© 2004 Foundation for Promotion of Cancer Research
Phase II Study of Sequential Methotrexate and 5-Fluorouracil Chemotherapy Against Peritoneally Disseminated Gastric Cancer with Malignant Ascites: a Report from the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group, JCOG 9603 Trial
1 Department of Internal Medicine, Cancer Institute Hospital, Tokyo, 2 Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, 3 Division of Gastrointestinal Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba, 4 Department of Internal Medicine, Mitoyo General Hospital, Mitoyo-gun, Kagawa, 5 Department of Internal Medicine, National Shikoku Cancer Center Hospital, Matsuyama, 6 Department of Internal Medicine, Yamagata Prefectural Hospital, Yamagata, 7 Department of Internal Medicine, National Nagoya Hospital, Nagoya, 8 Department of Internal Medicine, Tonan Hospital, Sapporo, 9 Department of Internal Medicine, Hyogo Medical Center for Adults, Akashi, Hyogo and 10 JCOG Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: The efficacy of systemic chemotherapy against peritoneal dissemination from advanced gastric cancer (AGC) remains unclear, because the peritoneal dissemination was not defined as a measurable lesion in conventional phase II studies. In this study, we evaluated the efficacy and toxicity of sequential MTX and 5FU therapy (MF) in chemotherapy-naive patients with AGC accompanied by malignant ascites in a phase II setting.
Methods: The treatment schedule comprised weekly administration of MTX (100 mg/m2, i.v. bolus) followed by 5FU (600 mg/m2, i.v. bolus) with a 3 h interval. Leucovorin rescue (10 mg/m2 every 6 h, for a total of six times) was commenced 24 h after MTX administration.
Results: Thirty-seven chemotherapy-naive patients with AGC presenting with malignant ascites were enrolled in this trial. The median age was 60 years (range, 25–74 years) and most patients (86%) had a performance status of 0–1. In total, 355 administrations of the sequential MTX/5FU therapy were performed. Major toxicity consisted of myelosuppression and gastrointestinal toxicity. Grade 4 neutropenia occurred in 10.8% of the patients. The overall objective response rate was 5.7% (two partial responses in 35 patients; 95% confidence interval: 0.7–19.2%). However, the response rate of ascites was 35.1% (complete disappearance in three patients and apparent decrease in 10 patients; 95% confidence interval: 20.2–52.5%).
Conclusions: Sequential MTX/5FU therapy is effective against AGC with malignant ascites with acceptable toxicity and warrants further investigations in a phase III setting.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Despite a declining incidence in many industrial countries, gastric cancer remains one of the most common malignancies globally. Although this tumor is potentially curable with surgery when diagnosed at an early stage, the prognosis for patients with unresectable or metastatic disease is very poor, with a median survival of 3–4 months when they receive the best supportive care without palliative surgery or chemotherapy (1–3). Gastric cancer can progress to systemic disease through various routes such as direct invasion or lymphatic or vascular spread. Peritoneal dissemination, i.e. peritoneal carcinomatosis, which occurs mainly as a result of direct invasion and/or lymphatic spread, is very common in advanced gastric cancer and is considered an incurable disease state (4). Peritoneal dissemination may cause serious complications, such as intestinal obstruction, massive ascites and hydronephrosis associated with the clinical presentation of abdominal pain and fullness, vomiting, constipation, malnutrition and renal dysfunction. From the clinical point of view, palliative management of those complications warrants special considerations and represents a therapeutic challenge in oncology (5,6). Although the major treatment option for unresectable or metastatic gastric cancer is systemic chemotherapy, this strategy has been generally believed to have little effect on peritoneal dissemination, because the drugs could not be delivered sufficiently through the peritoneum–plasma barrier to the disseminated tumor cells (7). However, the efficacy of systemic chemotherapy against peritoneal dissemination from gastric cancer remains unclear, because peritoneal dissemination was not defined as a measurable lesion in conventional phase II studies and therefore few reports are available about the efficacy of systemic chemotherapy against peritoneal dissemination. 