"Many of the new molecularly targeted anti-cancer agents work by inhibiting cancer cell division and growth -- but in doing so, the new agents could diminish the effectiveness of chemotherapy, which depends on rapid cell cycling," said senior investigator Paul Gumerlock, professor of hematology/oncology at UC Davis Cancer Center. "Because of this, it could be very important in what sequence the new agents are combined with standard chemotherapy drugs."
To test the notion, Gumerlock and his colleagues focused on a new oral epidermal growth factor receptor inhibitor known as erlotinib. Recently, several large clinical trials have compared standard chemotherapy alone to standard chemotherapy plus an oral EGFR inhibitor like erlotinib in the treatment of non-small cell lung cancer. Little if any benefit was found from the addition of an EGFR inhibitor in these trials, in which the EGFR inhibitor and chemotherapy were administered simultaneously.
The UC Davis Cancer Center team set out to determine whether sequential administration would make a difference. The researchers tested erlotinib alone, the standard chemotherapy agent docetaxel alone, the two drugs simultaneously, and the two drugs sequentially. All the tests were done in the laboratory using human non-small cell lung cancer cells.
"We predicted that giving docetaxel first, then erlotinib, would be more effective than giving the erlotinib first, giving both drugs simultaneously or giving either drug alone" Gumerlock said. "And that proved to be true."
Docetaxel, a standard first-line chemotherapy drug for non-small cell lung cancer, works in the same way other standard chemotherapy agents do: by killing rapidly dividing cells. The approach destroys cancer cells, which are characterized by out-of-control growth, but also some healthy growing cells, including cells in hair follicles.
Erlotinib, in contrast, works by blocking certain signals that cancer cells need in order to reach the cell-division stage, or mitosis.
Gumerlock theorizes that when erlotinib is given simultaneously or just before docetaxel, fewer cancer cells reach mitosis and become vulnerable to chemotherapy, thereby diminishing chemotherapy's effectiveness.
Clinical testing will be required to determine whether Gumerlock's laboratory findings hold true in patients. Based on his preclinical work, a phase I trial of docetaxel followed by erlotinib in patients with non-small cell lung cancer is already under way at UC Davis Cancer Center. Angela Davies, assistant professor of hematology/oncology at UC Davis Cancer Center, is principal investigator.
Gumerlock believes timing and sequencing may be crucial when combining chemotherapy with other molecularly targeted agents, not just erlotinib.
In a related presentation at the ASCO meeting, Gumerlock reported that in laboratory testing of tumors in mice, a selective proteasome inhibitor, PS-341, significantly inhibited non-small cell lung cancer growth when administered sequentially with docetaxel. But PS-341 had only a modest effect when delivered alone -- and no effect when delivered simultaneously with docetaxel.
"We've been delivering these drugs the same way we've delivered chemotherapy, assuming that the more we can give, and the longer we can give it, the better," Gumerlock said.
"But that may not be true. These molecularly targeted drugs are oral drugs, with such low toxicity and convenience that they can be given every day. But just because you can give a drug every day, it doesn't mean that is the best regimen. We hope to have some answers soon."
UC Davis Cancer Center is the only National Cancer Institute-designated cancer center between San Francisco and Portland, Ore., a region the size of Pennsylvania. It is ranked by U.S. News & World Report as one of the nation's top 50 cancer treatment centers.