© The Author (2008). Published by Oxford University Press. All rights reserved
A Phase II Study of Oxaliplatin with Low-dose Leucovorin and Bolus and Continuous Infusion 5-Fluorouracil (Modified FOLFOX-4) for Gastric Cancer Patients with Malignant Ascites
1 Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea
2 Department of Surgery Dong-A University College of Medicine, Busan, South Korea
3 Department of Pathology, Dong-A University College of Medicine, Busan, South Korea
1 For reprints and all correspondence: Hyo-Jin Kim, Department of Internal Medicine, Dong-A University College of Medicine, 3-1 Dongdaeshin-dong, Seo-gu, Busan 602-715, South Korea. E-mail: kimhj{at}dau.ac.kr
Received August 8, 2007; accepted September 12, 2007
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Abstract |
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Background: Clinical studies regarding chemotherapy for gastric cancer patients with malignant ascites have been classically rather limited in scope, largely because peritoneal seeding produces no measurable lesions, and patients generally exhibited poor performance status. Herein, we have evaluated the efficacy and toxicity of a fortnightly modified FOLFOX-4 (m-FOLFOX) regimen.
Methods: Gastric cancer patients with cytologically confirmed malignant ascites were treated with cycles of oxaliplatin at 85 mg/m2 plus leucovorin 20 mg/m2 on the first day of treatment, followed by 5-fluorouracil (5-FU) via a 400 mg/m2 bolus and a 22 h continuous infusion of 600 mg/m2 5-FU on Days 1–2 at 2-week intervals.
Results: Forty-eight patients participated in this study. Twenty-two patients (45.8%) were treated with m-FOLFOX-4 as a first line palliative treatment. Twenty-one patients (43.8%) were adjudged to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Thirty-six patients were assessable and exhibited measurable lesions. Twelve (33.3%) patients evidenced partial responses. Decreases or disappearances of ascites levels were observed in 17 (35.4%) patients. The median time to progression and overall survival time were 3.5 (95% CI: 2.9–4.1) months and 8.4 (95% CI: 4.9–11.9) months, respectively. Major hematologic toxicities included Grades 1–2 anemia (53.9%), neutropenia (41.6%) and, Grades 3–4 neutropenia (15.8%). The most frequently detected non-hematological toxicities were Grades 2 and 3 nausea/vomiting (17%). We noted no deaths related to treatment.
Conclusion: The m-FOLFOX-4 regimen utilized herein was determined to be both safe and feasible even for gastric cancer patients with malignant ascites in poor performance status.
Key Words: oxaliplatin • low-dose leucovorin • 5-fluorouracil • advanced gastric cancer • malignant ascites
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INTRODUCTION |
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Gastric cancer is one of the most common cancers in the world and is the most frequently detected cancer among Koreans (1). More than two-third of patients will suffer from unresectable disease (2). Peritoneal dissemination, which occurs principally as a consequence of direct invasion and/or lymphatic spread, is quite common in cases of advanced gastric cancer and is considered to constitute an incurable disease state (3). Peritoneal dissemination may cause serious complications, including intestinal obstruction, massive ascites, and hydronephrosis, which are associated clinically with abdominal pain and fullness, vomiting, constipation, malnutrition, and renal dysfunction. Peritoneal dissemination is a poor prognostic indicator (4). However, the efficacy of systemic chemotherapy against peritoneal dissemination from gastric cancer remains to be determined, as peritoneal dissemination is not defined as a measurable lesion in conventional Phase II studies, and thus only a few reports are currently available regarding the efficacy of systemic chemotherapy against peritoneal dissemination 5-Fluorouracil (5-FU) and platinum-based regimens have been suggested as effective first-line treatments for advanced gastric cancer. The response rate of advanced or metastatic gastric cancer to such first line therapies is normally approximately 30–55% (5). Recently, some studies have reported that the addition of another drug to 5-FU and platinum-based regimens, for example epirubicin or irinotecan, or the substitution of third generation platinum (oxaliplatin) for cisplatin increases efficacy and reduces toxicity. Oxaliplatin has been identified as an effective agent for the treatment of advanced gastric cancer (6,7). The role of LV dosage is unclear; however, in studies of colorectal cancer, low-dose leucovorin (ldLV) showed the same efficacy and toxicity as classically dosed LV (200 mg/m2) (8,9) and the same efficacy and low incidence of toxicity in advanced gastric cancer (6).
