the Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
    University of New Mexico, Albuquerque, NM
    University of Chicago
    Northwestern University, Chicago, IL
    University of Pennsylvania, Philadelphia, PA
    University of Southern California, Los Angeles
    Hazel Hawkins Hospital, Hollister, CA
    University of Bochum, Herne, Germany

    ABSTRACT

    PURPOSE: S-1 plus cisplatin is considered highly active in Japanese gastric cancer patients. We conducted a phase II multi-institutional trial, in the West, in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma to evaluate activity and safety of this combination.

    METHODS: Patients received cisplatin intravenously at 75 mg/m2 on day 1 and S-1 orally at 25 mg/m2/dose bid (50 mg/m2/d) on days 1 to 21, repeated every 28 days. Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with a Karnofsky performance status (KPS) of  70% and near-normal organ function were eligible. All patients provided a written informed consent. To observe a 45% confirmed overall response rate (ORR), 41 assessable patients were needed.

    RESULTS: All 47 patients were assessed for safety and survival, and 41 patients were assessed for ORR. The median age was 56 years and median KPS was 80%. The median number of chemotherapy cycles was four. The confirmed ORR was 51% (95% CI, 35% to 67%) and it was 49% by an independent review. At the 6-month interval, 71% of patients were alive, with a median survival time of 10.9 months. Frequent grade 3 or 4 toxicities included fatigue (26%), neutropenia (26%), vomiting (17%), diarrhea (15%), and nausea (15%); however, stomatitis (2%) and febrile neutropenia (2%) were uncommon. There was one (2%) treatment-related death.

    CONCLUSION: S-1 plus cisplatin is active against gastric cancer and has a favorable toxicity profile. A global phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin currently is accruing patients.

    INTRODUCTION

    Gastric cancer is rampant in several regions of the world, with approximately 930,000 new cases diagnosed each year.1 It is often diagnosed in late stages except in Japan and Korea, where early detection programs are in place. Once the disease becomes metastatic, gastric cancer is incurable and carries a dismal prognosis with a short median survival time. Even though many active agents have been identified, overall, patient benefit from the currently available regimens is limited and the toxicity profile is less than desirable. The need to develop effective treatments with a favorable safety profile is urgent.

    S-1, a fourth-generation oral fluoropyrimidine, is an oral formulation of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) at a molar ratio of 1:0.4:1.2 FT is the prodrug for cytotoxic fluorouracil (FU) and CDHP prevents its degradation. In animal models, Oxo is protective against FT-induced diarrhea.3,4 The diarrheagenic property of FU is due to its phosphorylation in the intestine primarily by orotate phosphoribosyltransferase. Oxo is a specific inhibitor for orotate phosphoribosyltransferase. Thus, the protective effect of Oxo is from its ability to reduce phosphorylation of FU; however, FU can also be phosphorylated by uridine phosphorylase or thymidine phosphorylase, generating fluorodeoxyuridine monophosphate and thus resulting in diarrhea. CDHP is a potent and competitive inhibitor of dihydropyrimidine dehydrogenase, and thus results in higher concentrations of FU.5 Pharmacokinetic studies of S-1 have demonstrated substantial prolongation of the half-life of FU.6 Given that FT is metabolized differently in Asians and whites due to polymorphic differences in the CYP2A6 gene, a phase I pharmacokinetic study in Western patients determined the maximum-tolerated dose of S-1 was 50 mg/m2 per day (on days 1 through 21) and that of cisplatin was 75 mg/m2 on day 1 of a 28-day cycle.7

    A number of studies have reported activity of S-1 as a single agent against gastric cancer,8-10 with response rates ranging from 26% to 45%. In addition, a 76% response rate was reported in one Japanese study of 25 patients when S-1 was combined with cisplatin; the study used a slightly different schedule and a higher dose of S-1.11 We report on activity and safety data of a phase II multi-institution trial in patients with untreated, advanced gastric cancer conducted at participating North American and European institutions.

