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Japanese Journal of Clinical Oncology Advance Access originally published online on June 21, 2007
Japanese Journal of Clinical Oncology 2007 37(6):469-472; doi:10.1093/jjco/hym046
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© 2007 Foundation for Promotion of Cancer Research

A Randomized Phase II Selection Trial in Patients with Advanced/Recurrent Gastric Cancer: Trial for Advanced Stomach Cancer (TASC)

Satoshi Morita1,, Hideo Baba2, Akira Tsuburaya3, Hiroya Takiuchi4, Takanori Matsui5, Yoshihiko Maehara6 and Junichi Sakamoto1

1 Department of Medical Administration, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya
2 Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto
3 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama
4 Second Department of Internal Medicine, Osaka Medical College, Osaka
5 Department of Clinical Research, Aichi Cancer Center Aichi Hospital, Aichi
6 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

For reprints and all correspondence: Satoshi Morita, Department of Medical Administration, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, 65 Tsuruma-Cho, Showa-Ku, Nagoya, 466-8550, Japan. E-mail: smorita{at}med.nagoya-u.ac.jp

Received December 15, 2006; accepted January 28, 2007


   Abstract
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 Abstract
INTRODUCTION
 PROTOCOL DIGEST OF THE...
 Conflict of interest statement
 References
 
A randomized phase II clinical trial is being conducted for patients with advanced or recurrent gastric cancer, in order to select the most promising treatment for subsequent evaluation in a large-scale phase III trial. We compare four chemotherapeutic treatments, which include two sequential and two combination regimens using paclitaxel with 5-fluorouracil or S-1, an oral fluorouracil derivative. The primary endpoint is 10-month overall survival rate, while the secondary endpoints are adverse events, time to treatment failure and progression-free survival. A Bayesian method is used to provide a statistical rule for monitoring the trial. Forty patients per treatment regimen (160 in total) were randomized into one of the four regimens using a centralized dynamic method.

Key Words: Randomized phase II trial • gastric cancer • chemotherapy • Bayesian trial monitoring


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PROTOCOL DIGEST OF THE...
 Conflict of interest statement
 References
 
In Japan, where the incidence of gastric cancer is the highest in the world, many clinical trials have been performed to investigate its optimal chemotherapeutic treatments (1,2). Based on the results of those trials,fluorinated pyrimidines such as 5-fluorouracil (5-FU) and tegafur/gimeracil/oteracil potassium (S-1), cisplatin (CDDP), paclitaxel (TXL), and irinotecan (CPT-11), have been used as key drugs for advanced gastric cancer.

To date, the Japan Clinical Oncology Group (JCOG) has conducted clinical trials to compare many combination therapies most often of two drugs, taking 5-FU monotherapy as control. For example, the JCOG Study 9205 compared two chemotherapeutic regimens, including UFT (uracil plus tegafur) plus mitomycin C (MMC) and 5-FU plus cisplatin (CDDP) to 5-FU monotherapy in patients with unresectable advanced gastric cancer (3). Inferiority of UFT plus MMC was demonstrated, while no significant survival difference was shown between 5-FU plus CDDP and 5-FU alone. Recently, many phase II and phase III studies have been conducted to examine S-1 containing regimens and S-1 monotherapy in Japan. Thus, a new phase III study (JCOG 9912) comparing two chemotherapeutic regimens of CPT-11 plus CDDP and S-1, with 5-FU as control, has been conducted. Patient enrollment in this trial was completed in January 2006 and the final data analysis will be performed in early 2007.

While initial treatment for patients with unresectable advanced gastric cancer in Western countries commonly includes combination therapy with three drugs, monotherapy and combination therapy with two drugs are more favored in Japan. There is an urgent need to develop more efficacious first-line and second-line treatment regimens for unresectable advanced gastric cancer. We are therefore performing a randomized phase II trial to compare the following four treatment regimens: (Group A) sequential 5-FU monotherapy followed by TXL monotherapy, (Group B) sequential S-1 monotherapy followed by TXL monotherapy, (Group C) concurrent 5-FU and TXL, and (Group D) concurrent S-1 and TXL.


   PROTOCOL DIGEST OF THE STUDY
TOP
 Abstract
 INTRODUCTION
 PROTOCOL DIGEST OF THE...
Conflict of interest statement
 References
 
Purpose
The purpose of the study is to select the most promising chemotherapy regimen among four regimens using paclitaxel (TXL) concurrently and as a second-line treatment, with fluorouracil (5-FU) or tegafur/gimeracil/oteracil potassium (S-1), for a future randomized phase III trial in patients with advanced or recurrent gastric cancer.