This phase II study was designed to evaluate the safety and efficacy of oxaliplatin with ldLV and bolus and continuous infusion 5-fluorouracil [modified FOLFOX-4 (m-FOLFOX-4)] for the treatment of patients with advanced gastric cancer including malignant ascites.
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PATIENTS AND METHODS |
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Eligibility
In order to be eligible for this study, patients must have had histologically confirmed adenocarcinoma of the stomach. All eligible patients also evidenced cytologically confirmed malignant ascites. Additionally, patients had to fulfill the following criteria: no central nervous system metastases; no active infections; no serious or uncontrolled concurrent medical illness; no history of other malignancies; sufficient hepatic, renal and bone marrow functions; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; and age exceeding 18 years. The study was approved by the local ethics committee, and informed consent was obtained from all patients before study entry.
Treatment Protocol and dose Modification
On Day 1, oxaliplatin 85 mg/m2 was administered via intravenous (i.v.) infusion in 500 ml of normal saline or dextrose, over a 2-h period. On Days 1 and 2, ldLV 20 mg/m2 was administered as an i.v. bolus, immediately followed by 5-FU 400 mg/m2 administered as a 10 min i.v. bolus, followed by 5-FU 600 mg/m2 as a continuous 22-h infusion, with a light shield. Dose modifications were made to the oxaliplatin or 5-FU for hematologic, gastrointestinal, or neurologic toxicity, based on the most severe grade of toxicity that had occurred during the previous cycle. The patients were assessed prior to the start of each 2-week cycle, in accordance with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), except in the case of neurotoxicity, in which case, an oxaliplatin-specific scale was used: Grade 1, paresthesias or dysesthesias of short duration, but resolving prior to the next cycle; Grade 2, paresthesias persisting between cycles (2 weeks); Grade 3, paresthesias interfering with function. Treatment was delayed for up to 2 weeks in cases in which symptomatic toxicity persisted, absolute neutrophil numbers were <1500/µl, or platelet counts were <100 000/µl. The dose of 5-FU was reduced by 25% for subsequent courses if NCI-CTC Grade 3 diarrhea, stomatitis, or dermatitis had occurred, and the dose of oxaliplatin was reduced by 25% in subsequent cycles in cases in which persistent paresthesias between cycles or paresthesias with functional impairment persisting for >7 days had occurred. Treatment was continued until signs of disease progression or unacceptable toxic effects developed, or until a patient refused further treatment.
Follow-up Evaluation and Assessment of Response
Prior to each course of treatment, a physical examination, routine hematologic studies, blood chemistry, and chest X-ray were performed. CT scans were conducted in order to define the extent of disease and response after three cycles of chemotherapy, or sooner in cases in which there was evidence of any clinical deterioration.
Responses were evaluated using RECIST criteria (10). Complete response (CR) was defined as the disappearance of all evidence of disease and the normalization of tumor markers for at least 2 weeks. Partial response (PR) was defined as a 
30% reduction in unidimensional tumor measurements, without the appearance of any new lesions or the progression of any existing lesion. Progressive disease (PD) was defined as any of the following: (i) 20% increase in the sum of the products of all measurable lesions, (ii) the appearance of any new lesion, or (iii) the reappearance of any lesion that had previously disappeared. Stable disease (SD) was defined as a tumor response not fulfilling the criteria for CR, PR, or PD.
Ascites responses were also evaluated by the Japanese conventional five-point method (11) on Fig. 1; (i) disappearance of ascites—disappearance of ascites visualized by CT scan; (ii) decrease of ascites—over 10% reduction in amount of ascites; (iii) no change of ascites—increase or decrease of amount of ascites within 10%; (iv) increase of ascites—increase in ascite levels of more than 10%.
