Japanese Journal of Clinical Oncology Advance Access published online on August 2, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym054
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© 2007 Foundation for Promotion of Cancer Research
Phase II Study of Biweekly Paclitaxel and Cisplatin Combination Chemotherapy in Advanced Gastric Cancer: Korea–Japan Collaborative Study Group Trial
1 Department of Hemato-Oncology, Korea University, College of Medicine, Seoul, Korea
2 Department of Gastroenterology, Saitama Cancer Center, Kita-Adachi gun, Saitama, Japan
3 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
4 Department of Gastroenterology, Osaka Medical College, Takatsuki, Osaka, Japan
5 Division of Hematology–Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
6 Department of Gastroenterology, Toyosu Hospital, Showa University School of Medicine, Tokyo, Japan
7 Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
8 Young Leaders Program, Department of Social Life Science, Nagoya University, Nagoya, Japan
9 Department of Epidemiological and Clinical Research Information Management, Kyoto University Graduate School of Medicine, Kyoto, Japan
10 Department of Internal Medicine, Misawa City Hospital, Misawa, Aomori, Japan
For reprints and all correspondence: Yuh Sakata, Department of Internal Medicine, Misawa City Hospital, Aomori, Japan. E-mail: ysakatam-101{at}r15.7-dj.com
Received November 22, 2006; accepted March 5, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: Benefits of chemotherapy have generally been modest in gastric cancer, although those regimens developed more recently have produced higher response rates. Paclitaxel plus cisplatin is one such regimen and divided administration of paclitaxel has been suggested to be associated with lower neurological and hematologic toxicities and be able to achieve higher paclitaxel dose intensities than paclitaxel administration at 175 mg/m2 every 3 weeks. This study was undertaked to assess the efficacy and toxicity of a biweekly paclitaxel and cisplatin combination treatment in advanced gastric cancer.
Methods: Twenty-five patients from Japan and Korea, 50 patients in total, were entered into this trial which was conducted from October 2004 to June 2005. Median age of the patients was 57 years (range: 26–78). Paclitaxel 140 mg/m2 was administered intravenously on days 1 and 15 of each 4-week cycle. Cisplatin 30 mg/m2 was also administered on days 1 and 15 with standard hydration. A total of 278 courses of treatment (two treatment courses per cycle) were conducted for 50 patients. The median number of treatment cycles per patient was two with a range of one to six.
Results: Nine of the 50 patients responded to the treatment, with an overall objective response rate of 18% (95% CI, 12–41), which included one complete response. Two patients were not evaluable and 14 patients had stable disease as best response. The median survival duration of the 50 patients was 333 days (range: 52–637+ days). The main toxicity was neutropenia. Significant toxicity (NCI-CTC grade 3 or 4) included neutropenia in 19 patients (38%), anorexia in four (8%), infection in three (6%), anemia in three (6%), and abdominal pain in three (6%).
Conclusions: Biweekly paclitaxel and cisplatin combination chemotherapy showed modest activity in advanced gastric carcinoma with a favorable toxicity pattern.
Key Words: gastric cancer • paclitaxel • cisplatin • combination chemotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Although the incidence of gastric carcinoma has fallen in most Western countries, it remains a significant problem in terms of global health and is the second most common cause of cancer mortality worldwide (1). Surgical resection is the only therapeutic modality capable of cure, while improvements in early diagnosis, pre-operative assessment, and surgical techniques have increased the number of potentially curative resections over the last 20 years. However, despite these improvements prognosis remains poor with less than a 30% 5-year survival rate in the USA (2).
The reasons for this grim outlook are that both local and distant relapses, even after apparently complete resection, are common and that many patients present inoperable disease at the time of diagnosis. Although it was previously not clear whether chemotherapy contributed to the survival of patients with unresectable advanced gastric cancer, recent studies that compared patients who received chemotherapy with those not treated with chemotherapy (best supportive care: BSC) strongly suggest that chemotherapy improves survival in advanced gastric cancer (3–5).
