title: Metastatic pancreatic cancer: Is there a light at the end of the tunnel?
abstract: Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate new effective chemotherapy regimens in earlier stages of disease (neoadjuvant, adjuvant, and multimodal approaches in both resectable and unresectable patients) are also briefly discussed.
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Vanja
authors.initials: V
authors.lastname: Vaccaro
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Vari
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Melisi
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Garufi
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Nuzzo
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Reni
authors.affiliation: Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D060046:Maintenance Chemotherapy; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012307:Risk Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Chemotherapy; Folfirinox; Metastatic disease; Pancreatic cancer; nab-Paclitaxel