    PATIENTS AND METHODS

    Eligibility

    All patients with advanced, unresectable, histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction were eligible provided they were  18 years of age with a Karnofsky performance status (KPS) of  70%, had a life expectancy of  12 weeks, absolute granulocyte count of  1,500/μL, a platelet count  100,000/μL, a hemoglobin of  9.0 g/dL, serum bilirubin of  1.5x the upper limit of normal (ULN), and a normal creatinine level. Patients also were required to have ALT and AST  2.5x the ULN ( 5x the ULN in the presence of liver metastases). The presence of measurable cancer by the Response Evaluation Criteria in Solid Tumors Group criteria was required. Only patients who could swallow tablets were eligible. Prior chemotherapy for advanced cancer was not allowed. Patients who received adjuvant therapy were eligible provided more than 6 months had elapsed between the end of adjuvant therapy and registration on this study. All patients were told to practice effective contraception. An approved written informed consent was required. Patients were excluded if they had brain metastases, severe comorbid conditions, or lack of the ability to comply with the requirements of the protocol. Patients receiving drugs with potential interactions with S-1 (flucytosine, allopurinol, and phenytoin) were excluded.

    Pretreatment Evaluations

    The baseline evaluations included history, complete physical examination, urine pregnancy test (for women), KPS, CBC, serum chemistries and electrolytes, urinalysis, chest x-ray, and recording of concomitant medications. In addition, imaging studies (computed tomography or magnetic resonance imaging) were performed.

    Chemotherapy

    Patients received S-1 at a dose of 25 mg/m2 orally twice daily on days 1 to 21 followed by a 7-day recovery period. The drug was administered at least 1 hour before or after a meal. Compliance and drug accountability were thoroughly scrutinized: patients were asked to keep a daily diary tracking S-1 and all other medications.

    Cisplatin was administered intravenously during 2 hours at 75 mg/m2 on day 1. Standard premedications and hydration were administered. Cycles were repeated every 28 days.

    If the limiting toxicity from cisplatin caused it to be discontinued (for example, creatinine elevations or neuropathy), S-1 could be continued as a single agent. Chemotherapy was continued until there was evidence of progression, consent withdrawal, or the development of unacceptable toxicity in the investigator's opinion.

    Evaluation During Therapy

    CBC and serum chemistries were monitored weekly during therapy. Response to therapy was assessed following the first cycle of the combination.

    Response and Toxicity Criteria

    Response Evaluation Criteria in Solid Tumors Group criteria were used to assess the type of response and National Cancer Institute Common Toxicity Criteria version 2.0 were used to assess toxicity (www.cancer.gov/).

    Response was evaluated after the first cycle and evaluation was repeated after the second cycle to confirm the response if the measurements after the first cycle suggested a partial or complete response. Thereafter, the evaluations were carried out every two cycles. Radiographs of all assessable patients were also reviewed externally to confirm investigator-designated responses.

    Dose Modifications

    Given that this study involved two agents, dose adjustments were made for each agent if a distinction in toxicity could be made. If both agents were believed to be causing the toxicity, dose reduction was performed for both. S-1 dose modification was to be made in two ways: during a 4-week cycle and at the initiation of a subsequent cycle. If a related grade 3 or 4 toxicity occurred during therapy, S-1 was withheld and resumed at a reduced (5 mg/m2) dose when toxicity resolved, and the reduce dose was used for subsequent cycles. Cisplatin was also reduced by 25% for the subsequent cycle if related grade 3 or 4 toxicity occurred. Drug doses were never increased.

    Statistical Considerations

    The primary end point of this study was to assess the overall response rate (ORR). An ORR of 45% was considered valuable enough to pursue this combination in a phase III trial. Simon's optimum two-stage design was used.12 The first stage required at least six or more patients of 17 to have a confirmed partial and complete response assuming P1 = .45, P0 = .25, with  = .05 and  = .2 before proceeding to the second stage. In the second stage, 24 assessable patients could be added and if a total of 15 or more patients achieved a confirmed objective response, then the primary end point would have been met.

    RESULTS

    Patient Population

    A total of 47 patients were recruited; 41 patients were assessable. All 47 were evaluated for safety and overall survival (OS) calculations. The majority of patients (75%) were white and 15% were black and/or Latino. Forty-one assessable patients were assessed for ORR and time to progression (TTP). An eligible patient was defined as one who received at least two cycles of chemotherapy. Patients were also considered assessable if there was evidence of rapid progression of cancer. Six patients were not assessable for ORR because one died as a result of a ruptured abdominal aortic aneurysm on day 8 of the second cycle after having an objective and subjective improvement; one required intervention for a known coronary artery disease after the first day of the first cycle (the patient never resumed therapy); an investigator inadvertently stopped therapy in one patient after one cycle; one responding patient required drainage of an abdominal abscess after one cycle in a non-neutropenic stetting (never resumed therapy); one patient withdrew consent after one cycle to relocate to another state; and there was one treatment-related death before completion of the first cycle. Patient characteristics are listed in Table 1. In this predominantly male population, gastroesophageal junction was involved in 25 patients (53%), the median KPS was 80%, and the majority of patients had two or more sites of metastases.

