The 25-Year-Old Cancer Pill Japan Relies On That America Still Can't Prescribe

Some medical gaps between Japan and the United States involve dazzling new technology — lasers, cell therapies, gene editing. This one is almost the opposite: a simple oral pill, developed a quarter-century ago, that quietly became one of Japan’s most-used cancer drugs while never making it onto American pharmacy shelves at all.

The drug is called S-1 (sold in Japan as TS-1), and its story is a reminder that “Japan is ahead” doesn’t always mean cutting-edge — sometimes it just means a treatment that works well never cleared the regulatory bar somewhere else.

How it works

S-1 is an oral fluoropyrimidine — a pill-form relative of the chemotherapy drug 5-fluorouracil (5-FU), which is normally given by intravenous infusion. It combines three components in one capsule: tegafur, which the body converts into 5-FU; gimeracil, which slows the breakdown of 5-FU so it stays active longer; and oteracil, which reduces gastrointestinal side effects by limiting 5-FU activation in the gut lining.

The result is a chemotherapy that patients can take at home as a pill, with an effectiveness profile aimed at matching infused 5-FU while easing the burden of hospital visits and IV lines — an appealing trade for people already managing a cancer diagnosis.

Where each country stands

Developed by Taiho Pharmaceutical, S-1 was approved in Japan in January 1999 for gastric cancer, after the manufacturer filed for approval in late 1997. It didn’t stay a niche option. The landmark ACTS-GC trial, published in the New England Journal of Medicine in 2007, showed that a year of S-1 given after gastrectomy for stage II or III gastric cancer meaningfully improved survival — five-year follow-up data published in the Journal of Clinical Oncology put five-year overall survival at 71.7% with adjuvant S-1 versus 61.1% with surgery alone. That result made postoperative S-1 a standard part of gastric cancer care in Japan, and the drug went on to gain Japanese approval for six additional cancers, including colorectal, head and neck, non-small cell lung, breast, pancreatic, and biliary tract cancer.

Europe eventually caught up, to a degree. The European Medicines Agency approved S-1 (marketed there as Teysuno) for advanced gastric cancer in 2011, based on the international FLAGS trial, and later expanded that approval to metastatic colorectal cancer in 2021.

The United States is the outlier. Despite the FLAGS trial itself being run partly in American and European cancer centers, S-1 has never been approved by the FDA, in any combination, for any indication. More than two decades after Japanese patients started receiving it as routine care, an American patient cannot get an S-1 prescription outside of a clinical trial.

Why this gap exists

This isn’t a story about American medicine lagging across the board — the United States remains a global leader in developing and approving novel cancer immunotherapies and targeted drugs, many of which reach American patients before anyone else. S-1’s story is narrower and more particular: the FLAGS trial, designed to test S-1 against infused 5-FU in a Western patient population, was built as a noninferiority study. It succeeded on those terms — supporting the European approval — but a noninferiority result for a drug with a different (not clearly superior) side-effect profile is a much harder case to bring through the FDA than it was through EMA’s process. With no U.S. approval ever formally pursued to completion, the drug simply stayed on the other side of the Pacific and the Atlantic.

The practical lesson is the same one this journal returns to often: a treatment’s absence from the American market doesn’t necessarily mean it failed or fell short. Sometimes it means the regulatory and commercial path simply never got built.

The bigger pattern: prevention

S-1 is a treatment story, but the more common version of this gap in Japan is preventive rather than curative — the routine, comprehensive screening captured by the Ningen Dock, which catches disease at a stage when a pill like S-1 might not even be necessary. Whether the gap is a drug patients in Japan have relied on for a generation, or a screening protocol that finds problems years before symptoms appear, the underlying pattern is consistent: different systems move at different speeds, and it’s worth knowing where those differences fall before you need to.

We’ll keep tracking these gaps — drugs, procedures, and preventive approaches where Japan leads — here in The Mirai Journal each week.

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Sources: Development History and Concept of an Oral Anticancer Agent S-1 (TS-1) — Japanese Journal of Clinical Oncology; Adjuvant Chemotherapy for Gastric Cancer with S-1 — New England Journal of Medicine; Five-Year Outcomes of ACTS-GC — Journal of Clinical Oncology; Tegafur/gimeracil/oteracil (S-1) approved for advanced gastric cancer — OncoTargets and Therapy; European Commission approves Teysuno in metastatic colorectal cancer — Nordic Pharma.