5-FU and/or cisplatin (CDDP)-based combination chemotherapy continues to be widely used, but the continuing lack of progress of chemotherapy for the treatment of gastric cancer has prompted the evaluations of new agents and/or combinations including taxanes, irinotecan, capecitabine, S-1 and others.
Paclitaxel (TXL) was originally extracted from the bark of Taxus brevifolia. It causes stabilization/hyperplasia of microtubules by facilitating microtubule protein polymerization, and thereby inhibits mitosis to display anti-tumor effects. TXL has shown encouraging activity as a single agent for gastric cancer treatment, with reported response rates ranging from 17 to 28% (6–9). A late phase II study in Japan produced favorable results with response rates of 23.3% for the entire population and 25.8% for cases that had undergone prior chemotherapy (7,10).
TXL and CDDP have different modes of action and fewer overlapping toxicities than other regimens. Moreover, TXL and CDDP combination therapy has been used across the world, including Japan and Korea. In particular, large-scale clinical studies have been conducted on this regimen in lung and ovarian cancers, and its clinical usefulness (including survival benefits) has been proven by comparisons with existing standard regimens. Weekly and biweekly administrations of both drugs have also been examined as short-term treatment and as means of increasing dose intensity (11–14).
Although cytotoxic chemotherapy has been widely used in advanced gastric cancer and has been demonstrated to be an effective palliative management, response duration of first-line chemotherapy is brief and survival gain is modest in gastric cancer. Moreover, the overall prognosis of patients failing first-line chemotherapy is poor, and although many of these patients are candidates for second-line chemotherapy at the time of first-line chemotherapy failure, no established second-line chemotherapeutic regimen is now available. Candidate regimens for first- or second-line chemotherapy for advanced/recurrent gastric cancer should have a good response rate and improve survival without compromising patient quality of life. We have thus sought to define optimal divided doses for TXL and TXL/CDDP-based therapies. In a Japanese phase I study, CDDP was fixed at 30 mg/m2 and TXL increased in increments of 20 mg/m2 from 100 mg/m2. The maximum tolerable dose (MTD) in this phase I study was set at TXL 180 mg/m2 + CDDP 30 mg/m2. Although the sample size was small, the response rate achieved was 46.1% (6/13), and median survival duration was 288 days. Subsequently, a pilot phase II study was conducted in Japan to examine the efficacy/safety of treatment at TXL 160 mg/m2 + CDDP 30 mg/m2; 20 patients were registered in this study. Unfortunately, a dose of TXL 160 mg/m2 + CDDP 30 mg/m2 was not feasible in this group of patients, because for 11 of the 20 patients (55%) it could not be administered on a biweekly schedule due to delayed myelosuppression recovery at this level (15). Therefore, at a core meeting of the Japan–Korea Cooperative Gastric Cancer Study Group, it was decided to reduce the dose to TXL 140 mg/m2 + CDDP 30 mg/m2.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Eligibility
Between October 2004 and June 2005, 50 patients from Japan and Korea were enrolled in this study. Patients with histologically or cytologically proven metastatic or locally advanced inoperable gastric carcinoma were eligible. Patients were required to be 20–80-years old with a life expectancy of >3 months and to have an Eastern Cooperative Oncology Group (ECOG) performance status of
2. All patients were required to have at least one target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Patients who had received less than one palliative chemotherapy (considering that patients receive one palliative chemotherapy if recurrence occurred within 6 months of adjuvant therapy) were eligible and patients should not be under the influence of the effects or side effects of previous treatments; at least 4 weeks must have passed since the last drug administration, excepting the administration of oral fluoropyrimidine or its derivatives (e.g. capecitabine or TS-1), in which case, a 2-week drug-free period was required. All eligible patients were also required to have adequate hematological counts (an absolute neutrophil count of 
2000/µl, a platelet count of 100 000/µl and hemoglobin 9.0 g/dl), laboratory results within the following limits (serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] < 2 x UNL (excepting patients with liver metastasis: <UNL x 3), serum bilirubin 1.5 mg/dl), and renal function (creatinine clearance >50 ml/min, according to the Cock–Loft formula). Exclusion criteria were as follows: cardiac disease, such as, ischemic heart disease or arrhythmia; a history of myocardial infarction within the previous 6 months; liver cirrhosis of Child class B or C; fresh gastrointestinal bleeding requiring repeated blood transfusion; psychotropic disease requiring major tranquilizer or major anti-psychotic medication; poorly controlled diabetes; a history of hypersensitivity to the treatment drugs or preparations containing polyoxyethylene castor oil (Cremophor EL®); a history of previous treatment with taxane compounds (TXL, docetaxel) or platinum compounds (excepting adjuvant chemotherapy undertaken prior to 6 months before study registration); or peripheral neuropathy of at least Grade 2 during previous chemotherapy. Pregnant or nursing women were also excluded. Finally, all patients provided informed consent and this study was approved by the review boards of each of the 15 participating institutions.
