Fluoropyrimidines have shown efficacy against a variety of cancers and have evolved into a range of different uses and formulations. These drugs have been tested extensively as monotherapies and as part of numerous different chemotherapy combinations. The efficacy and safety profile of bolus intravenous (IV) 5-fluorouracil (5-FU) has been improved by continuous IV administration. The availability of the first 5-FU oral form in Europe, capecitabine, has added a clear value in terms of convenience for patients, while forcing physicians and nurses to learn how to manage the toxicity profile of this compound. S-1 is a new oral formulation combining a 5-FU prodrug (tegafur) and two targeted modulators of its metabolism (gimeracil and oteracil) preserving the efficacy and improving the safety of the prodrug. S-1 has become the backbone treatment for advanced gastric cancer in Japan since its introduction in 1999. Extensive experience from clinical trials, post-marketing studies and patient registries of over 4,000 patients in Japan show that S-1 has improved measures of survival in advanced gastric cancer and has an acceptable safety profile. S-1 has recently been approved for advanced gastric cancer treatment in Europe. Since 5-FU metabolism differs between Asian and Caucasian populations, the introduction of S-1 in Caucasians has necessitated an entirely new clinical trial programme. Phase I trials indicated different dose levels were necessary in Westerners versus Asians (25 versus 40 mg/m²). In the FLAGS study of over 1,000 patients with advanced gastric cancer (the largest study ever conducted in this indication), S-1 plus cisplatin was demonstrated to be non-inferior in efficacy but superior in safety to 5-FU + cisplatin. Based on these results, S-1 was approved in Europe in March 2011 under the trade name Teysuno®. Further clinical trials are in progress to evaluate S-1 in advanced gastric cancer (AGC) and its use as part of triplet therapies is currently being investigated. This will further define the role of S-1 as a key part of advanced gastric cancer management in Western countries.
Cancer, Oncology, Gastric, Fluoropyrimidine, Alberto Sobrero , Yasuhide Yamada , Jean-Yves Douillard , Markus Moehler
The fluoropyrimidine drug 5-fluorouracil (5-FU) was originally patented in the US by Heidelberger and Duschinsky in 1957. Since that time, the use of the drug has been extensively developed and its analogues have played a continuing and pivotal role in cancer treatment. 5-FU was for a long time the only drug administered to gastric cancer patients but it subsequently evolved and underwent multiple manipulations, being administered with other compounds and in new schedules to increase its efficacy and safety.
In current clinical practice, fluoropyrimidines are likely to remain a central part of gastric cancer treatment for the foreseeable future; they are the backbone of most of the treatment regimens used in gastro-intestinal cancers. Efficacy and reduced toxicity are key requirements for oncologists and patients. New fluoropyrimidines in clinical development have considerable advantages over older drugs in terms of efficacy and safety. S-1 is a new formulation that consists of a 5-FU prodrug and two targeted modulators of its metabolism, preserving the efficacy and improving the safety of the prodrug.
Following the recent approval of S-1 for use in Western populations after more than 10 years of extensive experience in Japan, the history of the fluoropyrimidines in advanced gastric cancer will be considered, and evidence supporting the use of S-1 from early phases to more recent clinical studies will be reviewed.
Are all Fluoropyrimidines Equal?
The use of fluoropyrimidines in the treatment of advanced gastric cancer has undergone considerable development. In 1968, IV 5-FU was approved in Europe for the treatment of gastric carcinoma. In 2007, capecitabine became available for the first-line treatment of advanced gastric cancer in combination with a platinum salt. In 2011, S-1 was approved for first-line therapy of advanced gastric cancer in combination with cisplatin.
Four avenues have been exploited in order to improve the therapeutic index of 5-FU. The first avenue consisted of biochemical modulation with methotrexate, leucovorin and interferon.1,2 The second avenue involved optimising the dosing schedule. For many years, it has been believed that continuous infusion of 5-FU channels its mechanism of action toward the DNA pathway – the basis of its anti-tumour activity – whereas a bolus dose diverts its activity toward the RNA pathway, which is believed to be the main cause of toxicity. Fifty-six years later, this is not an established fact, merely a supposition. The third avenue involved the development of oral agents for the convenience of clinicians and patients through the development of the 5-FU prodrugs. Finally, the fourth avenue focused on the metabolism of the agent. An increased understanding of each step of the 5-FU metabolism has allowed the selection of modulator stargeting key enzymes involved in 5-FU degradation and activation.
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Markus Moehler has received honoraria and international meeting travel support from Taiho, Merck, Germany or Roche, Germany. Albert Sobrero has served on advisory boards for Roche, Merck, Amgen, Sanofi, Bayer, Nordic and as speaker at satellite symposia. Yasuhide Yamada has received honoraria from Taiho and Chugai, research funding from AstraZeneca, Bayer, Novartis and Yakult. Jean-Yves Douillard has served on advisory boards and participated in symposia for Roche, Merck, Amgen, Nordic, sanofi-aventis and has received a research grant from Merck. The remaining authors have no conflicts of interest to declare.
Jean-Yves Douillard, Professor of Medical Oncology, ICO R. Gauducheau, Bd j. Monod, 44805 St Herblain, France. E: firstname.lastname@example.org