Home > News > The Need for a New Fluoropyrimidine in Advanced Gastric Cancer Treatment
Gastrointestinal Oncology
Read Time: 2 mins

The Need for a New Fluoropyrimidine in Advanced Gastric Cancer Treatment

Published Online: August 5th 2012 European Oncology & Haematology, 2012;8(4):232-240 DOI: https://doi.org/10.17925/EOH.2012.08.4.232
Authors: Alberto Sobrero, Yasuhide Yamada, Jean-Yves Douillard, Markus Moehler
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

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.

Keywords

Cancer, Oncology, Gastric, Fluoropyrimidine, Alberto Sobrero , Yasuhide Yamada , Jean-Yves Douillard , Markus Moehler

Article:

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.

To view the full article in PDF or eBook formats, please click on the icons above.

Article Information:
Disclosure

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.

Correspondence

Jean-Yves Douillard, Professor of Medical Oncology, ICO R. Gauducheau, Bd j. Monod, 44805 St Herblain, France. E: jean-yves.douillard@ico.unicancer.fr

Received

2012-09-07T00:00:00

References

  1. Grem JL, Chu E, Boarman D, et al., Biochemical modulation of fluorouracil with leucovorin and interferon: preclinical and clinical investigations, Semin Oncol, 1992;19:36–44.
  2. Perez JE, Lacava JA, Dominguez ME, et al., Biochemical modulation of 5-fluorouracil by methotrexate in patients with advanced gastric carcinoma, Am J Clin Oncol, 1998;21:452–7.
  3. Ajani JA, Rodriguez W, Bodoky G, et al., Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial, J Clin Oncol, 2010;28:1547–53.
  4. Cunningham D, Starling N, Rao S, et al., Capecitabine and oxaliplatin for advanced esophagogastric cancer, N Engl J Med, 2008;358:36–46.
  5. Ryu MH, Kang YK, ML17032 trial: capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in advanced gastric cancer, Expert Rev Anticancer Ther, 2009;9:1745–51.
  6. Kim GM, Jeung HC, Rha SY, et al., A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer, Eur J Cancer, 2012;48:518–26.
  7. Yamada Y, Hamaguchi T, Goto M, et al., Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil, Br J Cancer, 2003;89:816–20.
  8. Nagashima F, Ohtsu A, Yoshida S, et al., Japanese nationwide post-marketing survey of S-1 in patients with advanced gastric cancer, Gastric Cancer, 2005;8:6–11.
  9. National Cancer Center, Cancer mortality from Vital Statistics in Japan (1958-2010). Vital Statistics in Japan, tabulated by Center for Cancer Control and Information Services, National Cancer Center, Japan, 2011.
  10. The Research Group for Population-based Cancer Registration in Japan, Annual reports 1997–2003, 1998–2004. Osaka: Research Group for Population-based Cancer Registration, 2004; and Inoue M, Tsugane S, Epidemiology of gastric cancer in Japan, Postgrad Med J, 2005;81:419–24.
  11. Sakata Y, Ohtsu A, Horikoshi N, et al., Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients, Eur J Cancer, 1998;34:1715–20.
  12. Koizumi W, Kurihara M, Nakano S, et al., Phase II Study of S-1, a Novel Oral Derivative of 5-Fluorouracil, in Advanced Gastric Cancer, Oncology, 2000;58:191–7.
  13. Ohtsu A, Shimada Y, Shirao K, et al., Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205), J Clin Oncol, 2003;21:54–9.
  14. Boku N, Yamamoto S, Fukuda H, et al., Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study, Lancet Oncol, 2009;10:1063–9.
  15. Yamada Y, Yamamoto S, Ohtsu A, Impact of dihydropyrimidine dehydrogenase status of biopsy specimens on efficacy of irinotecan plus cisplatin, S-1, or 5-FU as first-line treatment of advanced gastric cancer patients in JCOG9912, J Clin Oncol, 2009;27:15s (abstr 4535).
  16. Koizumi W, Narahara H, Hara T, et al., S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial, Lancet Oncol, 2008;9:215–21.
  17. Japanese Gastric Cancer Association, Japanese gastric cancer treatment guidelines 2010 (ver. 3), Gastric Cancer, 2011;14:113–23.
  18. Narahara H, Iishi H, Imamura H, et al., Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002), Gastric Cancer, 2011;14:72–80.
  19. Niitani H, Kimura K, Sato T, et al., Phase II study of 5'-deoxy- 5-fluorouridine (5'-DFUR) in patients with malignant cancer - a multi-institutional cooperative study, Jpn J Cancer Chemother, 1985;12:2044–51.