Treatment
TXL (Taxol®; Bristol-Myers-Squibb Company, Princeton, NJ) 140 mg/m2 was administered intravenously (i.v.) in 250–500 ml glucose solution or physiological saline solution for 1–3 h on days 1 and 15 of each 4-week cycle. Cisplatin 30 mg/m2 was also administered as a 1- or 2-h i.v. infusion on days 1 and 15 with standard hydration. As prophylactic agents, dexamethasone (i.v., 20 mg), diphenhydramine (p.o., 50 mg), and ranitidine hydrochloride (i.v., 50 mg) were given 30 min before TXL administration. All patients received adequate anti-emetic therapy prior to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) was administered at physician's discretion or taking insurance status of the countries in considerations. Treatment was repeated every 4 weeks as toxicity permitted and continued in the absence of disease progression or unacceptable toxicity.
Subsequent treatment cycles were started only when the neutrophil count was 1500/mm3 and the platelet count was 100 000/mm3. Planned treatment was withheld until recovery in cases with: a fever of 38°C or higher, an ECOG performance status of 3, or non-hematologic toxicity of grade 3 or higher. When drugs could not be administered owing to adverse events even after a 2-week postponement from the planned day of the next administration, treatment was stopped. If febrile neutropenia, thrombocytopenia grade 3, non-hematological toxicity grade 3 or peripheral neutropathy grade 2 were had occurred during the previous treatment, the dose of TXL was reduced to 120 mg/m2 for the following treatment. A second episode required a dose reduction of TXL to 100 mg/m2 on subsequent treatments. If repeated episodes of febrile neutropenia, thrombocytopenia grade 3, non-hematological toxicity grade 3, or peripheral neuropathy grade 2, occurred despite in spite of dose reduction of TXL to 100 mg/m2, treatment was stopped. Dose escalation after dose reduction was not permitted. Complete blood, differential and platelet counts were evaluated once a week or more frequently when patients were myelosuppressed during treatment resting periods. Serum creatinine, blood urea nitrogen, electrolyte and magnesium levels were checked before each chemotherapy cycle.
Response to Treatment and Adverse Effects
Before entering the study, all patients received physical examination, and full blood count and serum chemistry analyses. Chest X-ray, ECG, upper gastrointestinal endoscopies, abdominal computer tomographic scans and other appropriate procedures were also performed. Patients were given a physical examination, a subjective/objective symptom evaluation and routine blood tests twice-weekly. Every 4 weeks, a biochemistry blood examination was added to this basal evaluation. After every two cycles of treatment, response was evaluated using RECIST criteria. Of the lesions observed prior to treatment, a maximum of five measurable lesions from each metastasized organ up to a total of 10 lesions were selected as target lesions. In cases of partial or complete response, a confirmative computer tomographic (CT) scan was performed 4 weeks later and this was followed by a CT scan after every two treatment cycles. Toxicity was reported using a National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 2.0 toxicity scale.
