Japanese Journal of Clinical Oncology 33:238-240 (2003)
© 2003 Foundation for Promotion of Cancer Research
A Phase II Clinical Trial to Evaluate the Effect of Paclitaxel in Patients with Ascites Caused by Advanced or Recurrent Gastric Carcinoma: a New Concept of Clinical Benefit Response for Non-measurable Type of Gastric Cancer
1 Department of Epidemiological and Clinical Research Information Management, Kyoto University, Kyoto, 2 Department of Surgery, Osaka Kousei Nenkin Hospital, Osaka, 3 Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 4 Department of Surgery, Kitano Hospital, Osaka, 5 2nd Department of Surgery, Kansai Medical University, Osaka and 6 Department of Surgery, Kinki University School of Medicine, Osaka, Japan
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ABSTRACT |
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A phase II clinical trial has started in the South West region of Japan to investigate the efficacy and safety of weekly paclitaxel chemotherapy for the treatment of patients with ascites-forming advanced gastric cancer. A novel trial design was created to assess more effectively prospective changes in symptomatology. The study design focuses on the typical features seen in patients with ascites-forming advanced gastric cancer, including girth of the abdomen and impaired performance status, which is evaluated in the endpoint of ‘Clinical Benefit Response – Gastric Cancer’. The more traditional endpoints, objective tumor response and survival, are also included. As nearly 40% of patients with this disease are excluded from traditional phase II trials owing to the absence of ‘measurable’ disease, this study should more precisely illustrate the disease entity affecting patients with advanced gastric cancer.
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INTRODUCTION |
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Initial studies on giving paclitaxel to patients with ascites-forming advanced gastric cancer indicated greater relief of disease-related symptoms than expected from previous results detailing the traditional objective tumor response rate (1). Both Western and Japanese retrospective studies demonstrated that 10–46% of the patients exhibited peritoneal seeding as one of the earliest, perhaps the most troublesome, mode of failure in advanced or recurrent gastric cancers (2–6). As patients with ascites-forming advanced gastric cancer possess an extremely poor prognosis in the context of low objective ‘measurable’ disease, we have designed an open-label, single-arm phase II study to evaluate the efficacy of paclitaxel treatment. The novel design of this study was created to assess more accurately changes in symptomatology. This design focuses on the typical features seen in patients with ascites-forming advanced gastric cancer, by using a composite endpoint termed ‘Clinical Benefit Response – Gastric Cancer (GC)’. This endpoint was created referring to ‘Clinical Benefit Response’, a value created for the evaluation of advanced pancreatic cancers (7–9).
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PROTOCOL DIGEST OF THE STUDY |
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TOPABSTRACTINTRODUCTIONPROTOCOL DIGEST OF THE...ACKNOWLEDGMENTSREFERENCES |
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Purpose
To evaluate the effect of weekly paclitaxel in ascites-forming advanced gastric cancer patients through ‘Clinical Benefit Response – Gastric Cancer’ and survival.
Study Setting and Protocol Review
Open-label, single-arm, phase II clinical trial. Its protocol was approved by the Protocol Review Committee of the Japan South West Oncology Group (JaSWOG).
Resources
Research Grants from the Osaka Foundation of Cancer, Japan.
Endpoints
Primarily, ‘Clinical Benefit Response – GC’. Secondarily, survival, objective tumor response (if any), alterations in tumor markers.
Measurement of Clinical Benefit Response – GC
In this study, Clinical Benefit Response – GC is a composite endpoint of the typical debilitating symptoms of patients with ascites-forming gastric cancer. Ascites fluid (assessed by frequency of abdominal paracentesis, girth of abdomen and diuretic consumption) and functional impairment [assessed by an ECOG performance status (PS)] comprise the measures of the endpoint. Each patient is classified as either positive, stable or negative for each of the two measures. Regarding ascites fluid, positive indicates decrease in frequency of abdominal paracentesis, girth of abdomen or diuretic consumption. Stable represents no change in all the parameters. If any increase in either of the parameters is observed, the ascites fluid measure is designated as being negative. The functional impairment measure is determined in a similar fashion to the ascites fluid, that is, on the basis of change in the ECOG PS (improvement, no change or deterioration in PS).