5-Fluorouracil (5FU) remains the mainstay for chemotherapy against gastric cancer and a variety of drugs have been tested as modulators to increase its chemotherapeutic efficacy. The modulators that have been most widely used in clinical practice against gastrointestinal tract cancers are folinic acid (leucovorin) and methotrexate (MTX) (8,9). MTX enhances 5FU cytotoxicity via DNA and/or RNA synthesis inhibition when the two drugs are administered in sequence, with 5FU administered a few hours after MTX (10,11). A meta-analysis of randomized trials of sequential MTX/5FU therapy revealed a higher response rate than for single agent bolus 5FU in colorectal cancer (12). The toxicity of these sequential MTX/5FU regimens was comparable to that of 5FU alone (i.e. vomiting, stomatitis, diarrhea and leukopenia). The sequential MTX/5FU therapy was found in phase II trials for advanced gastric cancer to have antitumor activity against advanced gastric cancer (13,14). A Japanese phase II trial of sequential MTX/5FU therapy against advanced gastric cancer demonstrated that low- and intermediate-dose MTX regimens achieved response rates of 23% (13 PRs/56 patients) and 41% (15 PRs/37 patients), respectively (15). Sequential MTX/5FU therapy is widely used as one of the standard treatment regimens for patients with unresectable or metastatic gastric cancer at present in Japan. Konishi et al. reported that sequential MTX/5FU therapy was effective in patients with peritoneal dissemination with a response rate of 23% (6/26) and that ascites disappeared in eight of 16 patients (50%) treated with this therapy (16). Those findings suggest that sequential MTX/5FU might be effective in advanced gastric cancer with peritoneal dissemination.
The objective of this study was to evaluate the efficacy and toxicity of sequential MTX/5FU chemotherapy in advanced gastric cancer with malignant ascites in order to determine whether this regimen is worthy of further investigation in a phase III trial for the treatment of patients with peritoneal dissemination from advanced gastric cancer. The primary endpoints planned for this study were tumor response rate and response rate in ascites. Secondary endpoints were overall survival and toxicity. To our knowledge, there has been no prior study that evaluated the efficacy and toxicity of systemic chemotherapy in a phase II setting in patients with advanced gastric cancer who have peritoneal dissemination with malignant ascites.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Eligibility
Patients enrolled in this study were required to fulfill the following eligibility criteria: (1) histologically confirmed gastric cancer; (2) unresectable or recurrent disease; (3) peritoneal dissemination with cytologically confirmed malignant ascites evaluable by CT scan or ultrasonography; (4) measurable or evaluable disease; (5) age 20–75 years; (6) performance status (PS)
2 on Eastern Cooperative Oncology Group (ECOG) scale; (7) no prior chemotherapy with the exception of one adjuvant chemotherapy; (8) adequate bone marrow function (WBC 
4000/mm3 and platelets 100 000/mm3) (9) adequate liver function (serum bilirubin level 2.0 mg/dl and serum transaminase level 2.5-fold the upper limit of normal; (10) adequate renal function (serum creatinine and blood urea nitrogen within the upper limit of normal; (11) serum albumin 2.6 g/dl; (12) normal ECG; (13) currently hospitalized; (14) life expectancy at least 8 weeks; (15) written informed consent. Patients with active bleeding from the gastrointestinal tract, other active synchronous carcinoma, central nerve metastasis or concurrent uncontrolled medical illness and pregnant or lactating women were excluded. Patients with massive ascites that required drainage for the relief of symptoms were also excluded. The study protocol was approved by the JCOG Clinical Trial Review Committee and by the institutional review board of each participating center.
Treatment Plan
The treatment schedule comprised weekly administration of MTX (100 mg/m2, i.v. bolus) followed by 5FU (600 mg/m2, i.v. bolus) with a 3 h interval. Leucovorin rescue (10 mg/m2 orally or i.v. every 6 h, six times) was commenced 24 h after MTX administration. To prevent toxicity from MTX, acetazolamide (250 mg) was given intravenously immediately after the infusion of MTX and sodium bicarbonate (33.3 mequiv.) added to 500 ml of electrolyte solution was administered by drip infusion for urine alkalinization during the 3 h interval between the administration of MTX and 5FU. The plasma level of MTX was monitored 24 h after MTX administration and leucovorin rescue at 10 mg/m2 was administered every 6 h until the plasma level of MTX was <1 x 10 –6 mol/l. At the time of each administration, patients were required to fulfill the following criteria: leukocyte count 3000/ mm3; platelet count 75 000/ mm3; adequate liver and renal function as eligibility criteria; PS 0–2; and absence of toxicity grade 2 or greater. The treatment was repeated unless disease progression or severe toxicity was observed. The treatment was terminated when the ascites did not improve within 8 weeks or when toxicity did not disappear within 6 weeks.