Statistical Analysis
The present study was a confirmatory phase II study, and was undertaken to determine the response rate of biweekly TXL and CDDP combination chemotherapy for unresectable locally advanced or metastatic gastric cancer. The secondary objective was to evaluate the toxicity of this regimen and to determine survival duration and time to progression. The 95% confidence interval (CI) for response was calculated. Survival probabilities were estimated using the Kaplan–Meier method. Response duration was calculated from the date of response confirmation to the date when progressive disease was first observed. Survival duration was calculated from the first day of treatment until death or the last follow up. The target sample size was 50 cases. Because the response rate for TXL was determined to be 23% during its development, the threshold efficacy rate was set at 20% for combination chemotherapy. In addition, based on the prior phase I study and the results of other studies, the necessary sample size was calculated to be 50 cases when the expected efficacy rate for the combination chemotherapy was set at approximately 40%, and this corresponded to an 
of 0.05 and power (1 – ß) of 0.9.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Characteristics
Twenty-five patients from Japan and Korea (a total of 50 patients) were enrolled into this trial from October 2004 to June 2005. Patient characteristics are listed in Table 1. Forty-eight patients (96%) had a relatively good performance status of grade 0 or 1. Median patient age was 57 years with a range of 26–78 years. Korean patients tended to be younger than Japanese patients (median age 46 years (range: 26–78) versus 65 years (range: 50–78), respectively). Forty-one patients were male and 28 patients (17 Japanese and 11 Korean) had undergone surgical resection. Eleven (eight Japanese and three Korean) of the 28 had previously received adjuvant chemotherapy after curative surgery. The post-operative chemotherapy regimens of Korean patients were; 5-FU alone one patient, 5-FU + cisplatin (FP) one, and 5-FU + adriamycin + mitomycin (FAM) one, respectively. The post-operative regimens of Japanese patients were; TS-1 alone, 6, and UFT alone, 2. Fifteen patients had previously received palliative chemotherapy. The palliative chemotherapy regimens of the two Korean patients were Heptaplatin (Sunpla®, Sunkyung Pharm., Seoul, Korea) + 5-FU + leucovorin and TS-1 alone, respectively. The palliative chemotherapy regimens of the 13 Japanese patients were: 5-FU 1 patient, 5-FU + leucovorin 2, FP 1, TS-1 8, and TS-1 + irinotecan 1, respectively. Twenty-one patients were treatment naïve and one patient had received palliative radiation therapy for metastatic bone disease before enrollment.
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Response to Chemotherapy
A total of 278 treatment courses (two treatment courses per cycle) were conducted for the 50 patients. The median number of treatment cycles per patient was two with a range from one to six. As nine of the 50 enrolled patients responded to treatment, the overall objective response rate was 18% (95% CI, 12–41), which including one complete response (Table 2). Two patients were not evaluable (one for treatment refusal after the first treatment cycle, one for treatment refusal after the third cycle due to grade 4 anemia) and 14 patients achieved a best response of stable disease. Of the 15 patients, who had been previously received palliative chemotherapy, two (13%) achieved a response. The overall response rate was 22.2% (7/35) among chemotherapy naïve patients and the Korean patient response rate was twice that of the Japanese patients (6/25, 24% versus 3/25, 12%). After a median follow-up of 659 days, 42 patients had disease progression or had died and thus the median progression-free survival was 86.5 days (range: 27–608+ days; Fig. 1). At the last follow-up, which was performed during October 2006, median survival duration of the 50 patients was 333 days (range: 52–637+ days; Fig. 2). Thirty seven patients (74%) had subsequent therapy after failure, 12 patients did not get further therapy and post-treatment is unknown in one patient. All 37 patients (18 patients in Korea and 19 patients in Japan) were treated with chemotherapy after failure to biweekly TXL + cisplatin regimen. Although, palliative surgery and radiation therapy were given in five patients, respectively, chemotherapy was given concurrently or subsequently with those local treatments. Most commonly used chemotherapeutic regimen was irinotecan-based chemotherapy in 23 patients (12 patients in Korea and 11 patients in Japan).
