The dawn of
chemotherapy for
gastrointestinal cancers including
colorectal cancer was the inception of 5-fluorouraci (l 5-FU), produced by Dr. Heidelberger in 1957.
5-FU had been playing the leading role in
chemotherapy for
colorectal cancer for four decades until the Nineties. The second wave of
chemotherapy was biochemical modulation. For the enhancement of
5-FU effects, the sequential combination with
methotrexate and
leucovorin (LV) was devised. Among them, 5-FU/LV was established in standard
chemotherapy for
colorectal cancer, due to several meta-analyses. Oral
5-FU such as UFT,
TS-1 and
capecitabine derivatives are gaining an important position in
chemotherapy for
colorectal cancer based on the accumulation of evidence. The third wave enveloped
chemotherapy.
Irinotecan was developed for
gastrointestinal cancer. In 2000,
CPT-11+5-FU/LV became the standard and first-line
chemotherapy for
colorectal cancer in the U.S. and Europe. Unfortunately, we in Japan have lagged behind the U.S. and Europe, because,
5-FU with LV was not approved here until 1999.
Oxaliplatin was accepted in Europe first. FOLFOX, including continuous infusion of
5-FU, and LV were approved in 1998. In 2004,
oxaliplatin + 5-FU/LV, named FOLFOX 4, was approved as the first-line
chemotherapy treatment for
colorectal cancer in the U.S.
Oxaliplatin was the synthesized in Japan. At last, it was approved with usage restrictions the past March. We are now able to use FOLFOX 4, and this
chemotherapy strategy for
colorectal cancer in Japan is spreading rapidly. Recently, several new molecular targeted agents, which we call the fourth wave of
chemotherapy, have been available in clinical studies,and promising data have been presented. Among them, evacizumab and
cetuximab were tested in large phase III studies, their efficacies were upheld, and the drugs were approved in the U.S. Median survival time(MST) has been gradually prolonged through 5-FU/LV with
irinotecan and
oxaliplatin. Now, with the addition of molecular targeted agents, over 20 months of MST was reported.