Response and Toxicity Evaluation
Tumor response was assessed by CT scan or ultrasonography of the target lesions every 4 weeks after the first administration of MTX. Complete response (CR), partial response (PR), no change (NC) and progressive disease (PD) were defined according to the response assessment criteria proposed by the Japanese Research Society for Gastric Cancer (17). The response in ascites was evaluated by abdominal CT scan or ultrasonography based on the following specific criteria used in this study: (1) disappearance of ascites – disappearance of ascites visualized by CT scan or ultrasonography for at least 4 weeks; (2) decrease of ascites – apparent decrease of ascites visualized by CT scan or ultrasonography for at least 4 weeks; (3) no response of ascites – no change of ascites volume visualized by CT scan or ultrasonography. The data for tumor response in all responders was confirmed by an extramural review. The toxicity was evaluated according to the JCOG common toxicity criteria (18).
Statistical Analysis
The sample size was determined based on the precision of the estimates. The efficacy for malignant ascites was expected to be 30%. Fifty subjects and an observed efficacy of 30% would provide a 95% confidence interval of 17.9–44.6% or width of 26.7%. The expected accrual period was 1.5 years. Interim analysis was planned to test for inefficacy of the treatment by examining whether a 90% upper confidence bound of efficacy would exceed 25% for first 20–25 patients. The overall survival was calculated for the period from the date of registration to the date of death. Overall survival was calculated by the Kaplan–Meier method and confidence intervals were calculated based on Greenwood’s formula.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Population and Study Treatment
Between February 1997 and October 1999, 37 patients were enrolled in this trial from nine out of 13 participating institutions. Although this study was originally planned as a phase II study in which 50 patients would be enrolled within 1.5 years of the start of the study, the patient enrollment was delayed and was finally terminated before the projected number of patients had been achieved based on the decision of the JCOG monitoring committee that the evaluation of efficacy and toxicity was possible even with only 37 enrolled patients. Table 1 lists the demographic data, baseline disease and pretreatment characteristics of all patients. Twenty-one males and 16 females were registered as receiving first-line chemotherapy. The median age of the patients was 60 years (range, 25–74 years) and the majority of the patients (86%) had a good performance status of 0–1. Twenty-one patients (57%) had macroscopically scirrhous-type advanced gastric cancer. Twenty-five patients had histologically diffuse types (six poorly differentiated adenocarcinoma, two mucinous carcinoma and 17 signet-ring cell carcinoma). Two patients had undergone surgery prior to enrollment in this trial (one palliative total gastrectomy and the other exploratory laparotomy resulting in no resection). One patient suffered from hemilateral hydronephrosis due to peritoneal dissemination with normal range of renal function tests.
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In total, 355 administrations of the sequential MTX/5FU therapy were performed in 37 patients. The median number of administrations was eight (range, 1–42). Twenty-nine of 37 enrolled patients (78%) received at least four administrations of the sequential MTX/5FU therapy. All patients were assessable for toxicity and response of ascites to chemotherapy. Thirty-five patients were assessable for objective tumor response to chemotherapy. The most frequent reason for treatment termination was disease progression (27 patients, 73%). Other reasons for treatment termination were no response after 8 weeks from initiation of treatment in two, patient refusal in two, severe toxicity in two, death in three (one due to disease progression and two treatment-related) and medical judgment by the investigators in one.