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Toxicity
Seven patients completed six treatment cycles without progression and 32 patients could not complete treatment as a result of progressive disease. Other reasons for treatment discontinuation were; consent withdrawal after the third treatment cycle for one, treatment refusal after experiencing severe adverse events in five (grade 4 anemia, fatigue, sensory neuropathy, abdominal pain and fatigue), and repeated adverse events of more than grade 3 after two dose reductions in two (grade 3 anorexia and grade 4 neutropenia), unrecovered drug toxicity given the time limitation in two (neutropenia and neuropathy) and the need for another treatment in one (emphysema).
The main toxicities encountered were neutropenia (Table 3). NCI-CTC grade 3 and 4 neutropenia was observed in 12 (24%) and seven (14%) patients, respectively. Other noted hematologic toxicities of over grade 3 were anemia (10%), leucopenia (6%), and thrombocytopenia (2%), respectively. The incidence of hematologic toxicities over grade 3 was similar in both countries (Table 3). Of the 228 treatment courses administered, 42 (18.4%) were delayed as a result of myelosuppression. Overall, eight patients (16%) required dose modification during treatment. After the first treatment course, four patients required TXL dose reduction (three with grade 4 neutropenia and one with a grade 3 elevation of AST and ALT. Of the three patients requiring a TXL dose reduction after the first course of treatment as a result of neutropenia, two required a second dose reduction owing to repeated grade 4 neutropenia during the second treatment cycle and one patient terminated treatment owing to progressive disease). During the second treatment cycle, two patients required a TXL dose reduction (one patient requiring dose reduction as a result of grade 4 neutropenia during the second cycle, required a second dose reduction owing to repeated grade 4 neutropenia at the fifth cycle, and one patient requiring a dose reduction owing to anorexia during the second cycle, required another dose reduction owing redeveloped grade 3 anorexia during the third cycle). Another two patients required a dose reduction as result of a grade 4 neutropenia during their third and fourth cycles, respectively. The commonest non-hematologic toxicities in Korean patients were alopecia, nausea, myalgia and vomiting, each of which affected more than 10 patients (Table 4). Non-hematologic toxicities were more infrequent in Japanese patients than in Korean patients, and alopecia, fatigue, anorexia and sensory neuropathy were the commonest non-hematologic toxicities in Japanese patients, each of which affected seven patients. Grade 3 anorexia was observed in four (8%) of the 50 patients and grade 3 abdominal pain and grade 3 infection developed in three (6%) patients apiece (Table 4). Although 14 patients had sensory neuropathy, most patients had mild to moderate degree (10 patients with grade 1 and 3 patients with grade 2). No severe infection or treatment related death was observed.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The aim of this study was to assess the efficacy and toxicity of biweekly TXL + CDDP combination treatment. Since the response rate for TXL was determined to be 23% during its development, the threshold efficacy rate was set at 20% for combination chemotherapy in this study. In addition, the expected efficacy rate for the combination chemotherapy was set at approximately 40%. Although, the study confirms that the biweekly TXL + CDDP have favorable patterns of toxicity, we have failed to prove the expected efficacy rate of TXL + CDDP in this study. Its clinical objective response rate was 18%, with that of 22.2% (7/35) in chemotherapy naïve patients and 13% (2/15) in non-chemotherapy naïve patients. In advanced gastric cancer, a first-line TXL and platinum doublet combination administered 3-weekly produced a response rate of 33–46% (16–18). In terms of biweekly treatments, Kornek et al. (19) reported a study on TXL 160 mg/m2 + CDDP 60 mg/m2, and observed a response to treatment in 44.4% of the 41 cases, which included five cases of complete remission. Moreover, when administered as a second-line treatment, a response rate of 22–28% was observed when TXL was administered with carboplatin (20,21). Our response rate is inferior to the response rate of a similar regimen reported by Kornek et al. (19), but is similar to that of a phase II part of the study performed by the East Japan Gastric Cancer Study Group (15). The relatively low response rate of the present study may be due to our inclusion of 15 previously treated patients. In addition, multi-institute cooperative studies such as the present one tend to produce lower response rates than single institute studies.