To achieve a response in terms of an overall rating of the clinical benefit, patients have to be rated ‘positive’ for at least one of the two measures (ascites fluid or functional impairment) without being rated ‘negative’ for another. Otherwise, patients are classified as being non-responsive for the overall rating.
Eligibility Criteria
Tumors should be staged according to the UICC Classification of Gastric Carcinoma. Patients with clinically relevant ascites, defined as the peritoneal seeding of cancer cells determined by medical records including review of pathology report of the primary tumor and/or cytology of ascites fluid, were included.
Inclusion Criteria
1. Histologically demonstrated adenocarcinoma of the stomach.
2. Ascites, diagnosed either by physical examination, cytology, CT or other imaging modalities.
3. Ages over 20 years.
4. ECOG performance status 0–2.
5. Sufficient organ functions.
6. Written informed consent.
Exclusion Criteria
1. Medical history of allergy or hypersensitivity reactions to paclitaxel.
2. Synchronous or metachronous other types of malignancy except early-stage cervical cancer of the uterus and early-stage non-melanoma skin cancer.
Registration
Eligibility criteria checking report form will be sent by Fax to the ECRIN Data Center after confirmation of the above criteria. Patients are then registered; information regarding the necessary follow-up examinations and recommended chemotherapy schedule are then sent from the Data Center.
Treatment Methods
Single-agent paclitaxel (80 mg/m2) as one-hour intravenous infusion is given weekly for 3 weeks, followed by 1 week of rest (one cycle). Consecutive cycles of paclitaxel treatment should continue; the patients should remain in the study either until the appearance of dose-limiting toxicities defined by NCI–CTC criteria, objective evidence of tumor progression or until it is no longer in the patient’s best interest to continue.
A starting dosage of 80 mg/m2 was chosen based on the phase I data (10). Patients completing one cycle of therapy without toxicity should receive the same dose in the subsequent cycle. Dose modification should be based on blood cell count and non-hematological toxicity prior to injections. The dose should be reduced by 10 mg/m2 for grade 3 hematological toxicity. Therapy should be discontinued for grade 4 hematological and/or grade 3 or greater non-hematological toxicity.
Follow-up
Patients should be seen by their physicians every week before paclitaxel injection. Measurement of the girth of abdomen and body weight is performed on days 1 and 15 of each cycle. After the identification of a principal tumor marker, which is highest in comparison with other markers at registration, the FACT QOL questionnaire (11) should be completed and computed tomography studies (optional) should be performed prior to treatment and every month thereafter. The physician should record the frequency and quantity of ascites fluid each time abdominal paracentesis is performed during the study.
Study Design and Statistical Methods
This study is designed to evaluate 60 refractory or chemonaive patients with ascites-forming advanced gastric cancer. The sample size was calculated on the basis that a clinical benefit response rate was expected to range from 20 to 50%. Given the sample size, 95% two-sided confidence intervals for the rates were calculated to be ±10 to ±13% using the normal approximation to the binominal variable.
Participating Institutions
Kinki University, Kansai Medical University, Osaka City General Hospital, Kitano Hospital, Osaka Medical Center for Cancer and Cardiovascular Diseases
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ACKNOWLEDGMENTS |
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This study is supported in part by a non-profit organization Epidemiological and Clinical Research Information Network (ECRIN).
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FOOTNOTES |
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+ For reprints and all correspondence: Junichi Sakamoto, Department of Epidemiological and Clinical Research Information Management, Kyoto University, Kyoto, Japan. E-mail: sakamoto{at}pbh.med.kyoto-u.ac.jp
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REFERENCES |
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Received March 10, 2003; accepted April 23, 2003
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