    Antitumor Activity

    A median of four cycles per patient was administered with a range from 1 to 10. The confirmed ORR was 51% (95% CI, 35% to 67%). One patient achieved a compete response. The radiographs of all assessable patients were (independently) reviewed externally and the confirmed ORR by this process was 49% (95% CI, 33% to 65%). The median duration of response was 4.9 months. Twelve (29%) patients had stable cancer and eight patients (20%) had progression of cancer. At this writing, four patients are continuing therapy. More details are listed in Table 2.

    OS and TTP

    The median TTP, assessed in 41 patients, was 4.8 months (95% CI, 3.8 to 6.1 months; Fig 1). OS was calculated in all 47 patients and at a median follow-up time of 7.8 months, the median survival time was 10.9 months (95% CI, 7.9 months to not reached; Fig 2). Seventy-one percent of patients remained alive at the 6-month interval (95% CI, 55% to 82%). Approximately 40% of patients are projected to remain alive at 1 year.

    Safety

    All 47 patients were assessed for safety. One patient with a body surface area of 2.34 m2 who received a daily S-1 dose of 120 mg developed grade 4 diarrhea, neutropenia, and died before the end of the first cycle (treatment-related death). Twelve patients required S-1 dose reduction and six patients required cisplatin dose modification. Hematologic toxicities are listed in Table 3. Grade 3 or 4 neutropenia was recorded in 26% of patients. Grade 3 or 4 anemia (11%) and thrombocytopenia (4%) were not common. Nonhematologic toxicities are listed in Table 4. Among the grade 3 or 4 toxicities, the most frequent was fatigue (26%), vomiting (17%), diarrhea (15%), and nausea (15%). All other grade 3 or 4 toxicities were recorded in less than 15% of patients. Notably, febrile neutropenia occurred in 2% of patients and stomatitis occurred in 2% of patients. Grade 3 or 4 skin toxicity was not observed. Only one patient experienced grade 1 hand-foot syndrome. Grade 1 excessive lacrimation was reported by 21% of patients.

    DISCUSSION

    Even though worldwide gastric cancer incidence rivals that of colorectal cancer, the progress against advanced gastric cancer has been painfully slow. Only a few new active agents have been identified and the number of phase III trials conducted in the past decade pales in comparison with those performed in patients with advanced colorectal or pancreatic cancer. The reasons for such slow progress are difficult to characterize; however, its low incidence in the West probably is a contributing cause. Among the newly identified active agents or classes (camptothecins, taxanes, platinum analog, and S-1), only docetaxel and irinotecan have completed phase III investigation,13,14 and a phase III trial containing oxaliplatin has met its target accrual with preliminary response results published15 (final results are awaited). Tolerance of therapy and quality of life are of particular importance in patients with metastatic gastric cancer because a majority of patients have considerable symptoms at baseline that are significantly complicated by therapy. In that context, docetaxel, when combined with cisplatin plus FU provides significant prolongation of TTP and OS compared with cisplatin plus FU; however, the combination of docetaxel, cisplatin, plus FU is an intensive regimen and requires constant patient monitoring or intervention to improve safety.14,16

    S-1, a fourth-generation oral fluoropyrimidine, provides a considerable advantage in patient convenience and safety.7 Although approved for the gastric cancer indication in Japan and Korea, S-1 remains a subject of phase III investigation as a single agent and in combination with cisplatin in Japan. The interest in S-1 in the West has been considerable, but the well-tolerated doses used in Japan resulted in considerable toxicity in whites.7 This difference in tolerance is probably due to the differences in the efficiency of cytochrome P-450 enzyme system determined by polymorphisms in different populations. However, a phase I study of S-1 plus cisplatin in untreated gastric cancer patients established that only 50 mg/m2/d of S-1 was the maximum-tolerated dose with cisplatin in Western patients7 compared with 80 mg/m2/d proposed in Japanese patients.11