TXL and CDDP have different modes of action and fewer overlapping toxicities than other combinations. The most widely used TXL + CDDP regimen involves high dose TXL (175–200 mg/m2) and CDDP (60–75 mg/m2) administered 3-weekly. However, treatment is sometimes delayed by neurotoxicity and higher dose of CDDP is associated with higher neurotoxicity and more severe renal damage. Rosenberg et al. performed a comparative study on TXL administration modalities in patients with ovarian cancer and reported that weekly administration of TXL is better than a 3-weekly administration even though treatment effects are comparable, because the incidences of side effects are clearly lower for the weekly administration (particularly with respect to myelosuppression and peripheral neuropathy) (22). In addition, Seidman et al. conducted a phase II clinical study in which TXL was administered weekly at 80–120 mg/m2 to patients with adriamycin-resistant breast cancer and reported a response rate of 53% with high tolerability (23). Moreover, the weekly application of TXL 80 mg/m2 as an 1-h infusion has been suggested to be associated with lower hematologic toxicity while capable of achieving a higher dose intensity than TXL administration at 175 mg/m2 3-weekly (24). These results show that the divided administration of TXL may reduce myelosuppression and neurotoxicity. Two phase II studies using biweekly TXL + CDDP have been conducted and both reported a high response rate in esophageal cancer (biweekly administrations of TXL 180 mg/m2 + CDDP 30 mg/m2) (25) and in gastric cancer (biweekly administration of TXL 160 mg/m2 + CDDP 60 mg/m2) (19). However, grade 4 neutropenia occurred in 31 and 11% of patients, respectively, which required hospital admission or prophylactic G-CSF. Here, we conducted a multi-institutional cooperative phase II study of a biweekly regimen (biweekly administration of TXL 140 mg/m2 + CDDP 30 mg/m2) followed by a phase I–II study (15), because this biweekly schedule was suitable for outpatient clinical with modest efficacy and a safe toxicity profile.
The main toxicity of this regimen used in the present study was neutropenia. Hematologic toxicities consisted of neutropenia grade 3 in 24% and grade 4 in 14%, which is substantially lower than that reported by Polee et al. (25). Although the incidence of neutropenia was found to be similar with higher dose TXL and CDDP regimen (19), our study did not use prophylactic G-CSF. In the present study, only two patients could not complete treatment as a result of delayed or repeated severe neutropenia. The other significant toxicity was anorexia: four patients experienced grade 3 anorexia.
The median survival duration for all 50 patients was 333 days and considering that a substantial number of patients in the present study had been exposed to previous chemotherapy or surgery (56% of patients had undergone gastric resection, 22% had received adjuvant chemotherapy, and 30% had been received another palliative chemotherapy), this result appears to be promising. Furthermore, side effects of this regimen were tolerable and controllable in most patients, and only a small number of patients did not tolerate the treatment. Of the 11 patients who discontinued treatment owing to a severe adverse event or to delayed recovery from an adverse event, most had an unfavorable clinical characteristic (seven patients underwent previous surgery, three patients had received adjuvant chemotherapy and three previous palliative chemotherapy, and six patients were older than 60). Except those patients with severe adverse events or delayed recovery from an adverse event, 37 patients (74%) proceeded to salvage chemotherapy. Subsequent chemotherapies might contribute to prolongation of survival in our patient group.