Study Setting and Protocol Review
The study is an open-label, randomized phase II clinical trial (4,5). The protocol has been approved by the Protocol Review Committee of the Japan South West Oncology Group (JaSWOG).

Resources
Research grants are from the Epidemiological and Clinical Research Information Network (ECRIN) and the Kyoto University EBM Collaborative Research Center.

Endpoints
The primary endpoint is 10-month overall survival (OS) rate. The secondary endpoints are incidence of adverse events, time to treatment failure, progression-free survival time and OS time. In addition, objective tumor response is to be evaluated in a subpopulation of patients with measurable disease.

Eligibility Criteria
Patients with a histologically confirmed diagnosis of advanced or recurrent gastric cancer are eligible.

Inclusion Criteria

  1. Histologically confirmed gastric adenocarcinoma;
  2. No previous antitumor therapy expect for operation and postoperative adjuvant chemotherapy using an oral fluoropyrimidine, completed six months before enrollment into this trial;
  3. Age ≥ 20 years;
  4. ECOG performance status 0–1;
  5. Sufficient organ function before chemotherapy according to the following laboratory data: WBC ≥ 3000/mm3 or neutrocytes ≥ 1500/mm3; platelets ≥ 100 000/mm3; hemoglobin ≥ 8.0 g/dl; bilirubin ≤ 1.5 mg/dl; SGOT ≤ 100 IU; SGPT ≤ 100 IU; creatinine ≤ 1.5 mg/dl; creatinine clearance ≥ 50 ml/min; ECG showing no serious arrhythmia and no serious ischemic heart disease;
  6. Oral food intake possible; and
  7. Written informed consent.

Exclusion Criteria

  1. Serious complications including: cerebrovascular disease, poorly controlled diabetes or hypertension, serious infectious diseases, lung fibrosis, interstitial pneumonia, dyspnea, pleural effusion, ascites, hemorrhage, active intestinal ulcer, serious psychiatric disease;
  2. Symptomatic metastasis to the central nervous system;
  3. Patients with active synchronous or metachronous malignancy;
  4. Medical history of serious drug allergy or hypersensitivity to any drugs;
  5. Hypersensitivity to Cremophor EL;
  6. History of alcoholic anaphylaxis;
  7. Women with ongoing pregnancy or breast-feeding, or contemplating pregnancy;
  8. Mental disorders which may affect ability or willingness to provide informed consent or abide by the study protocol;
  9. Continual administration of a steroid; or
  10. Patients judged inappropriate for the study by the clinician.

Registration
Participating investigators are instructed to send an eligibility criteria report to the Data Center at the EBM Collaborative Research Center at Kyoto University. Eligible patients are registered and then randomized to one of the four groups (A, B, C and D) described in the next section by a centralized dynamic method using the following factors: measurable disease according to the RECIST criteria [yes/no], disease type [inoperable advanced/post-operative recurrent (with post-operative chemotherapy)/post-operative recurrent (with no post-operative chemotherapy)], PS [0/1], peritoneal metastasis based on diagnosis with images [yes/no], age [<75/≥75 years] and institution as balancing variables. Information regarding the necessary follow-up examinations and chemotherapy schedule are then sent from the Data Center. The accrual started in December 2005 and is to continue for two years.

Treatment Methods
The following four treatment groups are examined in the present trial.

Group A: Sequential 5-FU monotherapy followed by TXL monotherapy


Formula 046UM1


Group B: Sequential S-1 monotherapy followed by TXL monotherapy


Formula 046UM2


Group C: Concurrent 5-FU + TXL


Formula 046UM3


Group D: Concurrent S-1 + TXL


Formula 046UM4


In the sequential treatment groups A and B, the administration of 5-FU or S-1 monotherapy is to be discontinued if the following are observed: (i) disease progression or occurrence of new disease, (ii) grade 4 toxicities evaluated according to the CTCAE (Common Terminology Criteria for Adverse Events) ver.3.0, (iii) adverse events causing patients to refuse treatment or causing a clinician to discontinue treatment, (iv) increase in the tumor markers CEA and/or CA19–9 in two or more consecutive measurements or symptomatic progression (e.g. cancer pain, dysphagia). Thereafter, clinicians monitor the criteria for initiation of treatment with TXL monotherapy. A post-trial treatment, as a rule, should be a CPT-11 containing regimen.

