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Originally published as JCO Early Release 10.1200/JCO.2005.06.006 on September 6 2005 © 2005 American Society of Clinical Oncology.
Just When You Thought the Fluorouracil Debate Was Over: S-1 and Gastric CancerMemorial Sloan-Kettering Cancer Center, New York, NY Despite a decline in incidence in the United States and Western Europe, gastric cancer is common worldwide and remains the second leading cause of cancer-related death. In a shift in the epidemiology of gastric cancer, adenocarcinomas of the esophagus and gastroesophageal junction are increasing at a dramatic rate in the United States and Western Europe, and represent an even more virulent disease entity.1 The pattern of more distal gastric cancer elsewhere in the world may be a function of rates of infection by Helicobacter pylori, dietary practices, and potential dietary deficiency in micronutrients such as selenium and vitamin C. The predominance of adenocarcinoma of the esophagus and gastroesophageal junction in the West may reflect population trends in obesity and tobacco abuse, and paradoxically, a decrease in Helicobacter infection that may increase the risk of esophageal reflux disease.2 Because of the absence of effective screening, patients with gastric cancer in the United States usually present with symptomatic and either locally advanced or metastatic disease. High rates of recurrence after surgery have engendered decades of clinical trials evaluating the use of adjuvant chemotherapy, with or without radiation. Fortunately, recent clinical trials have made advances with the validation of the use of systemic chemotherapy to improve survival. Intergroup trial 116 showed that postoperative bolus fluorouracil (FU), leucovorin, and radiation therapy improved survival compared with surgery alone, despite the relative inactivity for FU and leucovorin in metastatic disease.3 Although postoperative adjuvant chemotherapy alone has failed to affect survival in gastric cancer, pre- and postoperative chemotherapy with epirubicin, cisplatin, and protracted-infusion FU (ECF) without the use of radiation, as recently reported in the MAGIC trial from the United Kingdom, significantly improved survival compared with surgery alone.4 The improvement in survival in recent adjuvant trials, however, is marginal, and the key to further progress is the identification of more active systemic agents in gastric cancer. The evaluation of a novel combination chemotherapy regimen, S-1 and cisplatin, is the focus of the phase I trial reported by Ajani et al in the current issue of the Journal of Clinical Oncology.5 This trial raises important issues about the pace of progress of chemotherapy development in gastric cancer, including the role of oral agents as a replacement for intravenous drugs. The trial also, for better or for worse, rekindles the time-worn debate of how best to administer fluoropyrimidines as part of combination chemotherapy. Conventional chemotherapy used in the treatment of gastric cancer has limited effectiveness and significant toxicity, depending on the dose and schedule of agents used. If we are searching for direction in gastric cancer drug development, colorectal cancer should clearly serve as a model. Progress has been made in colorectal cancer in the identification of new chemotherapy agents, optimal dosing and scheduling of agents, and the incorporation of targeted therapies. Colorectal cancer trials have firmly established that, in comparison with bolus FU, the use of continuous-infusion FU administered as a biweekly 48-hour infusion results in superior antitumor efficacy, longer patient survival, and improved therapy tolerance.6 The debate about the optimal schedule of FU has largely been replaced by discussion of the best sequencing of available therapies and the addition of targeted agents. The substitution of oral agents for continuous-infusion FU is a topic of more secondary interest given the accumulating data from phase III trials that show equivalence, but not necessarily superiority, of oral drugs.7 Whereas response, survival, and toxicity benefits have all been accomplished in colorectal cancer trials, such advances have eluded gastric cancer investigators. In gastric cancer, there has been a seeming reluctance to incorporate lessons learned from the trial experience in colorectal cancer. There is continued acceptance of the combination of a 5-day infusion of FU in combination with every 3- to 4-week dosing of relatively high doses of cisplatin. The toxicity and limited efficacy of this regimen was underscored in a phase III trial reported in the Journal, comparing FU and cisplatin to other FU-based regimens.8 The authors questioned the adoption of FU and cisplatin as a treatment standard, and by extension, whether or not FU and cisplatin is either the appropriate platform on which to add new agents, or the appropriate comparator arm for evaluating new therapies. The difficulty in building on FU and cisplatin was highlighted in a recent phase III trial attempting to combine a third agent, docetaxel, to conventional FU and cisplatin.9 Despite a higher response rate and improvement in time to progression for three-drug therapy with docetaxel, toxicity was prohibitive, and a survival improvement of only 0.6 months was achieved. Conversely, other investigators have started to take heed from the colorectal cancer trial experience, with phase II and III trials evaluating weekly and bi-weekly infusion schedules of FU in combination with platinum drugs, taxanes, and irinotecan. These trials indicate promising therapy activity and, of equal importance, potentially better therapy tolerance.10-12 In addition, the continued use of relatively high and relatively toxic doses of cisplatin (75 to 100 mg/m2) has also been called into question, given data from the phase III ECF trials indicating potential better therapy tolerance for 60 mg/m2 without evidently compromising treatment efficacy.13 In light of these data, is a 5-day infusion of FU in combination with cisplatin still the appropriate "standard" with which newer therapies should be compared? In past studies of colorectal cancer, the Mayo Clinic regimen of FU and leucovorin was the standard treatment. Given the toxicity of Mayo Clinic FU and leucovorin, other regimens invariably looked better. Comparison of newer gastric cancer therapies with FU and cisplatin may also give a potentially false sense of superiority. In what context should we place the current trial of S-1 and cisplatin reported by Ajani et al5? S-1 is an alternative formulation of the oral FU prodrug tegafur, combined with CDHP (5-chloro-2,4-dihydroxypyridine), a DPD (dihydropyrimidine dehydrogenase) inhibitor, and potassium oxonate, an agent which may reduce diarrheal toxicity of tegafur, but whose mechanism of action remains unclear. S-1 was evaluated in Japan in advanced gastric cancer, with single-agent and combination activity ranging from 20% to 50%.14,15 Based largely on only phase II studies, S-1 has been embraced as the preferred oral FU prodrug in Japan. The high response rate and tolerance of this agent reported in phase II trials in Japanese patients has not been duplicated in the United States. The current trial indicates a potential greater toxicity observed for S-1 in US patients, with the dose of S-1 (50 mg/m2) established for combination with cisplatin being significantly lower than the 80 mg/m2 dose reported in Japanese phase II trials. From the pharmacokinetic data, it appears that a higher area under the curve of FU is achieved in white patients at much lower doses of S-1 in comparison to Japanese patients. These data suggest differences in activation of tegafur to FU, potentially due to ethnic variation in isoforms of the enzyme cytochrome p450. Other authors have also speculated that the differences in toxicity of S-1 may arise from dosing to body-surface area, as Japanese patients tend to have a lower body-surface area than US patients.16 Ironically, the pharmacokinetic data for potassium oxonate, the agent in S-1 supposedly added to reduce diarrhea, indicate that the agent can be metabolized to a potentially toxic metabolite whose area under the curve correlates with increased diarrheal toxicity rather than bowel protection. The authors discuss the importance of evaluating potential individual and ethnic differences in drug metabolism leading to differential dose tolerance and toxicity. The study of individual and population pharmacogenomics represents a promising area of future research in the optimal selection of drug therapy for each patient. What is the potential of S-1 for future study? Do we really need yet another alternative dosing and schedule of FU administration in gastric cancer? Given only the availability of phase I/II data for S-1, the jury is still out. Phase III trials of S-1 will need to demonstrate compelling data not only for significantly greater efficacy, but also less therapy toxicity and improved patient quality of life and no excess cost in comparison to the optimal schedule of conventional FU infusion. We should accept the experience from colorectal cancer trials, and weekly or biweekly FU infusion should be considered as a replacement for "standard" 5-day FU infusion. This will ensure that evaluation of a new therapy will not yield what seems to be a superior alternative, rather than just a lesser evil. S-1 will also face comparison to other FU prodrugs such as capecitabine. S-1 combines three agents in one formulation, and the current phase I trial raises issues about patient variability of metabolism of each of the components leading to potentially greater toxicity. Capecitabine is a single drug, and although a three-step activation is required before the end production of FU, multiple components are not involved. Phase III evaluation of capecitabine combination therapy relative to protracted infusion FU on the ECF schedule is the subject of the ongoing REAL-2 trial in the United Kingdom in gastric cancer, which will evaluate a thousand patients with metastatic gastric cancer. The advent of targeted therapies has increased the sense of urgency to move beyond the reshuffling of dose and schedule of the older cytotoxic drugs to the evaluation of new agents combined or sequenced with the most active and the best-tolerated chemotherapy foundation. Such trials are already underway, incorporating epidermal growth factor receptor and vascular endothelial growth factor–targeted agents. Advances in pharmacogenomics, but also in pharmacogenetics, the germ-line variation of tumor target expression in each patient, will hopefully lead to better tailoring of therapy to the individual patient. Despite the enshrinement of FU in the field of gastric cancer oncology, it is clearly time to put the age old FU debate behind us. Author's Disclosures of Potential Conflicts of Interest The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCOapos;s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
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2. Engel LS, Chow WH, Vaughan TL, et al: Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst 95:1404-1413, 2003
3. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-734, 2001 4. Cunningham D, Allum W. Stenning SP, et al: Perioperative chemotherapy in operable gastric and lower oesophageal cancer: Final results of randomized, controlled trial. J Clin Oncol 23:308, 2005 (abstr 4001)
5. Ajani J, Faust J, Ikeda K, et al: Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol 23:6957-6965, 2005
6. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 7. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. Amer Soc Clin Oncol 19:2282-2292, 2001
8. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000 9. Moiseyenko VM, Ajani J, Tjulandin SA, et al: Final results of randomized controlled phase III trial (TAX 325) comparing docetaxel combined with cisplatin and 5-fluorouracil to CF in patients with metastatic gastric adenocarcinoma. J Clin Oncol 23:308s, 2005 (abstr 4002) 10. Dank M, Zaluski J, Barone C, et al: Randomized phase 3 trial of irinotecan + 5FU/folinic acid vs CDDP + 5FU in first line advanced gastric cancer patients. J Clin Oncol 23:308s, 2005 (abstr 4003) 11. Al-Batran SE, Stohlmacher J, Probst S, et al: Fluorouracil, leucovorin and oxaliplatin versus fluorouracil, leucovorin and cisplatin as first line therapy for patients with advanced gastric cancer. J Clin Oncol 23:311s, 2005 (abstr 4015)
12. Thuss-Patience PC, Kretzschmar A, Repp M, et al: Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: A randomized phase II study. J Clin Oncol 23:494-501, 2005
13. Ross P, Nicolson M, Cunningham D, et al: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996-2004, 2002 14. Sakata Y, Ohtsu A, Horikoshi N, et al: Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 in advanced gastric cancer. Eur J Cancer 34:1715-1720, 1998 15. Koizumi W, Tanabe S, Saigenji K, et al: Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer 89:2207-2212, 2003[CrossRef][Medline] 16. Comets E, Ikeda K, Hoff P, et al: Comparison of pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients. J Pharmacokinet Pharmacodyn 30:257-283, 2003[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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