PurposeOver the last couple of years, we have witnessed the availability of a wide variety of different therapeutic agents and the identification of effective combinations of existing ones that have transformed the way we approach and treat pancreatic cancer. Proof of this are the recent validations that combinations of conventional chemotherapy drugs, the FOLFIRINOX regimen and gemcitabine plus nab-paclitaxel, significantly improves clinical outcomes in patients with metastatic disease. However, deeper and more sophisticated understanding of the biology of this cancer as well as the ability to develop better and perhaps more precise drugs predict that the landscape may be changing even more.Methodology and ResultsIn this review, we will summarize the most recent treatment advances including FOLFIRINOX, gemcitabine plus nab-paclitaxel and discuss novel approaches such as immune-mediated therapies, drugs that disrupt the tumor-stromal compartment, PARP inhibitors for BRCA pathway-deficient pancreatic cancer and new generations of conventional chemotherapeutics, which are in early phases of clinical development and have shown promising early results. We will also discuss some examples of drugs that failed, despite very good preliminary data, in order to appraise the lessons learned from these negative clinical trials. Lastly, we will comment on ongoing adjuvant and neoadjuvant trials.ConclusionWe hope that at least some of these will result in positive trials and add to our armamentarium for treating this challenging malignancy.

At the dose and schedule used in this trial, 9-AC lacked antitumor activity in metastatic colorectal cancer. 9-AC infusion schedules of longer duration are currently being investigated in this disease.

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m2/day, with planned escalations to 250, 300, 350, and 400 mg/m2/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m2/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m2 level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m2/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and "hand-foot syndrome" were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.

No abstract

The discovery of the molecular processes involved in cancer development has led to the design of an array of targeted agents. These agents, directed to specific proteins in the machinery of cancer cells, interfere with vital cascades involved in cell invasion, metastasis, apoptosis, cell-cycle control and angiogenesis. In breast cancer, the main pathways studied and targeted by drugs are the HER2 pathway, EGFR, VEGF, PI3K/Akt/mammalian target of rapamycin (PI3K-M-Tor), IGF/IGFR, poly(ADP ribose) polymerase 1, HDAC and many others. In this review, we present the most promising studies of these new targeted therapies and novel combination of targeted therapies with cytotoxic agents for the treatment of breast cancer patients.