It was interesting to note that patients' characteristics were different between Korea and Japan. Korean patients tended to be younger (median age 46 versus 65), which is consistent with a review of surgically resected gastric cancer patients at a Korean and a Japanese hospital, which showed that patients under 40-years old composed 14.8% of Korean patients and only 6% of Japanese patients, whereas patients over 70 years of age accounted for 3.2 and 19.2% of the gastric cancer populations at Korea University Hospital and the Japan National Cancer Center Hospital, respectively (26). In particular, Korean gastric cancer cases tended to be of the poorly differentiated pathologic type (poorly differentiated adenocarcinoma, signet ring cell carcinoma and mucinous adenocarcinoma), whereas Japanese gastric cancer cases had a differentiated histology (papillary adenocarcinoma and tubular adenocarcinoma). Although Mok et al. suggested that such a difference in histologic type between two hospitals was mostly as a result of a greater frequency of early gastric cancer in Japan National Cancer Center Hospital patients (51.2%) than in Korea University Hospital patients (19.0%), this discrepancy in histologic type may represent the real difference of patient populations between two countries, because only advanced stage patients were enrolled in this study. The response rate of Korean patients was twice that of the Japanese patients (6/25, 24% versus 3/25, 12%) and the survival duration of Korean patients was also longer than that of Japanese patients (389 days versus 262 days). Non-hematologic toxicities were more infrequent in Japanese patients than in Korean patients, especially nausea, vomiting, myalgia and alopecia were infrequently noted in Japanese patients. However, the incidence of grade 3/4 neutropenia was more common in Japanese patients (12/25, 48% versus 7/25, 28%). Japanese patients tend to have been older and more pretreated patients, which might contribute to poor prognosis, resistance to treatment and high incidence of severe neutropenia. However, it is difficult to prove that the difference in treatment result was related with patient background or other prognostic factors.
In conclusion, biweekly TXL and CDDP combination chemotherapy showed modest activity in advanced gastric carcinoma and was characterized by a favorable toxicity pattern. However, this regimen has failed to achieve a superior efficacy to TXL monotherapy in this group of patients. Nonetheless, because of the 1-day infusion schedule used this regimen, it can be administered on an outpatient basis without disrupting daily life.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgments |
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Investigators who participated in this study were Masahiro Gotoh, Osaka Medical College Hospital, Osaka, Japan; Hoon-Kyo Kim, St Vincent's Hospital, The Catholic University of Korea, Suwon, Korea; Si-Young Kim, Kyung Hee University, Medical College, Seoul, Korea; Yoshito Komatsu, Hokkaido University Hospital, Hokkaido, Japan; Won Sup Lee, Gyeong-Sang National University Hospital, Jinju, Korea; Masaki Munakata, Misawa City Hospital, Aomori, Japan; Sook Ryeon Park, Research Institute and Hospital, National Cancer Center, Gyeonggi-do, Korea; Hiroshi Saito, Yamagata Prefectural Central Hospital, Yamagata, Japan; Soh Saitoh, Aomori Center Hospital, Aomori, Japan; Akinori Takagane, Iwate Medical College Hospital, Morioka, Japan; Takashi Yoshioka, Tohoku University Hospital, Sendai, Japan. This study was supported in part by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A040151), and by the non-profit organization Epidemiological & Clinical Research Network (ECRIN), Japan.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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1 Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin (2006) 56:106–30.
2 Gallo A, Cha C. Updates on esophageal and gastric cancers. World J Gastroenterol (2006) 12:3237–42.[Web of Science][Medline]
3 Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer (1995) 71:587–91.[Web of Science][Medline]
4 Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer (1993) 72:37–41.[CrossRef][Web of Science][Medline]
5 Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol (1997) 8:163–8.
6 Ajani JA, Fairweather J, Dumas P, Patt YZ, Pazdur R, Mansfield PF. Phase II study of Taxol in patients with advanced gastric carcinoma. Cancer J Sci Am (1998) 4:269–74.[Medline]
7 Yamaguchi K, Tada M, Horikoshi N, Otani T, Takiuchi H, Saitoh S, et al. Phase II study of paclitaxel with 3-h infusion in patients with advanced gastric cancer. Gastric Cancer (2002) 5:90–5.[CrossRef][Medline]
8 Ohtsu A, Boku N, Tamura F, Muro K, Shimada Y, Saigenji K, et al. An early phase II study of a 3-hour infusion of paclitaxel for advanced gastric cancer. Am J Clin Oncol (1998) 21:416–9.[CrossRef][Web of Science][Medline]
9 Cascinu S, Graziano F, Cardarelli N, Marcellini M, Giordani P, Menichetti ET, et al. Phase II study of paclitaxel in pretreated advanced gastric cancer. Anti-cancer drugs (1998) 9:307–10.[Medline]