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Dose intensity (mg/m2/week) was calculated as the total cumulative dose divided by the treatment duration. Relative dose-intensity (RDI) was calculated by dividing the dose-intensity by the planned dose-intensity and was expressed as a percentage. Planned dose-intensities, which were expressed as mg/m2/week, were 1000 for 5-FU and 42.5 for oxaliplatin.
Statistical Methods
This trial was designed to detect a response rate of 30%, as compared with the minimal, clinically meaningful response rate of 10%. A two-stage optimal design, as previously proposed by Simon, was adopted (12), with a statistical power of 80% for hypothesis acceptance and 5% significance for hypothesis rejection. Allowing for a follow-up loss rate of up to 10%, the total sample size required was 35 patients with measurable disease. Categorical variables in the two groups were compared by the 
2 test or Fisher's exact test. P-values <0.05 were considered statistically significant and all P-values correspond to two-sided significance tests. Time to progression (TTP) and overall survival (OS) were calculated via the Kaplan–Meier method. TTP was calculated from the date therapy was initiated to the date of disease progression, death, or final follow-up. OS was calculated from the date therapy was initiated to the date of death or final follow-up. All data were analysed with SPSS software (version 12.0, Chicago, IL, USA).
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RESULTS |
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Patient Characteristics
Beginning in January 2002, 48 patients were assigned for treatment at the Department of Internal Medicine at the Dong-A University Medical Center in Busan, South Korea. Patient basal characteristics are provided in Table 1. The male to female ratio in this study was 32:16, and the median patient age was 47 (range 31–76) years. Twenty-two patients (45.8%) were adjudged to have an ECOG performance status of 2. 20 patients were newly diagnosed, and 28 patients had recurrent gastric cancer. Twenty-one patients were treated with m-FOLFOX as a first-line palliative chemotherapy, in 19 patients, it was a second-line treatment, and in the remaining 8 patients, this treatment was at least a third-line treatment. Thirty patients (62.5%) initially presented with at least one measurable lesion. The most frequent site of involvement was abdominal lymph node (33.3%), followed by the ovary (8.3%), lung (8.3%), liver (4.2%), pancreas (4.2%), and bone (4.2%), in decreasing order of frequency.
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Response
A total of 36 patients were assessed for response with measurable lesions. Thirty patients initially evidenced measurable lesions and six patients developed new lesions. Twelve PR (33.3%) occurred, 13 patients (36.1%) had SD, and 11 patients (30.6%) manifested PD. Patients who were treated with m-FOLFOX-4 regimen as a first line palliative chemotherapy were observed better response rate than over second line treatment (P = 0.002). Decreases and disappearance of ascites were observed in 17 patients (35.4%), and 14 patients (29.3%) evidenced no changes in ascites levels (Table 2).
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TTP and OS
Median TTP was 3.5 (95% CI: 2.9–4.1) months, and the median OS duration was 8.4 (95% CI: 4.9–11.9) months. TTP and OS were evaluated via Kaplan–Meier analysis, as is shown in Figures 2 and 3. The 1-year survival rate was 27.2%. Early death—expired within 30 days from treatment—was observed in two patients related with disease progression.
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Toxicity and Dose Administration
Forty-eight patients received a total of 233 treatment cycles. The median number of m-FOLFOX-4 cycles administered was 5 (range 1–9) cycles. The median cumulative doses were as follows: oxaliplatin 451 (range, 85–1020) mg/m2, LV 110 (range 20–2400) mg/m2, and 5-FU 10600 (range, 2000–24 000) mg/m2. Dose reductions were required on nine occasions. The dose intensities of oxaliplatin and 5-FU were 40.6 mg/m2/week and 976.5 mg/m2/week, and the RDIs of oxaliplatin and 5-FU were 95.5 and 97.7%.