  20. Ota K, Taguchi T, Kimura K, Report on nationwide pooled data and cohort investigation in UFT phase II study, Cancer Chemother Pharmacol, 1988;22:333–8.
  21. Sakata Y, Yoshida Y, Phase II study of epirubicin inoperable or recurrent gastric cancer, Gan To Kagaku Ryoho, 1986;13:1887–92.
  22. Ishibiki K, Kumai K, Kodaira S, et al., [Phase II study with cisplatin in advanced stomach and colon carcinoma. Cooperative Study Group of Cisplatin for Stomach and Colon Carcinoma], Jpn J Cancer Chemother, 1989;16:3185–93.
  23. Futatsuki K, Wakui A, Nakao I, et al., [Late phase II study of irinotecan hydrochloride (CPT-11) in advanced gastric cancer. CPT-11 Gastrointestinal Cancer Study Group], Jpn J Cancer Chemother, 1994;21:1033–8.
  24. Taguchi T, Sakata Y, Kanamaru R, et al., Late phase II clinical study of RP56976 (docetaxel) in patients with advanced/recurrent gastric cancer: a Japanese Cooperative Study Group trial (group A), Gan To Kagaku Ryoho, 1998;25:1915–24.
  25. Mai M, Sakata Y, Kanamaru R, et al., A late phase II clinical study of RP56976 (docetaxel) in patients with advanced or recurrent gastric cancer: a cooperative study group trial (group B), Gan To Kagaku Ryoho, 1999;26:487–96.
  26. Yamada Y, Shirao K, Ohtsu A, et al., Phase II trial of paclitaxel by three-hour infusion for advanced gastric cancer with short premedication for prophylaxis against paclitaxel-associated hypersensitivity reactions, Ann Oncol, 2001;12:1133–7.
  27. Kim YH, Koizumi W, Lee KH, et al., Randomized phase III study of S-1 alone versus S-1 plus Docetaxel in the treatment for advanced gastric cancer: The START trial, J Clin Oncol, 2011;29(suppl. 4):abstract 7. - 27b. Yoshida K Fujii M, Koizumi W, et al., S-1 plus Docetaxel versus S-1 for Advanced Gastric Cancer (START trial) Update 2012, Ann Oncol, 2012;23(S9):(abstr LBA19).
  28. Koizumi W, Takiuchi H, Yamada Y, et al., Phase II study of oxaliplatin plus S-1 as first-line treatment for advanced gastric cancer (G-SOX study), Ann Oncol, 2010;21:1001–5.
  29. Koizumi W, Nakayama N, Tanabe S, et al., A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601), Cancer Chemother Pharmacol, 2012;69:407–13.
  30. Ajani JA, Faust J, Ikeda K, et al., Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma, J Clin Oncol, 2005;23:6957–65. 30b. Hoff PM, Saad ED, Ajani JA, et al., Phase I study with pharmacokinetics of S-1 on an oral daily schedule for 28 days in patients with solid tumors, Clin Cancer Res, 2003;9(1):134–42.
  31. Ajani JA, Lee FC, Singh DA, et al., Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma, J Clin Oncol, 2006;24:663–7.
  32. Lenz HJ, Lee FC, Haller DG, et al., Extended safety and efficacy data on S-1 plus cisplatin in patients with untreated, advanced gastric carcinoma in a multicenter phase II study, Cancer, 2007;109:33–40.
  33. Ajani JA, Pantigoso WR, Bodoky G, et al., Non inferiority analysis of multicenter phase III comparing Cisplatin/S-1 (CS) with Cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): Methodology and Results, Ann Oncol, 2012;23:(Suppl. 9):(abstr 668PD). - 33b. - Bodoky G, Carrato A, Ravaioli A, Ajani JA, Quality of life in FLAGS trial: A randomized, Phase III of Teysuno® (S-1) + cisplatin (CS) compared to 5-FU + cisplatin (CF) in untreated advanced gastric cancer (AGC) patients, Ann Oncol, 2012;(S9):(abstr 695P).
  34. Ajani JA, Rodriquez W, Bodoky G, et al., Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): Secondary and subset analyses, J Clin Oncol, 2009;27(suppl. 15) abstract 1145 (ASCO annual meeting, Orlando, Florida, US, 29 Mar – 2 June 2009).
  35. Cutsem EV, Moiseyenko VM, Tjulandin S, Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study Group, 2006;24(31):499–7.
  36. Tebbutt NC, Cummins MM, Sourjina T, Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: the AGITG ATTAX trial, Br J Cancer, 2010;102(3):475–81.
  37. Okines A, Verheij M, Allum W, et al., Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2010;21(Suppl. 5):v50–4.
  38. Chung KY, Saito K, Zergebel C, et al., Phase I study of two schedules of oral S-1 in combination with fixed doses of oxaliplatin and bevacizumab in patients with advanced solid tumors, Oncology, 2011;81(2):65–72.

Further Resources

Share this Article
Related Content In Gastrointestinal Oncology
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72