Toxicity
The toxicity observed in the study period is summarized in Table 2. The major toxicity was myelosuppression and gastrointestinal toxicity. Grades 3 and 4 neutropenia occurred in 16 and 11% of the patients, respectively. Severe thrombocytopenia was infrequent. The incidence of grade 3 diarrhea was 5%. Mild nausea and vomiting (grades 1 and 2) were frequently experienced (65%). An increase in total bilirubin of grade 4 was observed in one patient (2.7%) and was diagnosed as obstructive jaundice caused by the development of lymphadenopathy from the primary disease. An increase in total bilirubin grade 3 was observed in eight patients, three cases of which were judged to be treatment-related. An increase in serum creatinine grade 3 was observed in two patients (5.4%). One patient experienced grade 4 hyponatremia due to loss of oral intake associated with primary disease. Early death, which was defined as death within 30 days from the last administration of anti-cancer drugs, occurred in five patients. The causal relationship between the death and the study treatment was ‘unlikely’ in three of those five patients. However, the remaining two deaths were assessed to be treatment-related. One patient died of severe neutropenia and rapidly progressive disseminated intravascular coagulation (DIC), which was complicated with respiratory dysfunction, and the other patient died of progressive neutropenic sepsis.
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Efficacy
The efficacy-related data are summarized in Table 3. Only two of 35 response-assessable patients achieved objective partial response (response rate 5.7%; 95% confidence interval: 0.7–19.2%). However, in terms of the response of ascites, three disappearances and 10 decreases of ascites were obtained (response rate 35.1%; 95% confidence interval: 20.2–52.5%). The median duration of response of ascites was 103 days with a range of 52–337 days. The median survival time of all patients was 155 days (95% confidence interval: 131–225 days) and the 1 year survival rate was 16.2% (95% confidence interval: 4.3–28.1%).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Although unresectable or metastatic gastric cancer is potentially incurable, there is significant evidence that adding systemic chemotherapy to the best supportive care could provide benefits in survival and quality of life as compared with best supportive care alone (1–3). However, it has been difficult to assess which of many available regimens is the most effective, although several regimens have been tested in randomized controlled trials. Some randomized trials failed to demonstrate the superiority of 5FU-based combination regimens as compared with 5FU-monotherapy (19–21). A recent randomized controlled trial showed that three commonly used combination regimens, 5FU/adriamycin/MTX (FAMTX), 5FU/cisplatin (FP) and etoposide/leucovorin/5FU (ELF), have only modest activity and that there were no significant differences in overall survival among these regimens (22). More recently, infusional 5FU in combination with cisplatin and epirubicin (ECF) showed significant superiority over FAMTX in terms of response rate, quality of life and survival, suggesting that the ECF could be a new standard treatment for future clinical trials (23). However, regarding the median survival time in those large-scale trials, there was little substantial difference among the various regimens. Therefore, in general, 5FU-based or cisplatin-based combinations are widely accepted as a possible standard therapy (24). In clinical practice, oncologists need to select a regimen considered to be the most appropriate for each individual patient based on the medical condition of each patient, including such factors as age, performance status, organ function and extent of disease. The cisplatin-based regimens are usually inappropriate to be used for patients having peritoneal dissemination and retention of ascites, because such patients have potential renal impairment or poor performance status, which makes it difficult to tolerate the large volume hydration for the prevention of cisplatin-induced renal injury. Among several 5FU-based regimens, sequential MTX/5FU therapy is widely used because this regimen has definite anti-tumor activity against advanced gastric cancer with acceptable toxicity even in high-risk patients. The purpose of the present phase II study was to evaluate the efficacy and toxicity of the sequential MTX/5FU regimen in patients with unresectable gastric cancer with peritoneal dissemination accompanied by malignant ascites and to assess whether further investigation in a phase III setting is warranted.
Progression to peritoneal dissemination is very common in advanced gastric cancer and is frequently a component of the first episode of failure after surgery for primary gastric cancer (25). Therefore, intraperitoneal chemotherapy has previously been investigated for peritoneal dissemination for the purposes of palliation and the prevention of peritoneal metastasis after surgery in high-risk patients. The pharmacokinetic rationale for intraperitoneal therapy is that drug concentrations within the peritoneal cavity are several-fold to 1–2 logs higher than concentrations that can be achieved after oral or intravenous treatment (26,27). In ovarian cancer, a large randomized trial demonstrated a small but statistically and clinically significant survival advantage in patients receiving intraperitoneal therapy (28). However, generally the efficacy of intraperitoneal chemotherapy is considered to be modest because the penetration of intraperitoneally injected drug into submesothelial tissue is too limited to achieve anti-tumor activity. Moreover, intraperitoneal chemotherapy sometimes induces systemic adverse events similar to systemic chemotherapy in addition to local complications such as chemical peritonitis. No definite data are currently available to specify which treatment option, intraperitoneal or systemic chemotherapy, is more suitable for patients with peritoneal dissemination in terms of benefit regarding survival and quality of life.