Toxicities observed during the treatment are provided in Table 3. Grade 1 or 2 anemia (54.1%) was the most frequently observed hematological toxicity, and Grade 3 or 4 neutropenia was detected in 18.8% of the cycles. Six cycles (2.6%) of febrile neutropenia were recorded, and Grade 2 or 3 nausea/vomiting were noted in six patients (14.6%). Grade 1 and 2 neuropathy were observed in six patients (12.6). However, no patients experienced neuropathy of Grade 3 or more. No treatment-related deaths occurred in this study.
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DISCUSSION |
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5FU- or cisplatin-based combinations have come into general acceptance as a possible standard therapy (13). Cisplatin-based regimens tend to be inappropriate for use in patients with peritoneal dissemination and ascites retention, as such patients may potentially suffer from renal impairment or exhibit poor performance. Recently, the results of a first-line FOLFOX-4 treatment for advanced gastric cancer were released (7), in which they revealed a 38% overall response, as 7.1 month TTP, and an 11.2 month OS. These findings are consistent with those of previous studies, but less myelosuppressive and peripheral neuropathy toxicity were reported than with FOLFOX-6 treatment.
Although the principal treatment option for recurrent or metastatic gastric cancer is systemic chemotherapy, this strategy has generally been thought to exert little influence on peritoneal dissemination, as the drugs could not be delivered in sufficient amounts through the peritoneum–plasma barrier to the disseminated tumor cells (14).
In recent studies, however, it has been shown that chemotherapeutic regimens can reduce, or even eradicate, peritoneal disseminations and ascites in gastric cancer patients receiving S-1 and cisplatin (15) or S-1 alone (16). The Japan Clinical Oncology Group previously reported an ascite control rate of 35.1% with a combination of methotrexate and 5-FU administered as a first-line treatment (17). In the present study, although the CT ascite response evaluation criteria (11) are not universally used and the ‘no change’ criteria were also defined specifically for this study, malignant ascites were shown to have disappeared or decreased in 17 of the patients in this study (35.4%). Although performance status is included over 2 in 45.8% and over second line treatment in 56.2% of the patients, this may be because the median age was lower than in previous reports.
A m-FOLFOX-4 regimen identified as a tolerable and effective therapeutic modality in cases of advanced gastric cancer (6). Although oral 5-FU–TS-1 treatment was previously reported to be effective (median survival 257 days) and resulted in no Grade 3 or 4 neutropenia, in the current study (18), the incidence of Grade 3 or 4 neutropenia and neutropenic fever was comparable with other i.v. chemotherapeutic agents in patients evidencing peritoneal dissemination. Non-hematologic toxicity—including neurotoxicity, diarrhea, nausea, and vomiting—was also shown to be tolerable.
Intraperitoneal chemotherapy has previously been used in the treatment of peritoneal dissemination, but the therapy continues to be rather ineffective. Although aggressive treatment with a combination of surgical cytoreduction and intraperitoneal chemotherapy has been shown to improve the prognoses of patients with peritoneal dissemination, the efficacy of this treatment remains somewhat limited. The major problems with this treatment are associated not with the surgical techniques, but rather with the regimens or efficacy of the anticancer agents themselves (19).
Clinical studies regarding chemotherapy with gastric cancer patients with malignant ascites have been classically rather limited in scope, largely because peritoneal seeding produces no measurable lesions, and patients generally exhibited poor performance status. 10% cut-off value of ascites response evaluation also own determination. Because there is no previous study about ascites evaluation method and criteria. So we used Oriuchi method for ascites amount evaluation and 10% was permitted for minimal changes of ascites amount. Validity of cut-off value is questionable. Further study about ascites evaluation for patient without measurable lesion should be performed. And there were many censored cases in earlier period in the figures of OS and TTP, which seemed to be needed further follow-up for adequate results.
Advanced gastric cancer patients with malignant ascites have been shown to evidence poor general condition, and also regularly suffer from organ complications. However, the m-FOLFOX-4 regimen described herein may prove a significant and effective treatment option.
Conflict of interest statement
None declared.
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References |
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