    In this trial, the primary end point was ORR. A confirmed ORR of 51% (49% by an external review) in 41 assessable patients is encouraging, especially in view of the tolerance of this combination that resulted in a low rate of neutropenia (26%) and only a 2% rate of complicated neutropenia. Severe diarrhea was observed in 15% of patients and it was mainly grade 3. There was one treatment-related toxic death in a white patient with body surface area exceeding 2.3 m2 who had received a daily dose of 120 mg of S-1. This patient experienced grade 4 diarrhea associated with sepsis. We speculate that Western patients who receive a total daily dose of S-1 120 mg or more need to be monitored more closely. The median survival of 10.9 months for 47 patients is also cautiously encouraging, although the median follow-up time is 7.8 months at the time of this analysis.

    The entire arena of therapy of solid tumors is in need of a paradigm shift. Continuing to treat patients until clinical progression or unacceptable toxicity should no longer be considered routine or unchangeable. Consideration should be given to developing strategies in which initial therapies are used for maximum response and later therapies (those that permit chronic and either oral or infrequent parenteral administration) are used as maintenance therapy. This type of new paradigm, if it can be orchestrated successfully, is likely to result in a longer TTP and OS but also in improved safety and better quality of life. In that context, the TTP from prior studies in patients with metastatic gastric cancer has been less than 6 months (often approximately 5 months) and survival has not exceeded 9 months. We believe an expectation of a TTP of 6 to 7 months and median survival of 11 months could be the minimum from the agents currently under investigation. However, a median survival of at least 12 months and a TTP of at least 8 months would strongly suggest that a significant advance in the treatment of patients with advanced gastric cancer has been made. We hope and believe that milestone is around the corner.

    On the basis of the encouraging ORR results on this phase II trial, along with an excellent safety profile, a global phase III study has been launched. In this phase III study, activated in more than 150 institutions in 26 countries, approximately 700 patients with untreated advanced or locally unresectable gastric cancer are being stratified and randomly assigned to S-1 plus cisplatin or FU plus cisplatin. The primary end point of this study is OS; however, multiple secondary and exploratory end points have been built in. At this writing, this phase III study has already accrued more than 35% of total patients needed to meet its primary end point.

    In conclusion, the combination of S-1 and cisplatin is highly active and well tolerated. S-1 plus cisplatin has entered a prospective randomized phase III study.

    Authors' Disclosures of Potential Conflicts of Interest

    Although all authors completed the disclosure declaration, the following authors or their 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 ASCO'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.

    AuthorsEmploymentLeadershipConsultantStockHonorariaResearch FundsTestimonyOther

    Jaffer A. AjaniTaiho (B)Taiho (C)

    Fa-Chyi LeeTaiho (A)Taiho (A)Taiho (B)

    Deepti A. SinghTaiho (A)Taiho (B)

    Daniel G. HallerTaiho (A)Taiho (B)

    Heinz-Josef LenzTaiho (A)Taiho (B)

    Al B. Benson IIITaiho (A)Taiho (B)

    Ronald YanagiharaTaiho (B)Taiho (A)

    Dirk StrumbergTaiho (A)Taiho (A)

    Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)  $100,000 (N/R) Not Required

    Author Contributions

    Conception and design: Jaffer A. Ajani

    Provision of study materials or patients: Jaffer A. Ajani, Fa-Chyi Lee, Deepti A. Singh, Daniel G. Haller, Heinz-Josef Lenz, Al B. Benson III, Ronald Yanagihara, Alexandria T. Phan, James C. Yao, Dirk Strumberg

    Collection and assembly of data: Jaffer A. Ajani

    Data analysis and interpretation: Jaffer A. Ajani

    Manuscript writing: Jaffer A. Ajani

    Final approval of manuscript: Jaffer A. Ajani, Fa-Chyi Lee, Deepti A. Singh, Daniel G. Haller, Heinz-Josef Lenz, Al B. Benson III, Ronald Yanagihara, Alexandria T. Phan, James C. Yao, Dirk Strumberg

    Acknowledgment

    We thank Lukas Makris and John Ilgenfritz for data analysis at BioCor, Yardley, PA.

    NOTES

    Supported by a grant from Taiho Pharma USA Inc, Princeton, NJ.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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