When we perform systemic chemotherapy in patients who have fluid retention such as ascites or pleural effusion, we have to consider the pharmacokinetic alterations of the anti-tumor agents administered. Intravenously administered MTX penetrates the ascites or pleural effusion and the clearance rate of MTX from ascites and plasma is ~5 and ~120 ml/min, respectively (29). Therefore, the retention of body fluid prolongs the terminal plasma half-life of intravenously administered drug owing to the slow re-entry of the sequestered drug into the bloodstream. Such phenomena should be associated with both favorable anti-tumor activity against peritoneal or pleural dissemination and with the potential risk of systemic toxicity. In another phase II study of sequential MTX/5FU therapy against unresectable or metastatic gastric cancer previously conducted by the JCOG, in which the same dosage and schedule as in the present study were utilized but the patients having ascites were ineligible for entry (JCOG 9207 study), none of 56 enrolled patients experienced grade 3 or 4 neutropenia (data not shown). In the present study, grades 3 and 4 neutropenia were observed in six (16 %) and two patients (11 %), respectively. The incidence of leukopenia, anemia, increase in total bilirubin and increase in serum creatinine of grade 3 or 4 tended to be more frequent in the present study than in the JCOG 9207 study (data not shown). Therefore, the toxicity of the sequential MTX/5FU therapy might be more severe in patients with malignant ascites than in those without. Two treatment-related deaths were observed in the present study. These two patients developed progressive neutropenic sepsis, which is a major cause of death. Although these two patients had met the eligibility criteria required in the study, both patients were retrospectively shown to be at high-risk for neutropenic infection, because pretreatment serum CRP values were highly elevated in both patients and leukocytosis was also observed at the baseline in one patient. Therefore, we consider that patients with apparent inflammatory signs such as elevation of CRP or leukocytosis should be excluded from future studies to prevent neutropenic sepsis. It is known that the different methods of administration of 5FU, either as a bolus or by infusion, represent different efficacy and toxicity profiles, thus infusional 5FU has more clinical benefit in efficacy (response rate) and safety in metastatic colorectal cancer. At present, however, we do not have sufficient data to establish whether these clinical observations hold true in patients with peritoneal dissemination with malignant ascites and it seems to be important to investigate the infusional 5FU-based regimens in this clinical setting, which may contribute to reducing the toxicity.
It is difficult to evaluate the efficacy of chemotherapy against peritoneal dissemination in clinical trials as well as in clinical practice, because most disseminated tumor cells do not form a measurable mass but rather constitute a diffuse lesion. Clinicians have to assess the efficacy of treatment and disease status in each patient based on the integration of clinical information such as clinical imaging, tumor markers and clinical symptoms. In the present study, the therapeutic efficacy was assessed according to the specific criteria for the study based on the change in the volume of ascites visualized by abdominal CT scan or ultrasonography as a surrogate marker. Using these criteria, we found that the ascites disappeared or was decreased by the MTX/5FU therapy in 35% of the patients. Konishi et al. also reported that ascites disappeared in 50% (8/16) of patients with peritoneal-disseminated gastric cancer after MTX/5FU therapy (16). These results show that sequential MTX/5FU therapy is effective in controlling malignant ascites and also suggest that this regimen is effective against peritoneal dissemination from advanced gastric cancer.