Follow-up
Disease progression and occurrence of new disease are examined using, as needed, abdominal X-ray, abdominal computed tomography (CT) or magnetic resonance imaging (MRI), thoracic CT, and measurements of the tumor markers CEA and CA19–9, which are performed at baseline and at least every 4–5 weeks during treatment. Blood tests and symptom checks are carried out before treatment and at least every 2 weeks during treatment. In cases where therapy is discontinued owing to toxicity, clinicians should follow-up patients until they recover from the toxicity.

Study Design and Statistical Methods
The primary analysis in this study is aimed at comparing three treatment regimens B, C and D with regimen A, which is regarded as the reference regimen, in terms of the primary endpoint of 10-month OS rate. The comparisons are carried out using Bayesian statistics (6,7). The Bayesian paradigm treats a parameter characterizing important aspects of the phenomenon under study as a random quantity. The parameter of our primary interest is the 10-month OS rate of each regimen. Bayes' theorem is used to combine the observed OS data and the prior distribution that characterized our uncertainty or knowledge about the parameter before starting the trial. We asked a panel of oncologists for pretrial opinions on the endpoints, in order to construct the prior distributions of the treatment regimens (8). The posterior distribution of the parameter given the data is obtained through this Bayesian calculation. The Bayesian method (6,7) is used to provide a rule for selecting one regimen that is sufficiently efficacious to warrant termination of the phase II trial and commence with a future phase III trial. We carry out the Bayesian calculation to monitor the trial.

In addition, overall survival, progression-free survival and treatment success curves are constructed as time-to-event plots by the Kaplan-Meier method (9). Differences between the curves are estimated for superiority using the hazard ratio produced by the Cox regression model (10), accounting for the balancing variables as strata, which are used for randomization. Incidences of grade 3 or 4 adverse events are compared between the treatment groups. The number of patients to be accrued has been set at 40 per treatment regimen (160 in total).

Interim Analysis and Monitoring
The Data and Safety Monitoring Committee (DSMC) independently review the report of trial monitoring regarding efficacy and safety data from the present study. Based on the monitoring, DSMC can consider early termination of a treatment regimen during study and modification of the study protocol including increasing the sample size if any definitive selection is not possible at the end of study. Protocol compliance, safety and on-schedule study progress are also monitored by the DSMC.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PROTOCOL DIGEST OF THE...
 Conflict of interest statement
References
 
None declared.


   Acknowledgments
 
We would like to thank Dr Peter Thall and Dr Marc Buyse for their helpful comments and suggestions.


   References
TOP
 Abstract
 INTRODUCTION
 PROTOCOL DIGEST OF THE...
 Conflict of interest statement
 References
 
1 GLOBOCAN. (2002) databasehttp://www-dep.iarc.fr/globocan/globocan.html.

2 National Cancer Center. (2005) databasehttp://ganjoho.ncc.go.jp/professional/statistics/statistics.html.

3 Shimada Y, Shirao K, Ohtsu A, Hyodo I, Saito H, Yamamichi N, et al. Phase III study of UFT + MMC versus 5-FU + DDP versus 5-FU alone in patients with advanced gastric cancer: JCOG study 9205. (1999) The 35th Annual Meeting of American Society of Clinical Oncology. 272a. Atlanta.

4 Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep (1985) 69:1375–81.[Web of Science][Medline]

5 Lee JJ, Feng L. Randomized phase II designs in cancer clinical trials: current status and future directions. J Clin Oncol (2005) 23:4450–7.[Abstract/Free Full Text]

6 Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring multiple outcomes in clinical trials. Stat Med (1998) 17:1563–80.[CrossRef][Web of Science][Medline]

7 Thall PF, Wooten LH, Tannir NM. Monitoring event times in early phase clinical trials: some practical issues. Clin Trials (2005) 2:467–78.[Abstract/Free Full Text]

8 Spiegelhalter DJ, Freedman LS, Parmar MKB. Bayesian approaches to randomized trials. J Roy Statist Soc Ser A (1994) 157:357–416.[CrossRef]

9 Kaplan EL, Meier P. Nonparametric estimation form incomplete observations. J Am Stat Assoc (1958) 53:457–81.[CrossRef][Web of Science]

10 Cox DR, Oakes D. Analysis of Survival Data. (1984) London: Chapman and Hall.


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This Article
Right arrow Abstract Freely available
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