10 Yamada Y, Shirao K, Ohtsu A, Boku N, Hyodo I, Saitoh H, 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.
11 Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA, et al. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol (1991) 9:1692–703.[Abstract]
12 Gelmon KA. Biweekly paclitaxel (Taxol) and cisplatin in breast and ovarian cancer. Semin Oncol (1994) 21(Suppl 8):24–8.[Web of Science][Medline]
13 van der Gaast A, Kok TC, Kerkhofs L, Siersema PD, Tilanus HW, Splinter TA. Phase I study of a biweekly schedule of a fixed dose of cisplatin with increasing doses of paclitaxel in patients with advanced oesophageal cancer. Br J Cancer (1999) 80:1052–7.[CrossRef][Web of Science][Medline]
14 Polee MB, Verweij J, Siersema PD, Tilanus HW, Splinter TA, Stoter G, et al. Phase I study of a weekly schedule of a fixed dose of cisplatin and escalating doses of paclitaxel in patients with advanced oesophageal cancer. Eur J Cancer (2002) 38:1495–500.[CrossRef][Web of Science][Medline]
15 Yamaguchi K, Shimamura T, Komatsu Y, Takagane A, Yoshioka T, Saitoh S, et al. Phase I–II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer. Gastric Cancer (2006) 9:36–43.[CrossRef][Medline]
16 Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, et al. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol (2003) 26:37–41.[CrossRef][Web of Science][Medline]
17 Park SR, Oh DY, Kim DW, Kim TY, Heo DS, Bang YJ, et al. A multi-center, late phase II clinical trial of Genexol (paclitaxel) and cisplatin for patients with advanced gastric cancer. Oncol Rep (2004) 12:1059–64.[Web of Science][Medline]
18 Lee KW, Im SA, Yun T, Song EK, Na I, Shin H, et al. Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer. Jpn J Clin Oncol (2005) 35:720–6.
19 Kornek GV, Raderer M, Schull B, Fiebiger W, Gedlicka C, Lenauer A, et al. Effective combination chemotherapy with paclitaxel and cisplatin with or without human granulocyte colony-stimulating factor and/or erythropoietin in patients with advanced gastric cancer. Br J Cancer (2002) 86:1858–63.[CrossRef][Web of Science][Medline]
20 Stathopoulos GP, Rigatos SK, Fountzilas G, Polyzos A, Stathopoulos JG. Paclitaxel and carboplatin in pretreated advanced gastric cancer: a phase II study. Oncol Rep (2002) 9:89–92.[Web of Science][Medline]
21 Chang HM, Kim TW, Ryu BY, Choi SJ, Park YH, Lee JS, et al. Phase II study of paclitaxel and carboplatin in advanced gastric cancer previously treated with 5-fluorouracil and platinum. Jpn J Clin Oncol (2005) 35:251–5.
22 Rosenberg P, Andersson H, Boman K, Ridderheim M, Sorbe B, Puistola U, et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta oncol (2002) 41:418–24.[CrossRef][Web of Science][Medline]
23 Seidman AD, Hudis CA, Albanell J, Tong W, Tepler I, Currie V, et al. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol (1998) 16:3353–61.[Abstract]
24 Fennelly D, Aghajanian C, Shapiro F, O'Flaherty C, McKenzie M, O'Connor C, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol (1997) 15:187–92.
25 Polee MB, Eskens FA, van der Burg ME, Splinter TA, Siersema PD, Tilanus HW, et al. Phase II study of bi-weekly administration of paclitaxel and cisplatin in patients with advanced oesophageal cancer. Br J Cancer (2002) 86:669–73.[CrossRef][Web of Science][Medline]
26 Mok YJ, Koo BW, Whang CW, Kim SM, Maruyama K, Sasako M, et al. Cancer of the stomach: a review of two hospitals in Korea and Japan. World J Surg (1993) 17:777–82.[CrossRef][Web of Science][Medline]
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