Although the present study was originally planned as a phase II study involving 50 patients, patient enrollment had been delayed and finally terminated before the projected number of patients was achieved. The delay in patient enrollment was probably caused by the eligibility criteria for this study. Although peritoneal dissemination of advanced gastric cancer is very common in clinical practice, most patients with peritoneal dissemination accompanied by malignant ascites tend to have relatively poor performance status and impaired organ function, which was considered to be a critical issue delaying patient enrollment. The JCOG monitoring committee accepted the investigators’ decision that the objectives of this study, which were to calculate the response rate in ascites and to evaluate the safety of sequential MTX/5FU therapy for decision-making to pursue further investigation in a phase III study, were achieved even with the actual sample size of 37 patients and that the response rate in ascites of 35% (95% confidence interval: 20.2–52.5%) observed in this study was positive.
It is well known that peritoneal dissemination of gastric adenocarcinoma occurs more commonly as the histologically diffuse type than the intestinal type. Konishi et al. reported that sequential MTX/5FU therapy was more effective against undifferentiated gastric cancer (i.e. histologically diffuse type) than differentiated gastric cancer (i.e. histologically intestinal type), with a response rate of 32% (9 PRs/28 patients) vs 0% (0 PRs/10 patients) (16). A similar tendency was observed in the present study, namely that the response rate of ascites was higher for the histologically diffuse type than for the intestinal type (44%, 11 responders among 25 patients, versus 17%, two responders among 12 patients). The difference in the efficacy of the sequential MTX/5FU therapy depending on the histological type might be explained by the difference in the activities of two enzymes, thymidylate synthetase and thymidine kinase, in the various histological types of gastric cancer (30). However, other reports have suggested that there were no significant differences according to the histological type. (15)
In conclusion, the findings of the present study suggest that sequential MTX/5FU therapy is effective in controlling malignant ascites from gastric cancer with overall acceptable toxicity and that further investigations are warranted. However, the present study also suggests that severe toxicity may occur more frequently in patients with malignant ascites than in those without malignant ascites. Whether there is true clinical benefit in this regimen for patients with peritoneal dissemination from advanced gastric cancer should be evaluated in future randomized clinical trials. Since the peritoneal dissemination from gastric cancer is considered to be an incurable disease, the patient’s survival and quality of life will be important endpoints to be assessed in the future clinical trials. Recently, various new drugs with different mechanisms of action have been developed. However, since the patients whose main diseases are peritoneal dissemination are usually excluded from the phase II trials of new drugs or new combination regimens because of the lack of measurable lesions in those patients, the available data as to the efficacy against peritoneal dissemination are very limited unless we conduct trials specifically designed for this purpose as the present study. We think it is important to assess the roles of new drugs from the viewpoint of how we can maximize the potential value of each drug or regimen in disease-specific clinical situations. In this study we have focused on peritoneal dissemination with malignant ascites from advanced gastric cancer, which is very common and a major clinical problem. At present, any 5FU-based combination chemotherapies cannot prolong overall survival compared with 5FU alone. However, the present study brought us to the hypothesis that if we choose an appropriate regimen and administer it to the appropriate patient population (for example, to choose MTX/5FU therapy for the patients with peritoneal dissemination), survival may be prolonged compared with 5FU alone. We think that MTX/5FU therapy is the most reasonable regimen to be tested as a first-line chemotherapy in patients with peritoneal dissemination from advanced gastric cancer. From this clinical standpoint, a phase III randomized controlled trial comparing sequential MTX/5FU therapy with infusional 5FU-monotherapy (800 mg/m2 of 5FU continuous infusion over 5 days every 4 weeks) in patients with advanced gastric cancer who have peritoneal dissemination with or without ascites is currently being carried out by the Japan Clinical Oncology Group (JCOG 0106-MF study). As a final note, we suggest that in future trials we should investigate the therapeutic strategy not only with newer cytotoxic drugs including irinotecan, taxanes and oxaliplatine, but also with new molecular targeting drugs such as antibody, VEGF drugs and EGF drugs, to bring about a breakthrough in this dire clinical condition.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported by a Grant-in-Aid for Cancer Research (8S-1, 11S-3, 11S-4) and for the Second Term Comprehensive 10-year Strategy for Cancer Control (H10-Gan-027, H12-Gan-012) from the Ministry of Health, Labor and Welfare Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Yasuhiro Shimada, Division of Gastrointestinal Oncology, National Cancer Center Hospital, 5–1–1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: yshimada{at}ncc.go.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received January 26, 2004; accepted March 17, 2004
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