquiry.

Objectives

To study trends in the use of MIDP and compare the short-term outcomes of MIDP with those of open distal pancreatectomy.

Design, setting, and participants

Population-based retrospective cohort study evaluating perioperative outcomes and hospital charge measures for distal pancreatectomy, comparing the surgical approaches and adjusting for patient- and hospital-level factors, among patients undergoing elective distal pancreatectomy from 1998 to 2009 in the Nationwide Inpatient Sample in a 20% stratified sample of all US hospitals.

Main outcomes and measures

In-hospital mortality, rates of perioperative complications and splenectomy, total charges, and length of stay.

Results

A total of 8957 distal pancreatectomies were included in this analysis, of which 382 (4.3%) were MIDPs. On a national level, this projected to 42,320 open distal pancreatectomies and 1908 MIDPs. The proportion of distal pancreatectomies performed via minimally invasive approaches tripled between 1998 and 2009, from 2.4% to 7.3%. The groups were comparable for sex and comorbidity profiles, while patients who underwent MIDP were 1.5 years older. On multivariate analysis, MIDP was associated with lower rates of overall predischarge complications, including lower incidences of postoperative infections and bleeding complications, as well as a shorter length of stay by 1.22 days. There were no differences in rates of in-hospital mortality, concomitant splenectomy, or total charges.

Conclusions and relevance

This population-based study of MIDP reveals that the application of this approach has tripled in practice and provides strong evidence that MIDP has evolved into a safe option in the treatment of benign and malignant pancreatic diseases.